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Purpose: To answer the following question: "Do recombinant, purified, and concentrated growth factors enhance the regenerative potential of particulate bone graft substitutes in maxillary sinus floor augmentation (MSA)" Materials and Methods: Human studies comparing histomorphometric data on new bone formation, residual graft material, and fibrous tissue ratio (outcomes of interest) following MSA procedures employing particulate bone grafts/substitutes in combination or not with growth factors were retrieved from PubMed/MEDLINE, Web of Science, Cochrane, and Scopus online databases and complemented with a hand search. Controlled studies published in English up to December 2022 and reporting on histomorphometric data expressed as volume percentage of the outcomes of interest were considered. Risk of bias was assessed, and a meta-analysis was performed to investigate the effects of supplementary growth factors on new bone formation, remaining graft particles, and fibrous tissue ratio. Results: Data were included from 613 samples in 477 patients reported in 22 publications. Meta-analysis showed that platelet-rich plasma or platelet-rich fibrin resulted in 49% more new bone formation than in control group areas (P = .004), and those areas supplemented with growth factors presented 57% less residual graft particles after healing (P < .0001). A significant (P = .03) 1.85-fold increase in connective tissue formation was noted in areas treated with recombinant human bone morphogenetic proteins (rhBMPs) after healing. Conclusions: Selective supplementary growth factors may enhance new bone formation and accelerate particulate graft turnover, while rhBMP may significantly increase connective tissue formation in MSA procedures in humans. [ABSTRACT FROM AUTHOR]

Background: Platelet-rich fibrin (PRF) is used to prepare "sticky bone" by combining it with bone graft material. The present study investigated the ability of different bone grafts to absorb growth factors from the PRF and release them over time. Materials and Methods: Human blood was collected from 10 healthy volunteers for liquid PRF preparation. Bovine bone, allograft (mineralized and demineralized), and synthetic bone were each mixed with the PRF to prepare a sticky bone. All sticky bone samples were incubated for up to 4 days. The absorption and release pattern kinetics of two selective growth factors within the PRF--platelet-derived growth factor (PDGF) and bone morphogenetic protein-2 (BMP-2)--were quantified with immunofluorescence staining and enzyme-linked immunoassay (ELISA) testing. Results: All bone graft materials adsorbed the examined growth factors from the PRF. ß-TCP showed the highest adsorption levels, followed by the xenograft, and the allografts showed the lowest adsorption levels. Furthermore, PDGF showed a fast-release pattern from the grafts, whereas BMP-2 was released at a later stage. Similar to the adsorption pattern, the ß-TCP and xenograft were better able to sustain the release of the PRF growth factors from the graft than the allografts. Conclusions: The adsorption of PDGF and BMP-2 differ between graft materials, with superior results for ß-TCP, followed by xenograft, then allograft materials. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the present study was to compare the histomorphometrically evaluated new bone formation (NB), the radiographically measured graft stability, and the clinical implant outcome for maxillary sinus augmentation grafted with deproteinized bovine bone mineral (DBBM) with either small (Bio-Oss-S, Geistlich) or large (Bio-Oss-L, Geistlich) particles. Materials and Methods: Using a split-mouth study design, bilateral maxillary sinus augmentation was performed in 13 patients either with Bio-Oss-S particles (0.25 to 1 mm) or Bio-Oss-L particles (1 to 2 mm). After a healing period of 6 months, bone biopsies were axially retrieved in the molar region for histologic/histomorphometric analysis of NB, including subsequent staged implant placement. To determine graft stability, the maxillary sinus augmentation vertical graft heights were radiographically measured immediately after sinus augmentation, at implant placement, and at the 2- and 4-year post-augmentation follow-ups. In addition, the clinical implant-prosthodontic outcome (survival/success/marginal bone loss) was assessed at 1 and 3 years post-loading. Results: A total of 22 sinuses from 11 patients with split-mouth evaluation were ultimately available for data and statistical analysis. Histomorphometric analysis of the axially retrieved bone biopsies revealed the presence of NB (S: 25.5% ± 7.0% vs L: 23.6% ± 11.9%; P = .640), residual graft particles (S: 19.6% ± 9.2% vs L: 17.5% ± 6.3%; P = .365) as well as connective tissue (S: 54.9% ± 9.2% vs L: 58.9% ± 12.5%; P = .283), without significant differences between the use of small (Bio-Oss-S) and large (Bio-Oss-L) particles. However, there was significantly (P = .021) higher bone-to-graft contact (BGC) for the small-particle graft sites (27.9% ± 14.8%) compared to the large-particle graft sites (19.9% ± 12.9%), representing a significantly higher osteoconductivity. Both particle sizes showed significant (P < .01) vertical graft height reduction over time (4 years) of about 10%, with predominant graft reduction in the time period between sinus augmentation and implant placement compared to any follow-up periods after implant placement. At the 3-year post-loading implant evaluation, all implants and prostheses survived (100%), and the peri-implant marginal bone loss (S: 0.52 ± 0.19 mm; L: 0.48 ± 0.15 mm) as well as the peri-implant health conditions (S: 87.5%, L:81.2%) did not differ between implants inserted with the two different xenograft particles used. Conclusions: The use of small and large bovine xenograft particles for maxillary sinus augmentation provides for comparable bone formation, ensuring stable graft dimensions combined with high implant success and healthy peri-implant conditions. However, small particle size resulted in a higher BGC, providing for higher osteoconductivity than with the larger particle size. [ABSTRACT FROM AUTHOR]

Purpose: To study the effect of BMP-2 on the volumetric and histometric changes in peri-implant defect treatments in animal models. Materials and Methods: An electronic search of four databases and a manual search of peer-reviewed journals for relevant articles were performed. Animal studies with data that compared the volumetric and/or histometric outcomes of peri-implant defect treatment with and without the use of BMP-2 were included. Meta-analyses were performed to analyze the weighted mean difference (WMD) and confidence interval (CI) for the recorded variables. Results: After completing the search process, 21 randomized controlled trials were included. The results of the metaanalyses showed that the WMD of bone-to-implant contact (%BIC) with 4 to 8 weeks and 12 to 24 weeks of follow-up was 15.50% (95% CI = 3.28% to 27.72%, P = .01) and 16.17% (95% CI = 11.17% to 21.16%, P < .00001), respectively, favoring the BMP-2 group. The WMD for the percentage of defect fill with 4 to 8 weeks and 12 to 24 weeks of follow-up was 15.88% (95% CI = 3.90% to 27.86%, P = .009) and 10.48% (95% CI = 0.95% to 20.02%, P = .03), respectively, favoring the BMP-2 group. The WMD for the vertical bone gain with 8 to 16 weeks of follow-up was 1.63 mm (95% CI = 0.58 to 2.67 mm, P = .002), also favoring the BMP-2 group. Conclusion: This review demonstrated that the use of BMP-2 in treating periimplant defects showed better clinical and histometric outcomes than defects not treated with BMP-2 in animal models. [ABSTRACT FROM AUTHOR]

BACKGROUND: Heterotopic ossification of skeletal muscle is a clinically serious complication. For heterotopic ossification of skeletal muscles, the cells involved in the process of heterotopic ossification remain unclear. OBJECTIVE: To investigate the involvement of myocytes, fascia cells, and endothelial cells in the process of heterotopic ossification in skeletal muscle and to observe the cell origin of heterotopic ossification in skeletal muscle induced by bone morphogenetic protein 4. METHODS: Both C2C12 cells and the myotubes formed by the C2C12 cells in the induction medium were cultured, and 500 ng/mL bone morphogenetic protein 4 was added to the medium respectively, and whether the C2C12 cells and myotubes continued to proliferate within 10 days under the treatment were observed under a microscope. Myogenic cells (L6, derived from rats) and fibroblast-derived cells (derived from human) were co-cultured. After treatment with 500 ng/mL bone morphogenetic protein 4 and 10 ng/mL transforming growth factor-β, osteogenic and chondrogenic differentiation potential within 21 days were observed using Safranine O staining and Alcian blue staining. Using transgenic animal FVB/N-TgN (TIE2-LacZ) 182Sato mice, 15 μL of adeno-associated virus-bone morphogenetic protein 4 (5 × 1010 PFU/mL) were implanted in the thigh muscle space of genetic mice for 10 and 14 days. X-gal staining was used to observe the formation of new blood vessel endothelium in the differentiated bone. RESULTS AND CONCLUSION: (1) Bone morphogenetic protein 4 caused myotube breakdown and increased C2C12 cell proliferation. Compared with other groups, the pure fibroblast-derived cell group had a higher area of positive alcian blue and safarin O staining (P < 0.05) and a lower area of alkaline phosphatase staining (P < 0.05), while the pure L6 group had a bigger area of alkaline phosphatase staining (P < 0.05) but a smaller area of positive alcian blue and safarin O staining (P < 0.05). (2) Transplantation of adeno-associated virus-bone morphogenetic protein 4-adsorbed gelatin sponge into FVB/N-TgN (TIE2-LacZ)182Sato mice resulted in heterotopic ossification. (3) X-gal staining results demonstrated that there was no obvious staining in chondrocytes and differentiated bones and Tie2+ endothelial cells did not participate in the formation of the alienated bone. (4) These findings verify that fibroblasts are the primary source of osteoblasts during the adeno-associated virus-bone morphogenetic protein 4-induced ectopic endochondral ossification in skeletal muscle, but myogenic cells are the main source of osteoblasts. Tie2+ endothelial cells might not be the cell source for cartilage and bone. [ABSTRACT FROM AUTHOR]

The orange-spotted grouper (Epinephelus coioides) is one of the most popular fish in aquaculture due to its high economic value. However, the random occurrence of slow-growing population has led to profit loss. Therefore, transcriptomic analysis was performed to identify the molecular mechanisms involved in driving slow and fast growth, towards addressing this issue. Results show that low expression of developmental genes such as bone morphogenetic protein 1 (BMP 1) and somatostatin (SST), as well as GH/IGF axis-related genes (IGF-1, IGF2, IGFBP1, IGFBP2) and its downstream signalling pathways are correlated with the metabolism and digestive-system-related pathways in slow-growing groupers. Enrichment analysis further revealed that cellular process and biological regulation, as well as several pathways including glycolysis/gluconeogenesis, linoleic acid metabolism, protein digestion and absorption, and cholesterol metabolism were differentially expressed in slow-growing groups. The findings implied that the genomic architecture of growth between the different families raised and the likely problem of inbreeding have led to significantly reduced growth. It is also suggested that better husbandry practices (optimal dietary requirement) is also vital in supporting the success of a genetic improvement programme. These findings recommend growth improvement of orange-spotted groupers via molecular monitoring and artificial selection, complemented by specific dietary feeding. [ABSTRACT FROM AUTHOR]

Study Design. A retrospective chart review. Objective. The objective of this study is to investigate whether direct pars repair achieves bone healing and symptom relief in patients with spondylolitic spondylolisthesis. Summary of Background Data. While most cases of spondylolysis can be managed nonoperatively, a small percentage of patients require surgical intervention. The outcome of direct pars repair through a standard pedicle-screw with wiring technique is controversial in patients with lumbar spondylolitic spondylolisthesis. Materials and Methods. Medical records of patients who had undergone an open surgical pars repair were retrospectively reviewed. Standard demographic and surgical parameters were collected. All patients underwent a primary repair of the pars with an autograft or bone morphogenetic protein and instrumentation using a pedicle-screw with spinous process wiring. At 6 to 12 months after the surgery, patient's pain symptoms, and postoperative computed tomography (CT) scans were independently reviewed to assess healing; which was graded as nonunion, partial union, or solid union. Results. There were 68 patients identified (33 male and 35 female), with an average age of 18.6 years. The mean estimated blood loss was 139 ml, and the mean length of hospital stay was 3.7 days. CT evaluation revealed 35 (52%) solid unions, 21 (31%) partial unions, and 12 (18%) nonunions requiring revisions. Thirtyfour (50%) patients had no postoperative pain, 24 (35%) had mild pain, and 10 (15%) had persistent pain. The majority of patients with nonunions on CT had mild or persistent pain. Patients with no or mild pain tended to be younger than those with persistent pain (17.5 vs. 24.6 yr, P=0.163). Conclusion. This study demonstrated a partial or complete union rate of 82% and a postoperative persistent pain rate of 15%. These figures are comparable to the previous study, and this pediclescrew with wiring technique can be worth trying before interbody fusion for spondylolytic spondylolisthesis to preserve anatomical lumbar motion. [ABSTRACT FROM AUTHOR]

To fabricate and characterize an innovative gelatin methacryloyl/GelMA electrospun scaffold containing the citrus flavonoid naringenin/NA with osteogenic and anti-inflammatory properties. GelMA scaffolds (15 % w/v) containing 0/Control, 5, 10, or 20 % of NA w/w were obtained via electrospinning. The chemical composition, fiber morphology/diameter, swelling/degradation profile, and NA release were investigated. Cytotoxicity, cell proliferation, adhesion and spreading, total protein/TP production, alkaline phosphatase/ALP activity, osteogenic genes expression (OCN, OPN, RUNX2), and mineralized nodules deposition/MND with human alveolar bone-derived mesenchymal stem cells (aBMSCs) seeded on the scaffolds were assessed. Moreover, aBMSCs seeded on the scaffolds and stimulated with tumor necrosis factor-alpha/TNF-α were submitted to collagen, nitric oxide/NO, interleukin/IL-1α, and IL-6 production assessment. Data were analyzed using ANOVA and t-student/post-hoc tests (α = 5 %). NA-laden scaffolds presented increased fiber diameter, lower swelling capacity, and faster degradation profile over 28 days (p < 0.05). NA release was detected over time. Cell adhesion and spreading, and TP production were similar between GelMA and GelMA+NA5 % scaffolds, while cell proliferation, ALP activity, OCN/OPN/RUNX2 gene expression, and MND were higher for GelMA+NA5 % scaffolds (p < 0.05). Cells seeded on control scaffolds and TNF-α-stimulated presented higher levels of NO, IL-1α/IL-6, and lower levels of collagen (p < 0.05). In contrast, cells seeded on GelMA+NA5 % scaffolds showed downregulation of inflammatory markers and higher collagen synthesis (p < 0.05). GelMA+NA5 % scaffold was cytocompatible, stimulated aBMSCs proliferation and differentiation, and downregulated inflammatory mediators' synthesis, suggesting its therapeutic effect as a multi-target bifunctional scaffold with osteogenic and anti-inflammatory properties for bone tissue engineering. • GelMA+NA 5 % scaffold degradation matches the bone healing timeline. • GelMA+NA 5 % enhanced cell viability and osteoinductive properties. • GelMA+NA 5 % controlled the NO, IL-1α, and IL-6 expression in TNF-a stimulated cells. [ABSTRACT FROM AUTHOR]

• The mediators of extracellular matrix deregulation downstream of Insulin-like growth factor II (IGF-II) were investigated. • Levels of pro-Lysyl Oxidase (ProLOX), its cleavage products LOX, and Lysyl oxidase propeptide (LOX-PP) as well as the enzymes that cleave ProLOX, Tolloid-like 1 (TLL1) isoforms and bone morphogenetic protein 1 (BMP1), increased in response to IGF-II. • LOX-PP levels were increased in human systemic sclerosis lung tissues and experimental murine lung fibrosis, and LOX-PP increased levels of markers of fibrosis by primary pulmonary fibroblasts. • The class E basic helix-loop-helix protein 40 (BHLHE40) regulates IGF-II-induced LOX-PP and TLL1 isoforms, and its deficiency increases matrix metalloprotease (MMP) 1, and restores MMP3 and cathepsin K levels repressed in response to IGF-II. • Our findings suggest that LOX-PP and BHLHE40 are new potential therapeutic targets in SSc-associated pulmonary fibrosis. Pulmonary fibrosis (PF) is a clinically severe and commonly fatal complication of Systemic Sclerosis (SSc). Our group has previously reported profibrotic roles for Insulin-like Growth Factor II (IGF-II) and Lysyl Oxidase (LOX) in SSc-PF. We sought to identify downstream regulatory mediators of IGF-II. In the present work, we show that SSc lung tissues have higher baseline levels of the total (N-glycosylated/unglycosylated) LOX-Propeptide (LOX-PP) than control lung tissues. LOX-PP-mediated changes were consistent with the extracellular matrix (ECM) deregulation implicated in SSc-PF progression. Furthermore, Tolloid-like 1 (TLL1) and Bone Morphogenetic Protein 1 (BMP1), enzymes that can cleave ProLOX to release LOX-PP, were increased in SSc lung fibrosis and the bleomycin (BLM)-induced murine lung fibrosis model, respectively. In addition, IGF-II regulated the levels of ProLOX, active LOX, LOX-PP, BMP1, and isoforms of TLL1. The Class E Basic Helix-Loop-Helix protein 40 (BHLHE40) transcription factor localized to the nucleus in response to IGF-II. BHLHE40 silencing downregulated TLL1 isoforms and LOX-PP, and restored features of ECM deregulation triggered by IGF-II. Our findings indicate that IGF-II, BHLHE40, and LOX-PP may serve as targets of therapeutic intervention to halt SSc-PF progression. [ABSTRACT FROM AUTHOR]

Chronic stress is a universal condition commonly associated with many psychiatric diseases. An extensive body of evidence discussed hippocampal affection upon chronic stress exposure, however, the underlying molecular pathways still need to be identified. We investigated the impact of chronic stress on miR200/BMP/Olig‐2 signaling and hippocampal myelination. We also compared the effects of chronic administration of amitriptyline and cholecalciferol on chronically stressed hippocampi. Both amitriptyline and cholecalciferol significantly decreased serum cortisol levels, reduced immobility time in the forced swim test, increased the number of crossed squares in open field test, decreased the hippocampal expression of bone morphogenetic protein 4 (BMP4) and its messenger RNA (mRNA) levels, reduced miR200 expression as compared to untreated chronically stressed rats. Also, both drugs amended the hippocampal neuronal damage, enhanced the surviving cell count, and increased the pyramidal layer thickness of Cornu Ammonis subregion 1 (CA1) and granule cell layer of the dentate gyrus. Cholecalciferol was more effective in increasing the area percentage of myelin basic protein (MBP) and Olig‐2 positive cells count in hippocampi of chronic stress‐exposed rats than amitriptyline, thus enhancing myelination. We also found a negative correlation between the expression of BMP4, its mRNA, miR200, and the immunoexpression of MBP and Olig‐2 proteins. This work underscores the amelioration of the stress‐induced behavioral changes, inhibition of miR200/BMP4 signaling, and enhancement of hippocampal myelination following chronic administration of either amitriptyline or cholecalciferol, though cholecalciferol seemed more effective in brain remyelination. [ABSTRACT FROM AUTHOR]

The aim of this retrospective study was to assess the efficacy of recombinant human bone morphogenetic protein-2 (rhBMP-2) with hydroxyapatite (HA) granules and fibrin sealant (FS) in maxillary sinus floor augmentation (MSFA), with a focus on the volume change. Fifty-two of 137 patients who underwent MSFA with rhBMP-2/HA grafting between June 2016 and December 2022 met the study inclusion criteria; 25 had received rhBMP-2/HA without FS and 27 had received rhBMP-2/HA with FS. Computed tomography (CT) images were obtained preoperatively, immediately following the operation, and at 6 months postoperative. These images were three-dimensionally reconstructed to measure the volumetric and height changes following MSFA. The mean ± standard deviation percentage of volumetric change at 6 months was 48.75 ± 37.44% in the group with FS and 29.77 ± 13.42% in the group without FS (P = 0.019). The vertical height measured at a specific site of the grafted area showed a mean percentage change at 6 months of 4.05 ± 12.08% in the group with FS and 6.07 ± 10.15% in the group without FS (P = 0.518). The additional use of FS as a carrier for rhBMP-2/HA in MSFA was found to improve surgical convenience and bone regeneration ability. [ABSTRACT FROM AUTHOR]

Hyriopsis cumingii is a major freshwater pearl mussel in the world. In order to investigate the functional roles of the growth- and mineralization-related genes involved in the pearl formation process after the inserting nucleus into the mantle tissue of H. cumingii, we conducted a transcriptome analysis of data from different time periods after the pearl-nucleus insertion. We screened a total of 1,898 growthrelated unigenes and 716 mineralization-related unigenes, including 12 growthrelated differential genes and eight mineralization-related differential genes that showed sustained differential expression throughout the pearl formation. The results of the gene expression patterns among samples at different time points showed that the Mcon group and theM05d group clustered together, theM50d group and the M90d group clustered together, while the M20d group clustered separately. The overall density distribution of differential gene analysis at different periods after pearlnucleus insertion of H. cumingii, cluster analysis, differential gene analysis, differential gene differential, and co-expression analysis together revealed that growth and mineralization-related genes have the same expression pattern and jointly regulate pearl formation. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment revealed that the same functional cluster and pathway were together present on the enrichment results of both growth- and mineralization-related genes, suggesting a synergistic effect between growth and mineralization. We found that genes such as bone morphogenetic proteins (BMPs) and calmodulin (CALM) are jointly involved in growth and mineralization processes. The study indicate that growth genes cooperate with mineralization genes to play biological roles in the early process of pearl formation in H. cumingii. [ABSTRACT FROM AUTHOR]

Human retinal organoids have become indispensable tools for retinal disease modeling and drug screening. Despite its versatile applications, the long timeframe for their differentiation and maturation limits the throughput of such research. Here, we successfully shortened this timeframe by accelerating human retinal organoid development using unique pharmacological approaches. Our method comprised three key steps: 1) a modified self-formed ectodermal autonomous multizone (SEAM) method, including dual SMAD inhibition and bone morphogenetic protein 4 treatment, for initial neural retinal induction; 2) the concurrent use of a Sonic hedgehog agonist SAG, activin A, and all-trans retinoic acid for rapid retinal cell specification; and 3) switching to SAG treatment alone for robust retinal maturation and lamination. The generated retinal organoids preserved typical morphological features of mature retinal organoids, including hair-like surface structures and well-organized outer layers. These features were substantiated by the spatial immunostaining patterns of several retinal cell markers, including rhodopsin and L/M opsin expression in the outermost layer, which was accompanied by reduced ectopic cone photoreceptor generation. Importantly, our method required only 90 days for retinal organoid maturation, which is approximately two-thirds the time necessary for other conventional methods. These results indicate that thoroughly optimized pharmacological interventions play a pivotal role in rapid and precise photoreceptor development during human retinal organoid differentiation and maturation. Thus, our present method may expedite human retinal organoid research, eventually contributing to the development of better treatment options for various degenerative retinal diseases. [ABSTRACT FROM AUTHOR]

Efforts to develop advanced bone substitutes for effective bone regeneration in substantial defects have led to the fabrication of tissue‐engineered scaffolds. These scaffolds, featuring hierarchical structures, specific chemical compositions, and functional qualities, are essential in mimicking native bone tissue. Inspired by the biomineralization process, hydrothermal treatment is used to synthesize micro‐/nano‐hydroxyapatite bioceramics functionalized with tea polyphenols (TP‐nwHA), closely resembling the structure of bone‐like apatite induced by hydroxyapatite bioceramics in vivo. The in vitro results demonstrate TP‐nwHA's superior biocompatibility, enhancing cell proliferation and adhesion. Furthermore, TP‐nwHA scaffolds significantly influence mesenchymal stem cells, promoting osteogenic differentiation while inhibiting osteoclastogenic differentiation. The upregulation of osteogenic proteins BMP2 and ITGB1, along with the downregulation of osteoclastic proteins FGF21 and IGFBP1, demonstrate the synergistic effect of the biomimetic structure and polyphenols on the activation of the MAPK signaling pathway. In vivo, TP‐nwHA showe early angiogenic capabilities, leading to improved bone regeneration in critical‐size femoral bone defects in osteoporotic rats. Histological staining confirms the complete bridging of defects with new bone tissue in the TP‐nwHA group, and nanoindentation tests indicate the formation of mature mineralized bone tissue. Collectively, these findings suggest a novel strategy for fabricating bone‐mimicking constructs with potential applications in disease modeling. [ABSTRACT FROM AUTHOR]

Primary membranous nephropathy (PMN) is one of the leading causes of end‐stage renal disease, and the most frequent cause of massive proteinuria in nondiabetic adults, resulting in fatal complications. However, the underlying pathomechanisms of PMN remain largely unclear. Here, single‐cell RNA sequencing is employed to analyze kidney biopsies from eleven PMN patients and seven healthy subjects. Profiling 44 060 cells from patients allowed us to characterize the cellular composition and cell‐type‐specific gene expression in the PMN kidney. The complement‐induced BMP2/pSMAD1/COL4 pathway is identified as the pathogenic pathway in podocytes, bridging two key events, i.e., complement system activation and glomerular basement membrane thickening in PMN. Augmented infiltration and activation of myeloid leukocytes and B lymphocytes are found, profiling delicate crosstalk of immune cells in PMN kidneys. Overall, these results provide valuable insights into the roles of podocytes and immune cells in PMN, and comprehensive resources toward the complete understanding of PMN pathophysiology. [ABSTRACT FROM AUTHOR]

Minerals play a vital role, working synergistically with enzymes and other cofactors to regulate physiological functions including tissue healing and regeneration. The bioactive characteristics of mineral‐based nanomaterials can be harnessed to facilitate in situ tissue regeneration by attracting endogenous progenitor and stem cells and subsequently directing tissue‐specific differentiation. Here, cellular responses of human mesenchymal stem/stromal cells to traditional bioactive mineral‐based nanomaterials, such as hydroxyapatite, whitlockite, silicon‐dioxide, and the emerging synthetic 2D nanosilicates are investigated. Transcriptome sequencing is utilized to probe the cellular response and determine the significantly affected signaling pathways due to exposure to these inorganic nanomaterials. Transcriptome profiles of stem cells treated with nanosilicates reveals a stabilized skeletal progenitor state suggestive of endochondral differentiation. This observation is bolstered by enhanced deposition of matrix mineralization in nanosilicate treated stem cells compared to control or other treatments. Specifically, use of 2D nanosilicates directs osteogenic differentiation of stem cells via activation of bone morphogenetic proteins and hypoxia‐inducible factor 1‐alpha signaling pathway. This study provides insight into impact of nanomaterials on cellular gene expression profile and predicts downstream effects of nanomaterial induction of endochondral differentiation. [ABSTRACT FROM AUTHOR]

The transmembrane protein β-amyloid precursor protein (APP) is central to the pathophysiology of Alzheimer's disease (AD). The β-amyloid hypothesis posits that aberrant processing of APP forms neurotoxic β-amyloid aggregates, which lead to the cognitive impairments observed in AD. Although numerous additional factors contribute to AD, there is a need to better understand the synaptic function of APP. We have found that Drosophila APP-like (APPL) has both shared and non-shared roles at the synapse with Kismet (Kis), a chromatin helicase binding domain (CHD) protein. Kis is the homolog of CHD7 and CHD8, both of which are implicated in neurodevelopmental disorders including CHARGE Syndrome and autism spectrum disorders, respectively. Loss of function mutations in kis and animals expressing human APP and BACE in their central nervous system show reductions in the glutamate receptor subunit, GluRIIC, the GTPase Rab11, and the bone morphogenetic protein (BMP), pMad, at the Drosophila larval neuromuscular junction (NMJ). Similarly, processes like endocytosis, larval locomotion, and neurotransmission are deficient in these animals. Our pharmacological and epistasis experiments indicate that there is a functional relationship between Kis and APPL, but Kis does not regulate appl expression at the larval NMJ. Instead, Kis likely influences the synaptic localization of APPL, possibly by promoting rab11 transcription. These data identify a potential mechanistic connection between chromatin remodeling proteins and aberrant synaptic function in AD. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a chronic disease characterized by a progressive increase in mean pulmonary arterial pressure. Mutations in the BMPR2 and AQP1 genes have been described in familial PAH. The bone morphogenetic proteins BMP9 and BMP10 bind with high affinity to BMPR2. Administration of BMP9 has been proposed as a potential therapeutic strategy against PAH, although recent conflicting evidence dispute the effect of such a practice. Considering the involvement of the above molecules in PAH onset, progression, and therapeutic value, we examined the effects of modulation of BMP9, BMPR2, and AQP1 on BMP9, BMP10, BMPR2, AQP1, and TGFB1 expression in human pulmonary microvascular endothelial cells in vitro. Our results demonstrated that silencing the BMPR2 gene resulted in increased expression of its two main ligands, namely BMP9 and BMP10. Exogenous administration of BMP9 caused the return of BMP10 to basal levels, while it restored the decreased AQP1 protein levels and the decreased TGFB1 mRNA and protein expression levels caused by BMPR2 silencing. Moreover, AQP1 gene silencing also resulted in increased expression of BMP9 and BMP10. Our results might possibly imply that the effect of exogenously administered BMP9 on molecules participating in the BMP signaling pathway could depend on the expression levels of BMPR2. Taken together, these results may provide insight into the highly complex interactions of the BMP signaling pathway. [ABSTRACT FROM AUTHOR]

The present study aimed to evaluate the effect of photobiomodulation therapy (PBM) on different stages of osteogenesis in vitro. For this, osteoblastic-like cells (Saos-2 cell lineage) were irradiated in two different periods: during the Proliferation phase (PP; from the second to the fourth day) and during the Differentiation phase (DP; from the seventh to the ninth day). The energy density used in the study was 1.5 J/ cm2. The following parameters were evaluated: 1) quantification of collagen type 1 (COL 1), osteopontin (OPN), and bone morphogenetic protein 2 (BMP-2); 2) quantification of alkaline phosphatase (ALP) activity; and 3) quantification of extracellular matrix (ECM) mineralization. Non-irradiated cultures were used as controls. The data were analyzed using the Student's t-test or one-way ANOVA, considering a significance level of 5%. The results indicated that COL 1 and BMP-2 quantification was higher in Saos-2 irradiated during the DP in relation to the control group at day 10 (p < 0.05). No differences were observed for other comparisons at this time point (p > 0.05). OPN expression was greater in PP compared with the other experimental groups at day 10 (p < 0.05). Irradiation did not affect ALP activity in Saos-2 regardless of the exposure phase and the time point evaluated (p > 0.05). At day 14, ECM mineralization was higher in Saos-2 cultures irradiated during the DP in relation to the PP (p < 0.05). In conclusion, the results suggested that the effects of PBM on osteoblastic cells may be influenced by the stage of cell differentiation. [ABSTRACT FROM AUTHOR]

Introduction: Hypertension can accelerate and aggravate the process of arterial ageing and calcification. However, the mechanism behind has yet to be well elucidated. Methods: Here, we monitored the dynamic changes of fibronectin (FN)/α5 integrin, bone morphogenetic protein 2/matrix Gla protein (BMP2/MGP), and Runx2 in the aorta of spontaneously hypertensive rats (SHRs) and thoracic aortic vascular smooth muscle cells (VSMCs), also the phenotypic transformation of VSMCs during the process of arterial ageing and calcification. Further, study on arterial ageing and calcification through antagonist experiments at the molecular level was explored. Results: We found extracellular FN and its α5 integrin receptor expressions were positively associated with arterial ageing and calcification in SHR during ageing, as well in VSMCs from SHR in vitro. Integrin receptor inhibitor of GRGDSP would delay this arterial ageing and calcification process. Moreover, the elevated FN and α5 integrin receptor expression evoked the disequilibrium of BMP2/MGP, where the expression of BMP2, a potent osteogenic inducer, increased while MGP, a calcification inhibitor, decreased. Furthermore, it was followed by the upregulation of Runx2 and the phenotypic transformation of VSMCs from the contractile phenotype into the osteoblast-like cells. Notably, BMP2 antagonist of rmNoggin was sufficient to ameliorate the ageing and calcification process of VSMCs and exogenous BMP2-adding accelerate and aggregate the process. Conclusion: Our study revealed that hypertension-associated arterial ageing and calcification might be a consequence that hypertension up-regulated FN and its high binding affinity integrin α5 receptor in the aortic wall, which in turn aggravated the imbalance of BMP2/MGP, promoted the transcription of Runx2, and induced the phenotypic transformation of VSMCs from the contractile phenotype into the osteoblast-like cells. Our study would provide insights into hypertension-associated arterial ageing and calcification and shed new light on the control of arterial calcification, especially for those with hypertension. [ABSTRACT FROM AUTHOR]

This study aimed to determine the function of angiopoietin-related protein 4 (ANGPTL4) and bone morphogenetic protein 7 (BMP7) on hepatocellular carcinoma (HCC). Overexpressing plasmids were cotransfected into HepG2 cells to determine the interaction between ANGPTL4 and BMP7. The effect of ANGPTL4 on the stability of BMP7 is examined by detecting the expression and ubiquitination levels. In vitro and in vivo experiments of knocking down ANGPTL4 while overexpressing BMP7 were performed to investigate whether the effects of ANGPTL4 on HCC proliferation, migration, and downstream signaling pathways were dependent on BMP7. ANGPTL4 is able to interact with BMP7, and knockdown of ANGPTL4 increased BMP7 expression and ubiquitination. Overexpression of BMP7 reversed the inhibition of HCC proliferation and migration as well as the decrease in the expression levels of Smad1/5/8 and MAPK14 caused by knockdown of ANGPTL4. ANGPTL4 promotes the proliferation and migration of HCC by inhibiting the ubiquitination degradation of BMP7 and the Smad/MAPK pathway, providing a novel mechanism and a potential therapeutic target for the treatment of HCC. [ABSTRACT FROM AUTHOR]

The Murray cod (Maccullochella peelii), an economically and recologically valuable fish species, is extensively cultured in the aquaculture industry. However, the severe skeletal deformities that occur during the rearing process pose a significant challenge, profoundly impacting growth performance and economic sustainability. Despite recognition of these deformities, comprehensive studies investigating the underlying mechanisms of skeletal deformities in Murray cod remain scarce. To solve this problem, our study combines histological and molecular studies to understand the characteristics and mechanisms of these deformities. The results are as follows: (i) At the histological level, we observed notable abnormalities in the brain and muscle tissues of deformed Murray cod, including an enlarged ventricle and irregular muscle fiber structure. These observed abnormalities could potentially impact the skeletal development of Murray cod. (ii) At the molecular level, we performed a comprehensive transcriptome analysis of the brain and muscle tissues of normal and deformed Murray cod. Our analysis identified 8834 differentially expressed genes (DEGs), of which 3788 up-regulated genes and 4555 down-regulated genes. Enrichment analysis of GO and KEGG pathways showed that Cell Adhesion, Notch Signaling, Wnt Signaling, Cell Adhesion Molecules, The ECM-Receptor Interaction Pathway, and PI3K-Akt Signaling pathways may be involved in vertebral deformities. Notably, in deformed Murray cod, we observed significant changes in the expression of certain genes closely associated with skeletal development. For example, down-regulated expression of Fibronectin 1 (FN1) and Bone Morphogenetic Protein 2 (BMP2) was found in brain tissue. These genes may play a crucial role in the process of skeletal formation and development. At the same time, we verified through qRT-PCR to ensure the reliability of our data. In conclusion, our study provides a comprehensive understanding of Murray cod's skeletal deformities through histological and transcriptomic analyses and reveals the molecular mechanism of Murray cod's skeletal development. And provide insights to address these economically important anomalies. [ABSTRACT FROM AUTHOR]

The article focuses on the transformative impact of orthobiologics in orthopaedic care, highlighting their role in enhancing natural healing processes and reducing the reliance on invasive surgeries and long recovery times. Topics include the wide-ranging applications of orthobiologics such as PRP, BMPs, and stem cell therapies in treating conditions like osteoarthritis, tendon injuries, and spinal disorders.

Background: Bone morphogenetic protein 9 (BMP9) is a hepatokine that plays a pivotal role in the progression of liver diseases. Moreover, an increasing number of studies have shown that BMP9 is associated with hepatopulmonary syndrome (HPS), but its role in HPS is unclear. Here, we evaluated the influence of CBDL on BMP9 expression and investigated potential mechanisms of BMP9 signalling in HPS. Methods: We profiled the circulating BMP9 levels in common bile duct ligation‐induced HPS rat model, and then investigated the effects and mechanisms of HPS rat serum on pulmonary vascular endothelial dysfunction in rat model, as well as in primarily cultured rat pulmonary microvascular endothelial cells. Results: Our data revealed that circulating BMP9 levels were significantly increased in the HPS rats compared to control group. Besides, the elevated BMP9 in HPS rat serum was not only crucial for promoting endothelial cell proliferation and tube formation through the activin receptor‐like kinase1 (ALK1)‐Endoglin‐Smad1/5/9 pathway, but also important for accumulation of monocytes. Treatments with ALK1‐Fc or silencing ALK1 expression to inhibit the BMP9 signalling pathway effectively eliminated these effects. In agreement with these observations, increased circulating BMP9 was associated with an increase in lung vessel density and accumulation of pro‐angiogenic monocytes in the microvasculature in HPS rats. Conclusions: This study provided evidence that elevated circulating BMP9, secreted from the liver, promote pulmonary angiogenesis in HPS rats via ALK1‐Endoglin‐Smad1/5/9 pathway. In addition, BMP9‐regulated pathways are also involved in accumulation of pro‐angiogenic monocytes in the pulmonary microvasculature in HPS rats. [ABSTRACT FROM AUTHOR]

Recent advances in bone tissue engineering have shown promise for bone repair post osteosarcoma excision. However, conflicting research on mesenchymal stem cells (MSCs) has raised concerns about their potential to either promote or inhibit tumor cell proliferation. It is necessary to thoroughly understand the interactions between MSCs and tumor cells. Most previous studies only focused on the interactions between cells within the tumor tissues. It has been challenging to develop an in vitro model of osteosarcoma excision sites replicating the complexity of the bone microenvironment and cell distribution. In this work, we designed and fabricated modular bioceramic scaffolds to assemble into a co-culture model. Because of the bone-like composition and mechanical property, tricalcium phosphate bioceramic could mimic the bone microenvironment and recapitulate the cell-extracellular matrix interaction. Moreover, the properties for easy assembly enabled the modular units to mimic the spatial distribution of cells in the osteosarcoma excision site. Under this co-culture model, MSCs showed a noticeable tumor-stimulating effect with a potential risk of tumor recurrence. In addition, tumor cells also could inhibit the osteogenic ability of MSCs. To undermine the stimulating effects of MSCs on tumor cells, we present the methods of pre-differentiated MSCs, which had lower expression of IL-8 and higher expression of osteogenic proteins. Both in vitro and in vivo studies confirm that pre-differentiated MSCs could maintain high osteogenic capacity without promoting tumor growth, offering a promising approach for MSCs' application in bone regeneration. Overall, 3D modular scaffolds provide a valuable tool for constructing hard tissue in vitro models. Bone tissue engineering using mesenchymal stem cells (MSCs) and biomaterials has shown promise for bone repair post osteosarcoma excision. However, conflicting researches on MSCs have raised concerns about their potential to either promote or inhibit tumor cell proliferation. It remains challenges to develop in vitro models to investigate cell interactions, especially of osteosarcoma with high hardness and special composition of bone tissue. In this work, modular bioceramic scaffolds were fabricated and assembled to co-culture models. The interactions between MSCs and MG-63 were manifested as tumor-stimulating and osteogenesis-inhibiting, which means potential risk of tumor recurrence. To undermine the stimulating effect, pre-differentiation method was proposed to maintain high osteogenic capacity without tumor-stimulating, offering a promising approach for MSCs' application in bone regeneration. [Display omitted] [ABSTRACT FROM AUTHOR]

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by the development of arteriovenous malformations (AVMs) that can result in significant morbidity and mortality. HHT is caused primarily by mutations in bone morphogenetic protein receptors ACVRL1/ALK1, a signaling receptor, or endoglin (ENG), an accessory receptor. Because overexpression of Acvrl1 prevents AVM development in both Acvrl1 and Eng null mice, enhancing ACVRL1 expression may be a promising approach to development of targeted therapies for HHT. Therefore, we sought to understand the molecular mechanism of ACVRL1 regulation. We previously demonstrated in zebrafish embryos that acvrl1 is predominantly expressed in arterial endothelial cells and that expression requires blood flow. Here, we document that flow dependence exhibits regional heterogeneity and that acvrl1 expression is rapidly restored after reinitiation of flow. Furthermore, we find that acvrl1 expression is significantly decreased in mutants that lack the circulating Alk1 ligand, Bmp10, and that, in the absence of flow, intravascular injection of BMP10 or the related ligand, BMP9, restores acvrl1 expression in an Alk1-dependent manner. Using a transgenic acvrl1:egfp reporter line, we find that flow and Bmp10 regulate acvrl1 at the level of transcription. Finally, we observe similar ALK1 ligand-dependent increases in ACVRL1 in human endothelial cells subjected to shear stress. These data suggest that ligand-dependent Alk1 activity acts downstream of blood flow to maintain or enhance acvrl1 expression via a positive feedback mechanism, and that ALK1 activating therapeutics may have dual functionality by increasing both ALK1 signaling flux and ACVRL1 expression. [ABSTRACT FROM AUTHOR]

Objective: The present study aimed to investigate the involvement of aberrant BMP8A expression in TNBC and bone metastasis. Methods: Aberrant expression of BMP8A in breast cancer was first determined by analyzing The Cancer Genome Atlas breast cancer cohort (TCGA-BRCA) and an immunohistochemical (IHC) staining of BMP8A in a breast cancer tissue microarray (TMA). Clinical relevance of deregulated BMP8A in breast cancer was assessed using Kaplan-Meier online analysis. The influence of BMP8A on cellular functions of two TNBC cell lines was assessed using in vitro assays. Conditional medium (CM) collected from the supernatant of hFOB cells and bone matrix extract (BME) was applied to mimic the bone micro-environment to evaluate the role played by BMP8A in bone metastasis. Correlations with both osteolytic and osteoblastic markers were evaluated in the TCGA-BRCA cohort. Expression of certain responsive genes was quantified in the BMP8A overexpression cell lines. Additionally, signal transduction through both Smad-dependent and independent pathways was evaluated using Western blot assay. Results: Compared to the adjacent normal tissues, BMP8A expression was significantly increased in primary tumors (p < 0.05) which was associated with shorter distant metastasis free survival (DMFS) in TNBC (p < 0.05). BMP8A was observed to enhance cell invasion and migration within TNBC cells. In the simulated bone milieu, both MDA-MB-231BMP8Aexp and BT549BMP8Aexp cells presented enhanced invasiveness. BMP8A level was strongly correlated with most osteolytic and osteoblastic markers, suggesting the potential involvement of BMP8A in bone metastasis in TNBC. Receptor activator of nuclear factor kappa-B ligand (RANKL) expression was significantly increased in BMP8A overexpressed triple-negative cell lines (MDA-MB-231 and BT549 Furthermore, enhanced phosphorylation of Smad3 and increased expression of epidermal growth factor receptor (EGFR) were observed in MDA-MB-231 cells overexpressing BMP8A. Conclusion: BMP8A was upregulated in TNBC which was associated with poorer DMFS. BMP8A overexpression enhanced the invasion and migration of TNBC cells. With a putative role in osteolytic bone metastasis in TNBC, BMP8A represents a promising candidate for further investigation into its therapeutic potential. [ABSTRACT FROM AUTHOR]

Amniogenesis, a process critical for continuation of healthy pregnancy, is triggered in a collection of pluripotent epiblast cells as the human embryo implants. Previous studies have established that bone morphogenetic protein (BMP) signaling is a major driver of this lineage specifying process, but the downstream BMP-dependent transcriptional networks that lead to successful amniogenesis remain to be identified. This is, in part, due to the current lack of a robust and reproducible model system that enables mechanistic investigations exclusively into amniogenesis. Here, we developed an improved model of early amnion specification, using a human pluripotent stem cell-based platform in which the activation of BMP signaling is controlled and synchronous. Uniform amniogenesis is seen within 48 hr after BMP activation, and the resulting cells share transcriptomic characteristics with amnion cells of a gastrulating human embryo. Using detailed time-course transcriptomic analyses, we established a previously uncharacterized BMP-dependent amniotic transcriptional cascade, and identified markers that represent five distinct stages of amnion fate specification; the expression of selected markers was validated in early post-implantation macaque embryos. Moreover, a cohort of factors that could potentially control specific stages of amniogenesis was identified, including the transcription factor TFAP2A. Functionally, we determined that, once amniogenesis is triggered by the BMP pathway, TFAP2A controls the progression of amniogenesis. This work presents a temporally resolved transcriptomic resource for several previously uncharacterized amniogenesis states and demonstrates a critical intermediate role for TFAP2A during amnion fate specification. [ABSTRACT FROM AUTHOR]

Background: This study was performed to determine the therapeutic effects of diosgenin (DG) which is a steroidal saponin, administered at different doses on alveolar bone loss (ABL) in rats with experimental periodontitis using immunohistochemical and cone-beam computed tomography (CBCT). Methods: Thirty-two male Wistar rats divided into four equal groups: control (non-ligated), periodontitis (P), DG-48, and DG-96. Sutures were placed at the gingival margin of the lower first molars to induce experimental periodontitis. Then, 48 and 96 mg/kg of DG was administered to the study groups by oral gavage for 29 days. At day 30, the animals were sacrificed and ABL was determined via CBCT. The expression patterns of osteocalcin (OCN), alkaline phosphatase (ALP), type I collagen (Col-1), B cell lymphoma 2 (Bcl 2), Bcl 2-associated X protein (Bax), bone morphogenetic protein 2 (BMP-2), and receptor activator of NF κB ligand (RANKL) were examined immunohistochemically. Results: Histopathologic examination showed all features of the advanced lesion in the P group. DG use decreased all these pathologic changes. It was observed that periodontitis pathology decreased as the dose increased. DG treatment increased the ALP, OCN, Bcl 2, Col-1, and BMP-2 levels in a dose-dependent manner, compared with the P group (p < 0.05). DG decreased the expression of RANKL and Bax in a dose-dependent manner (p < 0.05). ABL was significantly lower in the DG-48 and DG-96 groups than in the P group (p < 0.05). Conclusion: Collectively, our findings suggest that DG administration protects rats from periodontal tissue damage with a dose-dependent manner, provides an increase in markers of bone formation, decreases in Bax/Bcl-2 ratio and osteoclast activation. [ABSTRACT FROM AUTHOR]

The biophysical heterogeneity of the bone–cartilage interface requires complex materials to mimic differences in bone density, extracellular matrix composition, and mineralization. Biomaterial approaches to repair osteochondral tissue typically use multilayer scaffolds, which require multistep fabrication and may undergo delamination at the construct interface. This work describes the development of functionalized microgels for the repair of osteochondral tissues using an N‐cadherin peptide, bone morphogenetic protein‐2 (BMP‐2) peptide, and changes in stiffness to create pro‐osteogenic and prochondrogenic microgels. Microgels, when annealed into a scaffold, outperforms bulk hydrogel controls evidenced by upregulation of osteogenic and chondrogenic markers in mesenchymal stromal cells (MSCs). The macroporous void space present in microgel anneals scaffolds enabled robust cell proliferation and extracellular matrix (ECM) deposition throughout the entire scaffold. A bilayer functionalized annealed microgel scaffold is then created and the ability to spatially control the differentiation of MSCs is assessed. Osteochondral bilayer scaffolds exhibit distinct regions of osteogenic and chondrogenic protein expression as a function of microgel population upon immunostaining for osteocalcin and aggrecan, respectively. Spatial transcriptomics confirm osteogenic and chondrogenic genes are upregulated in their respective microgel regions. These studies highlight the tunable and functionalizable nature of microgels and the importance of macroporous void space. [ABSTRACT FROM AUTHOR]

Heterotopic ossification (HO), defined as the formation of extraskeletal bone in muscle and soft tissues, is a diverse pathological process caused by either genetic mutations or inciting trauma. Fibrodysplasia ossificans progressiva (FOP) is a genetic form of HO caused by mutations in the bone morphogenetic protein (BMP) type I receptor gene activin A receptor type 1 (ACVR1). These mutations make ACVR1 hypersensitive to BMP and responsive to activin A. Hedgehog (Hh) signaling also contributes to HO development. However, the exact pathophysiology of how skeletogenic cells contribute to endochondral ossification in FOP remains unknown. Here, we showed that the wild-type or FOP-mutant ACVR1 localized in the cilia of stem cells from human exfoliated deciduous teeth with key FOP signaling components, including activin A receptor type 2A/2B, SMAD family member 1/5, and FK506-binding protein 12kD. Cilia suppression by deletion of intraflagellar transport 88 or ADP ribosylation factor like GTPase 3 effectively inhibited pathological BMP and Hh signaling, subdued aberrant chondro-osteogenic differentiation in primary mouse or human FOP cells, and diminished in vivo extraskeletal ossification in Acvr1Q207D, Sox2-Cre; Acvr1R206H/+ FOP mice and in burn tenotomy–treated wild-type mice. Our results provide a rationale for early and localized suppression of cilia in affected tissues after injury as a therapeutic strategy against either genetic or acquired HO. Editor's summary: Heterotopic ossification (HO) is ectopic bone formation common in fibrodysplasia ossificans progressiva (FOP). Cellular mechanisms of HO are not fully understood. He et al. found that inhibiting cilia formation on stem cells prevented HO in vitro and in mice. Genetically inhibiting two regulators of cilia formation, ADP ribosylation factor like GTPase 3 (ARL3) or intraflagellar transport 88, blocked HO in stem cells from exfoliated deciduous teeth from patients with FOP. Inhibiting these two genes in different mouse models of FOP resulted in decreased HO. Inhibiting Arl3 with a small interfering RNA treatment also reduced HO in a burn tenotomy model in wild-type mice. These data suggest that suppressing stem cell cilia could be a therapeutic approach to treat HO. —Brandon Berry [ABSTRACT FROM AUTHOR]

Obesity impairs tissue insulin sensitivity and signaling, promoting type-2 diabetes. Although improving insulin signaling is key to reversing diabetes, the multi-organ mechanisms regulating this process are poorly defined. Here, we screen the secretome and receptome in Drosophila to identify the hormonal crosstalk affecting diet-induced insulin resistance and obesity. We discover a complex interplay between muscle, neuronal, and adipose tissues, mediated by Bone Morphogenetic Protein (BMP) signaling and the hormone Bursicon, that enhances insulin signaling and sugar tolerance. Muscle-derived BMP signaling, induced by sugar, governs neuronal Bursicon signaling. Bursicon, through its receptor Rickets, a Leucine-rich-repeat-containing G-protein coupled receptor (LGR), improves insulin secretion and insulin sensitivity in adipose tissue, mitigating hyperglycemia. In mouse adipocytes, loss of the Rickets ortholog LGR4 blunts insulin responses, showing an essential role of LGR4 in adipocyte insulin sensitivity. Our findings reveal a muscle-neuronal-fat-tissue axis driving metabolic adaptation to high-sugar conditions, identifying LGR4 as a critical mediator in this regulatory network. Obesity induces insulin resistance and impairs insulin signaling, causing diabetes. Here, the authors show that BMP and LGR signaling mediate communication between muscle, neuronal, and adipose tissues to enhance insulin signaling, identifying LGR as key in protecting against insulin resistance. [ABSTRACT FROM AUTHOR]

Background: This study evaluated the osseointegration potential of functionalised high-performance oxide ceramics (HPOC) in isolation or coated with BMP-2 or RGD peptides in 36 New Zeeland female rabbits using micro-computed tomography (micro CT). The primary outcomes of interest were to assess the amount of ossification evaluating the improvement in the bone volume/ total volume (BV/TV) ratio and trabecular thickness at 6 and 12 weeks. The second outcome of interest was to investigate possible differences in osteointegration between the functionalised silanised HPOC in isolation or coated with Bone Morphogenetic Protein 2 (BMP-2) or RGD peptides. Methods: 36 adult female New Zealand white rabbits with a minimum weight of three kg were used. One-third of HPOCs were functionalised with silicon suboxide (SiOx), a third with BMP-2 (sHPOC-BMP2), and another third with RGD (sHPOC-RGD). All samples were scanned with a high-resolution micro CT (U-CTHR, MILabs B.V., Houten, The Netherlands) with a reconstructed voxel resolution of 10 µm. MicroCT scans were reconstructed in three planes and processed using Imalytics Preclinical version 2.1 (Gremse-IT GmbH, Aachen, Germany) software. The total volume (TV), bone volume (BV) and ratio BV/TV were calculated within the coating area. Results: BV/TV increased significantly from 6 to 12 weeks in all HPOCs: silanised (P = 0.01), BMP-2 (P < 0.0001), and RGD (P < 0.0001) groups. At 12 weeks, the BMP-2 groups demonstrated greater ossification in the RGD (P < 0.0001) and silanised (P = 0.008) groups. Trabecular thickness increased significantly from 6 to 12 weeks (P < 0.0001). At 12 weeks, BMP-2 promoted greater trabecular thickness compared to the silanised group (P = 0.07), although no difference was found with the RGD (P = 0.1) group. Conclusion: Sinalised HPOC in isolation or functionalised with BMP-2 or RGD promotes in vivo osteointegration. The sinalised HOPC functionalised with BMP-2 demonstrated the greatest osseointegration. [ABSTRACT FROM AUTHOR]

Previous studies have suggested a potential role of bone morphogenetic protein 6 (BMP6) in glucose metabolism, which also seems to be regulated by serotonin (5-hydroxytryptamine, 5HT), a biogenic amine with multiple roles in the organism. In this study, we explored possible interactions between BMP6, serotonin, and glucose metabolism regulation. The effect of BMP6 or 5HT on pancreatic β-cells has been studied in vitro using the INS-1 832/13 rat insulinoma cell line. Studies in vivo have been performed on mice with the global deletion of the Bmp6 gene (BMP6−/−) and included glucose and insulin tolerance tests, gene expression studies using RT-PCR, immunohistochemistry, and ELISA analyses. We have shown that BMP6 and 5HT treatments have the opposite effect on insulin secretion from INS-1 cells. The effect of BMP6 on the 5HT system in vivo depends on the tissue studied, with no observable systemic effect on peripheral 5HT metabolism. BMP6 deficiency does not cause diabetic changes, although a mild difference in insulin tolerance test between BMP6−/− and WT mice was observed. In conclusion, BMP6 does not directly influence glucose metabolism, but there is a possibility that its deletion causes slowly developing changes in glucose and serotonin metabolism, which would become more expressed with ageing. [ABSTRACT FROM AUTHOR]

BACKGROUND: An imbalance of antiproliferative BMP (bone morphogenetic protein) signaling and proliferative TGF-β (transforming growth factor-β) signaling is implicated in the development of pulmonary arterial hypertension (PAH). The posttranslational modification (eg, phosphorylation and ubiquitination) of TGF-β family receptors, including BMPR2 (bone morphogenetic protein type 2 receptor)/ALK2 (activin receptor-like kinase-2) and TGF-βR2/R1, and receptor-regulated Smads significantly affects their activity and thus regulates the target cell fate. BRCC3 modifies the activity and stability of its substrate proteins through K63-dependent deubiquitination. By modulating the posttranslational modifications of the BMP/TGF-β–PPARγ pathway, BRCC3 may play a role in pulmonary vascular remodeling, hence the pathogenesis of PAH. METHODS: Bioinformatic analyses were used to explore the mechanism by which BRCC3 deubiquitinates ALK2. Cultured pulmonary artery smooth muscle cells (PASMCs), mouse models, and specimens from patients with idiopathic PAH were used to investigate the rebalance between BMP and TGF-β signaling in regulating ALK2 phosphorylation and ubiquitination in the context of pulmonary hypertension. RESULTS: BRCC3 was significantly downregulated in PASMCs from patients with PAH and animals with experimental pulmonary hypertension. BRCC3, by de-ubiquitinating ALK2 at Lys-472 and Lys-475, activated receptor-regulated Smad1/5/9, which resulted in transcriptional activation of BMP-regulated PPARγ, p53, and Id1. Overexpression of BRCC3 also attenuated TGF-β signaling by downregulating TGF-β expression and inhibiting phosphorylation of Smad3. Experiments in vitro indicated that overexpression of BRCC3 or the de-ubiquitin–mimetic ALK2-K472/475R attenuated PASMC proliferation and migration and enhanced PASMC apoptosis. In SM22α-BRCC3-Tg mice, pulmonary hypertension was ameliorated because of activation of the ALK2-Smad1/5-PPARγ axis in PASMCs. In contrast, Brcc3 -/- mice showed increased susceptibility of experimental pulmonary hypertension because of inhibition of the ALK2-Smad1/5 signaling. CONCLUSIONS: These results suggest a pivotal role of BRCC3 in sustaining pulmonary vascular homeostasis by maintaining the integrity of the BMP signaling (ie, the ALK2-Smad1/5-PPARγ axis) while suppressing TGF-β signaling in PASMCs. Such rebalance of BMP/TGF-β pathways is translationally important for PAH alleviation. [ABSTRACT FROM AUTHOR]

The aim of this study was to develop a three-dimensional (3D) cell model in order to evaluate the effectiveness of a traditional Chinese medicine decoction in the treatment of arthritis. Chondrocytes (ATDC5) and osteoblasts (MC3T3-E1) were 3D printed separately using methacryloyl gelatin (GelMA) hydrogel bioinks to mimic the natural 3D cell environment. Both cell types showed good biocompatibility in GelMA. Lipopolysaccharide (LPS) was added to the cell models to create inflammation models, which resulted in increased expression of inflammatory factors IL-1β, TNF-α, iNOS, and IL-6, and decreased expression of cell functional genes such as Collagen II (COLII), transcription factor SOX-9 (Sox9), Aggrecan, alkaline phosphatase (ALP), RUNX family transcription factor 2 (Runx2), Collagen I (COLI), Osteopontin (OPN), and bone morphogenetic protein-2 (BMP-2). The created inflammation model was then used to evaluate the effectiveness of Dangguiniantongtang (DGNT) decoctions. The results showed that DGNT reduced the expression of inflammatory factors and increased the expression of functional genes in the cell model. In summary, this study established a 3D cell model to assess the effectiveness of traditional Chinese medicine (TCM) decoctions, characterized the gene expression profile of the inflammatory state model, and provided a practical reference for future research on TCM efficacy evaluation for arthritis treatment. [ABSTRACT FROM AUTHOR]

Aim Methodology Results Conclusions The regenerative capacity of dental pulp relies on the odonto/osteogenic differentiation of dental pulp cells (DPCs), but dynamic microenvironmental changes hinder the process. Bone morphogenetic protein 9 (BMP9) promotes differentiation of DPCs towards an odonto/osteogenic lineage, forming dentinal‐like tissue. However, the molecular mechanism underlying its action remains unclear. This study investigates the role of DLX6 antisense RNA 1 (DLX6‐AS1) in odonto/osteogenic differentiation induced by BMP9.Custom RT2 profiler PCR array, quantitative Real‐Time PCR (qRT‐PCR) and western blots were used to investigate the expression pattern of DLX6‐AS1 and its potential signal axis. Osteogenic ability was evaluated using alkaline phosphatase and alizarin red S staining. Interactions between lncRNA and miRNA, as well as miRNA and mRNA, were predicted through bioinformatic assays, which were subsequently validated via RNA immunoprecipitation and dual luciferase reporter assays. Student's t‐test or one‐way ANOVA with post hoc Tukey HSD tests were employed for data analysis, with a p‐value of less than .05 considered statistically significant.DLX6‐AS1 was upregulated upon BMP9 overexpression in DPCs, thereby promoting odonto/osteogenic differentiation. Additionally, miR‐128‐3p participated in BMP9‐induced odonto/osteogenic differentiation by interacting with the downstream signal MAPK14. Modifying the expression of miR‐128‐3p and transfecting pcMAPK14/siMAPK14 had a rescue impact on odonto/osteogenic differentiation downstream of DLX6‐AS1. Lastly, miR‐128‐3p directly interacted with both MAPK14 and DLX6‐AS1.DLX6‐AS1 could regulate the odonto/osteogenic differentiation of DPCs under the control of BMP9 through the miR‐128‐3p/MAPK14 axis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Growth differentiation factor 5, a member of the transforming growth factor-β superfamily and bone morphogenetic protein family, plays an important role in articular cartilage injury repair, bone regeneration, improvement of intervertebral disc degeneration, tendon healing, and neurodevelopment. OBJECTIVE: To review the research progress of growth differentiation factor 5 in inducing chondrocytes, nucleus pulposus-like cells, tendon cell differentiation, as well as inducing bone formation and neurodevelopment. METHODS: The search terms “growth differentiation factor 5, articular cartilage, bone, nucleus pulposus cells, tendon, nerve regeneration” were used in CNKI, WanFang and PubMed. According to the inclusion and exclusion criteria, the articles not related to the subject matter were excluded and 69 articles related to growth differentiation factor 5 were included. RESULTS AND CONCLUSION: (1) Growth differentiation factor 5 can induce chondrogenic and osteoblastic differentiation of mesenchymal stem cells, but the concentration boundary of growth differentiation factor 5 to induce chondrogenic or osteoblastic differentiation remains unclear. (2) Growth differentiation factor 5 can induce mesenchymal stem cells to differentiate into nucleus pulposus cells, which may play a role in the treatment of intervertebral disc degeneration. (3) Growth differentiation factor 5 can induce mesenchymal stem cells to differentiate into tendon cells and play an important role in tendon repair and prevention of postoperative tendon adhesion. (4) Growth differentiation factor 5 can induce neurodevelopment and promote nerve regeneration. [ABSTRACT FROM AUTHOR]

BACKGROUND: The research of dental stem cells in the fields of regenerative medicine and tissue engineering has been deepening, bringing hope for the repair of tooth-related tissues and the treatment of systemic diseases. However, there is a lack of systematic research and analysis on the biological characteristics of dental stem cells in different age groups. OBJECTIVE: To explore the biological characteristics of the human deciduous tooth and permanent tooth pulp stem cells cultured in umbilical cord blood platelet lysate to provide a reliable basis for human platelet lysates to replace fetal bovine serum. METHODS: The pulp tissues of deciduous teeth, juvenile permanent teeth and adult permanent teeth were taken out and cultured in DMEM/F-12 medium supplemented with 10% fetal bovine serum or different concentrations (5%, 10% and 15%) of human platelet lysates. Cell proliferation in the four groups was detected by cytometry. The optimal concentration of human platelet lysates was selected for subsequent experiments. Under the optimal concentration of human platelet lysates, human deciduous tooth and juvenile and adult permanent tooth pulp stem cells were cultured in vitro. The cell growth status was observed under the microscope. The specific antigen on the cell surface was detected by flow cytometry. The cell proliferation ability was tested by the cell counting method and CCK-8 assay. The cell differentiation ability in vitro was observed by a three-line differentiation assay. RESULTS AND CONCLUSION: (1) The cell proliferation rate of the 10% human platelet lysate group was the highest. (2) In all three groups, fusiform fibrous cells grew and expanded from around the tissue block. There was no significant difference between deciduous teeth and juvenile permanent tooth cells, but the adult permanent tooth cells were larger than the deciduous and juvenile permanent tooth cells of the same generation. (3) The results of flow cytometry showed that deciduous teeth, juvenile permanent teeth and adult permanent teeth conformed to the phenotypic characteristics of mesenchymal stem cells. (4) The proliferative capacity of adult permanent dental pulp stem cells was significantly lower than those of deciduous teeth and juvenile permanent dental pulp stem cells (P < 0.01). (5) mRNA expressions of osteoblast-related genes alkaline phosphatase and bone morphogenetic protein 2, lipoprotein lipase and peroxisome proliferator-activated receptor γ2, mRNA expressions of chondroblast related gene type II collagen α1 and cartilage oligomeric matrix protein in adult pulp stem cells of permanent teeth were significantly lower than those of deciduous teeth and juvenile permanent teeth pulp stem cells (P < 0.01). (6) Compared with adult dental pulp stem cells, human deciduous teeth and juvenile permanent teeth dental pulp stem cells have the stronger proliferative capacity and multidirectional differentiation potential, and are more suitable for clinical research and disease treatment. [ABSTRACT FROM AUTHOR]

Ameloblasts are the specialized dental epithelial cell type responsible for enamel formation. Following completion of enamel development in humans, ameloblasts are lost and biological repair or regeneration of enamel is not possible. In the past, in vitro models to study dental epithelium and ameloblast biology were limited to freshly isolated primary cells or immortalized cell lines, both with limited translational potential. In recent years, large strides have been made with the development of induced pluripotent stem cell and organoid models of this essential dental lineage – both enabling modeling of human dental epithelium. Upon induction with several different signaling factors (such as transforming growth factor and bone morphogenetic proteins) these models display elevated expression of ameloblast markers and enamel matrix proteins. The advent of 3D bioprinting, and its potential combination with these advanced cellular tools, is poised to revolutionize the field – and its potential for tissue engineering, regenerative and personalized medicine. As the advancements in these technologies are rapidly evolving, we evaluate the current state-of-the-art regarding in vitro cell culture models of dental epithelium and ameloblast lineage with a particular focus toward their applicability for translational tissue engineering and regenerative/personalized medicine. Future perspectives for in vitro modeling of dental epithelium and ameloblasts. Development of iPSC and organoid models that can reliably generate dental epithelium and ameloblast-like cells, together with advances in 3D bioprinting, provide promising tools for enamel research. Advanced models will provide new avenues for development of enamel repair/regeneration approaches, for testing of dental materials or drugs, studying host-pathogen and/or cell-cell interactions, in vitro modeling of enamel diseases (e.g. amelogenesis imperfecta) and developing novel insights in fundamental tooth biology (e.g. regulation of amelogenesis, lineage specification). Abbreviations: iPSC: induced pluripotent stem cells; TO: tooth organoids; DE: dental epithelium; AB: ameloblast. [ABSTRACT FROM AUTHOR]

This document summarizes a research study conducted in India on the differentiation of human hematopoietic stem cells (HSCs) into articular chondrocytes, the main cells in articular cartilage. The study found that HSCs can transform into chondrocytes when stimulated by external signals and identified specific genes involved in this process. The researchers also explored the role of different components in the differentiation medium in promoting chondrogenesis. The study suggests that HSCs have potential for regenerating injured articular cartilage. The document includes tables with details of the research methods and acknowledgements for the support and facilities provided by the institute. It also mentions the funding source and information about ethical approval and conflicts of interest. [Extracted from the article]

Peptide-based drug development is a promising direction due to its excellent biological activity, minimal immunogenicity, high in vivo stability, and efficient tissue penetrability. GV1001, an amphiphilic peptide, has proven effective as an anti-cancer vaccine, but its effect on osteoblast differentiation is unknown. To identify proteins interacting with GV1001, biotin-conjugated GV1001 was constructed and confirmed by mass spectrometry. Proteomic analyses were performed to determine GV1001's interaction with osteogenic proteins. GV1001 was highly associated with peptidyl-prolyl isomerase A and co-immunoprecipitation assays revealed that GV1001 bound to peptidyl-prolyl cis-trans isomerase 1 (Pin1). GV1001 significantly increased alkaline phosphatase (ALP) activity, bone nodule formation, and the expression of osteogenic gene markers. GV1001-induced osteogenic activity was enhanced by Pin1 overexpression and abolished by Pin1 knockdown. GV1001 increased the protein stability and transcriptional activity of Runx2 and Osterix. Importantly, GV1001 administration enhanced bone mass density in the OVX mouse model, as verified by µCT analysis. GV1001 demonstrated protective effects against bone loss in OVX mice by upregulating osteogenic differentiation via the Pin1-mediated protein stabilization of Runx2 and Osterix. GV1001 could be a potential candidate with anabolic effects for the prevention and treatment of osteoporosis. [ABSTRACT FROM AUTHOR]

Simple Summary: Therapies to prevent osteoporosis are relevant since it is one of the most common non-communicable human diseases in the world and the most prevalent bone disorder in adults. Jaboticaba is a small, round fruit with white pulp and purple peel that concentrates compounds that may have therapeutic applications. Since jaboticaba peel extract (JPE) enhances the activity of osteoblasts (the cells that form bone) under osteoporotic conditions, we hypothesized that JPE prevents the development of osteoporosis induced by the removal of the ovaries. Ovariectomized rats were treated with either JPE (30 mg/kg of body weight) or its vehicle for 90 days, starting 7 days after the ovariectomy. JPE attenuated ovariectomy-induced bone loss due to its ability to prevent the imbalance between osteoblast and adipocyte (the cells that produce bone and fat, respectively) differentiation. These data indicate the potential therapeutic use of JPE to prevent osteoporosis. Therapies to prevent osteoporosis are relevant since it is one of the most common non-communicable human diseases in the world and the most prevalent bone disorder in adults. Since jaboticaba peel extract (JPE) added to the culture medium enhanced the osteogenic potential of mesenchymal stem cells (MSCs) derived from osteoporotic rats, we hypothesized that JPE prevents the development of ovariectomy-induced osteoporosis. Ovariectomized rats were treated with either JPE (30 mg/kg of body weight) or its vehicle for 90 days, starting 7 days after the ovariectomy. Then, the femurs were subjected to microcomputed tomography and histological analyses, and the osteoblast and adipocyte differentiation of MSCs was evaluated. JPE attenuated ovariectomy-induced bone loss, as evidenced by higher bone volume/total volume and trabecular number, along with lower trabecular separation and bone marrow adiposity. These protective effects of JPE on bone tissue are due to its ability to prevent the imbalance between osteoblast and adipocyte differentiation of MSCs, since, compared with MSCs derived from ovariectomized rats treated with vehicle, MSCs treated with JPE exhibited higher gene and protein expression of osteogenic markers and extracellular matrix mineralization, as well as lower gene expression of adipogenic markers. These data highlight the potential therapeutic use of JPE to prevent osteoporosis. [ABSTRACT FROM AUTHOR]

Protein synthesis regulation is critical for skeletal muscle hypertrophy, yet other established cellular processes are necessary for growth-related cellular remodeling. Autophagy has a well-acknowledged role in muscle quality control, but evidence for its role in myofiber hypertrophy remains equivocal. Both mammalian target of rapamycin complex I (mTORC1) and bone morphogenetic protein (BMP)-Smad1/5 (Sma and Mad proteins from Caenorhabditis elegans and Drosophila, respectively) signaling are reported regulators of myofiber hypertrophy; however, gaps remain in our understanding of how this regulation is integrated with growth processes and autophagy regulation. Therefore, we investigated the mTORC1 and Smad1/5 regulation of protein synthesis and autophagy flux during serum-stimulated myotube growth. Chronic serum stimulation experiments were performed on day 5 differentiated C2C12 myotubes incubated in differentiation medium [2% horse serum (HS)] or growth medium [5% fetal bovine serum (FBS)] for 48 h. Rapamycin or LDN193189 was dosed for 48 h to inhibit mTORC1 and BMP-Smad1/5 signaling, respectively. Acute serum stimulation was examined in day 7 differentiated myotubes. Protein synthesis was measured by puromycin incorporation. Bafilomycin A1 and immunoblotting for LC3B were used to assess autophagy flux. Chronic serum stimulation increased myotube diameter 22%, total protein 21%, total RNA 100%, and Smad1/5 phosphorylation 404% and suppressed autophagy flux. Rapamycin, but not LDN193189, blocked serum-induced myotube hypertrophy and the increase in total RNA. Acute serum stimulation increased protein synthesis 111%, Smad1/5 phosphorylation 559%, and rpS6 phosphorylation 117% and suppressed autophagy flux. Rapamycin increased autophagy flux during acute serum stimulation. These results provide evidence for mTORC1, but not BMP-Smad1/5, signaling being required for serum-induced myotube hypertrophy and autophagy flux by measuring LC3BII/I expression. Further investigation is warranted to examine the role of autophagy flux in myotube hypertrophy. NEW & NOTEWORTHY: The present study demonstrates that myotube hypertrophy caused by chronic serum stimulation requires mammalian target of rapamycin complex 1 (mTORC1) signaling but not bone morphogenetic protein (BMP)-Smad1/5 signaling. The suppression of autophagy flux was associated with serum-induced myotube hypertrophy and mTORC1 regulation of autophagy flux by measuring LC3BII/I expression. Rapamycin is widely investigated for beneficial effects in aging skeletal muscle and sarcopenia; our results provide evidence that rapamycin can regulate autophagy-related signaling during myotube growth, which could benefit skeletal muscle functional and metabolic health. [ABSTRACT FROM AUTHOR]

Introduction: Medication‐related osteonecrosis of the jaw (MRONJ) is uncommon but can result in severe destruction of the jaw. This case–control study investigated the therapeutic effects of daily or weekly administration of teriparatide in the management of MRONJ using a cohort for osteonecrosis of the jaw. Methods: Patients who were diagnosed with MRONJ and consented to teriparatide administration were assigned either to a group of daily injection or of weekly injection and completed a 4‐week course of injection preoperatively and at least an 8‐week course postoperatively. The control group received either the intraoperative rhBMP treatment (CG_BMP) or no additional perioperative treatment (CG_noBMP). The state of MRONJ was evaluated 2 months (T1) and 6 months (T2) postoperatively for all participants. Results: Either group of daily injection (8.35 weeks ± 1.58; n = 17) or weekly injection (9.17 ± 3.79; n = 12) showed significantly faster healing than those of CG_BMP (14.40 ± 6.08; n = 25) or CG_noBMP (15.79 ± 9.79; n = 39). MRONJ was resolved completely in 24 out of 29 participants who completed the course of teriparatide injections, whereas 46.9% of CG showed delayed resolution. Multiple regression analysis indicated 7.50 times (95% CI, 1.77–31.82) more likelihood of complete resolution of MRONJ for participants with teriparatide injections. Conclusion: A course of daily or weekly administration of teriparatide injections may improve treatment outcomes for patients with MRONJ. [ABSTRACT FROM AUTHOR]

Background: Bone defects, resulting from substantial bone loss that exceeds the natural self-healing capacity, pose significant challenges to current therapeutic approaches due to various limitations. In the quest for alternative therapeutic strategies, bone tissue engineering has emerged as a promising avenue. Notably, excretory proteins from Toxoplasma gondii (TgEP), recognized for their immunogenicity and broad spectrum of biological activities secreted or excreted during the parasite's lifecycle, have been identified as potential facilitators of osteogenic differentiation in human bone marrow mesenchymal stem cells (hBMSCs). Building on our previous findings that TgEP can enhance osteogenic differentiation, this study investigated the molecular mechanisms underlying this effect and assessed its therapeutic potential in vivo. Methods: We determined the optimum concentration of TgEP through cell cytotoxicity and cell proliferation assays. Subsequently, hBMSCs were treated with the appropriate concentration of TgEP. We assessed osteogenic protein markers, including alkaline phosphatase (ALP), Runx2, and Osx, as well as components of the BMP/Smad signaling pathway using quantitative real-time PCR (qRT-PCR), siRNA interference of hBMSCs, Western blot analysis, and other methods. Furthermore, we created a bone defect model in Sprague-Dawley (SD) male rats and filled the defect areas with the GelMa hydrogel, with or without TgEP. Microcomputed tomography (micro-CT) was employed to analyze the bone parameters of defect sites. H&E, Masson and immunohistochemical staining were used to assess the repair conditions of the defect area. Results: Our results indicate that TgEP promotes the expression of key osteogenic markers, including ALP, Runx2, and Osx, as well as the activation of Smad1, BMP2, and phosphorylated Smad1/5—crucial elements of the BMP/Smad signaling pathway. Furthermore, in vivo experiments using a bone defect model in rats demonstrated that TgEP markedly promoted bone defect repair. Conclusion: Our results provide compelling evidence that TgEP facilitates hBMSC osteogenic differentiation through the BMP/Smad signaling pathway, highlighting its potential as a therapeutic approach for bone tissue engineering for bone defect healing. [ABSTRACT FROM AUTHOR]

Dynamic presynaptic actin remodeling drives structural and functional plasticity at synapses, but the underlying mechanisms remain largely unknown. Previous work has shown that actin regulation via Rac1 guanine exchange factor (GEF) Vav signaling restrains synaptic growth via bone morphogenetic protein (BMP)-induced receptor macropinocytosis and mediates synaptic potentiation via mobilization of reserve pool vesicles in presynaptic boutons. Here, we find that Gef26/PDZ-GEF and small GTPase Rap1 signaling couples the BMP-induced activation of Abelson kinase to this Vav-mediated macropinocytosis. Moreover, we find that adenylate cyclase Rutabaga (Rut) signaling via exchange protein activated by cAMP (Epac) drives the mobilization of reserve pool vesicles during post-tetanic potentiation (PTP). We discover that Rap1 couples activation of RutcAMP- Epac signaling to Vav-mediated synaptic potentiation. These findings indicate that Rap1 acts as an essential, convergent node for Abelson kinase and cAMP signaling to mediate BMP-induced structural plasticity and activity-induced functional plasticity via Vav-dependent regulation of the presynaptic actin cytoskeleton. [ABSTRACT FROM AUTHOR]

Background: Current research on ethanol‐induced cardiovascular anomalies has focused on left ventricular (LV) function and blood pressure. To extend this area of research, we sought to determine whether ethanol‐induced alterations in the structure and function of the right cardiac ventricle (RV) and pulmonary artery (PA) lead to pulmonary arterial hypertension (PAH). Methods: Two groups of male Sprague–Dawley rats received a balanced liquid diet containing 5% ethanol (w/v) or a pair‐fed isocaloric liquid diet for 8 weeks. Weekly echocardiography was conducted to evaluate cardiopulmonary function, and lung and RV tissues were collected for ex vivo histological and molecular studies. Results: The ethanol‐treated rats exhibited: (1) Elevated mean pulmonary arterial pressure and decreased pulmonary artery acceleration time/ejection time; (2) Pulmonary vascular remodeling comprising intrapulmonary artery medial layer thickening; and (3) RV hypertrophy along with increased RV/LV + septum, RV diameter, RV cardiomyocyte cross‐sectional area, and LV mass/body weight ratio. These responses were associated with increased lung and RV pro‐inflammatory markers, endothelin‐1 (ET‐1), TNF‐α, and IL‐6 levels and higher ET‐1, ET‐1 type A/B receptor ratio, and downregulation of the cytoprotective protein, bone morphogenetic protein receptor 2 (BMPR2), in the lungs. Conclusion: These findings show that moderate ethanol‐induced cardiopulmonary changes underlie progression to PAH via an upregulated proinflammatory ET1‐TNFα‐IL6 pathway and suppression of the anti‐inflammatory BMPR2. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the potential relationship between bone morphogenetic protein 7 (BMP-7) and peritoneal permeability, as well as clinical outcomes. Methods: We conducted a cross-sectional study involving 67 peritoneal dialysis (PD) patients who had been on PD for at least 1 year. We measured BMP-7 levels in both plasma and PD effluent fluid. Two peritoneal equilibration tests, the first and last ones, were compared to assess alterations in peritoneal membrane permeability. Dialysate to plasma ratio for creatinine (DPRC) was used to define membrane permeability. BMP-7 level was measured concurrently in both plasma and PD effluent. Results: Among the patients, 81% (n = 51) were on ambulatory PD, while 19% (n = 12) were on automated PD. The average PD duration was 58.9 months. Increased DPRC was determined in 61.9% of the patients. There was a positive correlation between plasma BMP-7 levels and the change in DPRC (r = 0.323, P = .004). No correlation was determined between effluent BMP-7 levels and changes in DPRC. A statistically significant negative correlation was determined between plasma BMP-7 levels and serum albumin levels (r = -0.274, P = .02). Plasma BMP-7 levels independently predicted changes in DPRC (P = .02), while effluent BMP-7 levels did not (P = .212). Conclusion: We identified a correlation between plasma BMP-7 level and changes in peritoneal membrane permeability. However, we did not find any relationship with the PD clinical outcomes. Plasma BMP-7 levels can serve as a parameter for predicting alterations in permeability. [ABSTRACT FROM AUTHOR]

BACKGROUND The placenta is a unique and pivotal organ in reproduction, controlling crucial growth and cell differentiation processes that ensure a successful pregnancy. Placental development is a tightly regulated and dynamic process, in which the transforming growth factor beta (TGFβ) superfamily plays a central role. This family of pleiotropic growth factors is heavily involved in regulating various aspects of reproductive biology, particularly in trophoblast differentiation during the first trimester of pregnancy. TGFβ signalling precisely regulates trophoblast invasion and the cell transition from cytotrophoblasts to extravillous trophoblasts, which is an epithelial-to-mesenchymal transition-like process. Later in pregnancy, TGFβ signalling ensures proper vascularization and angiogenesis in placental endothelial cells. Beyond its role in trophoblasts and endothelial cells, TGFβ signalling contributes to the polarization and function of placental and decidual macrophages by promoting maternal tolerance of the semi-allogeneic foetus. Disturbances in early placental development have been associated with several pregnancy complications, including preeclampsia (PE) which is one of the severe complications. Emerging evidence suggests that TGFβ is involved in the pathogenesis of PE, thereby offering a potential target for intervention in the human placenta. OBJECTIVE AND RATIONALE This comprehensive review aims to explore and elucidate the roles of the major members of the TGFβ superfamily, including TGFβs, bone morphogenetic proteins (BMPs), activins, inhibins, nodals, and growth differentiation factors (GDFs), in the context of placental development and function. The review focusses on their interactions within the major cell types of the placenta, namely trophoblasts, endothelial cells, and immune cells, in both normal pregnancies and pregnancies complicated by PE throughout pregnancy. SEARCH METHODS A literature search was carried out using PubMed and Google Scholar, searching terms: 'TGF signalling preeclampsia', 'pregnancy TGF signalling', 'preeclampsia tgfβ', 'preeclampsia bmp', 'preeclampsia gdf', 'preeclampsia activin', 'endoglin preeclampsia', 'endoglin pregnancy', 'tgfβ signalling pregnancy', 'bmp signalling pregnancy', 'gdf signalling pregnancy', 'activin signalling pregnancy', 'Hofbauer cell tgfβ signalling', 'placental macrophages tgfβ', 'endothelial cells tgfβ', 'endothelium tgfβ signalling', 'trophoblast invasion tgfβ signalling', 'trophoblast invasion Smad', 'trophoblast invasion bmp', 'trophoblast invasion tgfβ', 'tgfβ preeclampsia', 'tgfβ placental development', 'TGFβ placental function', 'endothelial dysfunction preeclampsia tgfβ signalling', 'vascular remodelling placenta TGFβ', 'inflammation pregnancy tgfβ', 'immune response pregnancy tgfβ', 'immune tolerance pregnancy tgfβ', 'TGFβ pregnancy NK cells', 'bmp pregnancy NK cells', 'bmp pregnancy tregs', 'tgfβ pregnancy tregs', 'TGFβ placenta NK cells', 'TGFβ placenta tregs', 'NK cells preeclampsia', 'Tregs preeclampsia'. Only articles published in English until 2023 were used. OUTCOMES A comprehensive understanding of TGFβ signalling and its role in regulating interconnected cell functions of the main placental cell types provides valuable insights into the processes essential for successful placental development and growth of the foetus during pregnancy. By orchestrating trophoblast invasion, vascularization, immune tolerance, and tissue remodelling, TGFβ ligands contribute to the proper functioning of a healthy maternal–foetal interface. However, dysregulation of TGFβ signalling has been implicated in the pathogenesis of PE, where the shallow trophoblast invasion, defective vascular remodelling, decreased uteroplacental perfusion, and endothelial cell and immune dysfunction observed in PE, are all affected by an altered TGFβ signalling. WIDER IMPLICATIONS The dysregulation of TGFβ signalling in PE has important implications for research and clinical practice. Further investigation is required to understand the underlying mechanisms, including the role of different ligands and their regulation under pathophysiological conditions, in order to discover new therapeutic targets. Distinguishing between clinically manifested subtypes of PE and studying TGFβ signalling in different placental cell types holistically is an important first step. To put this knowledge into practice, pre-clinical animal models combined with new technologies are needed. This may also lead to improved human research models and identify potential therapeutic targets, ultimately improving outcomes for affected pregnancies and reducing the burden of PE. [ABSTRACT FROM AUTHOR]