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Osteoporotic fractures, also known as fragility fractures, are prevalent in the elderly and bring tremendous social burdens. Poor bone quality, weak repair capacity, instability, and high failure rate of internal fixation are main characteristics of osteoporotic fractures. Osteoporotic bone defects are common and need to be repaired by appropriate materials. Proximal humerus, distal radius, tibia plateau, calcaneus, and spine are common osteoporotic fractures with bone defect. Here, the consensus from the Osteoporosis Group of Chinese Orthopaedic Association concentrates on the epidemiology, characters, and management strategies of common osteoporotic fractures with bone defect to standardize clinical practice in bone repair of osteoporotic fractures. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a degenerative joint disease in the elderly. Although OA has been considered as primarily a disease of the articular cartilage, the participation of subchondral bone in the pathogenesis of OA has attracted increasing attention. This review summarises the microstructural and histopathological changes in subchondral bone during OA progression that are due, at the cellular level, to changes in the interactions among osteocytes, osteoblasts, osteoclasts (OCs), endothelial cells and sensory neurons. Therefore, we focus on how pathological cellular interactions in the subchondral bone microenvironment promote subchondral bone destruction at different stages of OA progression. In addition, the limited amount of research on the communication between OCs in subchondral bone and chondrocytes (CCs) in articular cartilage during OA progression is reviewed. We propose the concept of 'OC-CC crosstalk' and describe the various pathways by which the two cell types might interact. Based on the 'OC-CC crosstalk', we elaborate potential therapeutic strategies for the treatment of OA, including restoring abnormal subchondral bone remodelling and blocking the bridge-subchondral type H vessels. Finally, the review summarises the current understanding of how the subchondral bone microenvironment is related to OA pain and describes potential interventions to reduce OA pain by targeting the subchondral bone microenvironment. [ABSTRACT FROM AUTHOR]

The invasion of osteoclasts into the cartilage via blood vessels advances the process of endochondral ossification, and dysregulation of dynamic intercellular interactions results in skeletal dysplasias. Although the regulation of osteoclasts by growth plate chondrocytes has been reported in detail, the effect of osteoclasts on chondrocytes remains to be determined. In this study, ATDC5 cells and bone marrow mesenchymal stem cells were differentiated into chondrocytes and treated with conditioned medium obtained from bone marrow macrophages differentiated to osteoclast precursors and osteoclasts. Exosomes were inhibited in conditioned medium or isolated directly from osteoclasts to further determine whether osteoclast-derived exosomes play an important role in chondrocyte hypertrophy. Additionally, exosomal miRNAs were detected, and let-7a-5p was selected as an miRNA with significantly increased expression in osteoclast-derived exosomes. Experiments were performed to verify the potential target Smad2 and investigate how let-7a-5p affected chondrocytes. The results suggest that both osteoclast precursors and osteoclasts promote chondrocyte hypertrophy and that the promotive effect of osteoclasts is more significant than that of osteoclast precursors. Osteoclast-derived exosomes promote the hypertrophic differentiation of chondrocytes. Moreover, osteoclast-derived exosomal let-7a-5p inhibits Smad2 to decrease the transforming growth factor-β-induced inhibition of chondrocyte hypertrophy. Our research reveals the role of osteoclasts in the regulation of chondrocytes and provides insights into the highly coordinated intercellular process of endochondral ossification. [ABSTRACT FROM AUTHOR]

Background: The recruitment of a sufficient number of endogenous mesenchymal stem cells (MSCs) is the first stage of in-situ tissue regeneration. Transforming growth factor beta-3 (TGFβ3) could recruit stem or progenitor cells and endothelial cells to participate in tissue regeneration. However, the mechanism of TGFβ3 recruiting MSCs toward bone regeneration has remained obscure. Methods: We estimated the promigratory property of TGFβ3 on human bone marrow MSCs (hBMSCs) cocultured with the vascular cells (human umbilical artery smooth muscle cells or human umbilical vein endothelial cells) or not by Transwell assay. After the addition of the inhibitor (SB431542) or Smad3 siRNA, the levels of MCP1 and SDF1 in coculture medium were tested by ELISA kit, and then the migratory signaling pathway of hBMSCs induced by TGFβ3 was investigated by western blot analysis. In vivo, a 2-mm FVB/N mouse femur defect model was used to evaluate chemokine secretion, endogenous cell homing, and bone regeneration induced by scaffolds loading 1 μg TGFβ3 through qPCR, immunofluorescent staining, immunohistochemical analysis, and Micro-CT, compared to the vehicle group. Results: TGFβ3 (25 ng/ml) directly showed a nearly 40% increase in migrated hBMSCs via the TGFβ signaling pathway, compared to the vehicle treatment. Then, in the coculture system of hBMSCs and vascular cells, TGFβ3 further upregulated nearly 3-fold MCP1 secretion from vascular cells in a Smad3-dependent manner, to indirectly enhance nearly more than 50% of migrated hBMSCs. In vivo, TGFβ3 delivery improved MCP1 expression by nearly 7.9-fold, recruited approximately 2.0-fold CD31+ vascular cells and 2.0-fold Sca-1+ PDGFR-α+ MSCs, and achieved 2.5-fold bone volume fraction (BV/TV) and 2.0-fold bone mineral density, relative to TGFβ3-free delivery. Conclusions: TGFβ3, as a MSC homing molecule, recruited MSCs to initiate bone formation in the direct-dependent and indirect-dependent mechanisms. This may shed light on the improvement of MSC homing in bone regeneration. [ABSTRACT FROM AUTHOR]

Chondrocyte hypertrophy is a physiological process in endochondral ossification. However, the hypertrophic‑like alterations of chondrocytes at the articular surface may result in osteoarthritis (OA). In addition, the generation of fibrocartilage with a decreased biological function in tissue engineered cartilage, has been attributed to chondrocyte hypertrophy. Therefore, suppressing chondrocyte hypertrophy in OA and the associated regeneration of non‑active cartilage is of primary concern. The present study examined the effects of xanthotoxin (XAT), which is classified as a furanocoumarin, on chondrocyte hypertrophic differentiation of mesenchymal stem cells. Following XAT treatment, the expression levels of genes associated with chondrocyte hypertrophy were detected via immunohistochemistry, western blotting and reverse transcription‑quantitative polymerase chain reaction. The results revealed that XAT inhibited the expression of various chondrocyte hypertrophic markers, including runt related transcription factor 2 (Runx2), matrix metalloproteinase 13 and collagen type X α1 chain. Further exploration indicated that XAT reduced the activation of p38‑mitogen activated protein kinase and then increased the expression of histone deacetylase 4 to suppress Runx2. The findings indicated that XAT maintained the chondrocyte phenotype in regenerated cartilage and therefore may exhibit promise as a potential drug for the treatment of OA in the future. [ABSTRACT FROM AUTHOR]

The healthy skeleton requires a perfect coordination of the formation and degradation of bone. Metabolic bone disease like osteoporosis is resulted from the imbalance of bone formation and/or bone resorption. Osteoporosis also reflects lower level of bone matrix, which is contributed by up-regulated osteoclast-mediated bone resorption. It is reported that monocytes/macrophage progenitor cells or either hematopoietic stem cells (HSCs) gave rise to multinucleated osteoclasts. Thus, inhibition of osteoclastic bone resorption generally seems to be a predominant therapy for treating osteoporosis. Recently, more and more natural compounds have been discovered, which have the ability of inhibiting osteoclast differentiation and fusion. Alliin (S-allyl-L-cysteine sulfoxides, SACSO) is the major component of aged garlic extract (AGE), bearing broad-spectrum natural antioxidant properties. However, its effects on bone health have not yet been explored. Hence, we designed the current study to explore its effects and role in receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast fusion and differentiation. It was revealed that alliin had an inhibitory effect in osteoclasteogenesis with a dose-dependent manner via blocking the c-Fos-NFATc1 signaling pathway. In addition, alliin decreased the generation of reactive oxygen species (ROS) and down-regulated the expression of NADPH oxidase 1 (Nox1). The overall results revealed that alliin could be a potential therapeutic agent in the treatment of osteoporosis. [ABSTRACT FROM AUTHOR]

The bone-resorbing osteoclast (OC) is essential for bone homeostasis, yet deregulation of OCs contributes to diseases such as osteoporosis, osteopetrosis, and rheumatoid arthritis. Here we show that histone deacetylase 2 (HDAC2) is a key positive regulator during receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis and bone resorption. Bone marrow macrophages (BMMs) showed increased HDAC2 expression during osteoclastogenesis. HDAC2 overexpression enhanced, whereas HDAC2 deletion suppressed osteoclastogenesis and bone resorption using lentivirus infection. Mechanistically, upon RANKL activation, HDAC2 activated Akt; Akt directly phosphorylates and abrogates Forkhead box protein O1 (FoxO1), which is a negative regulator during osteoclastogenesis through reducing reactive oxygen species. HDAC2 deletion in BMMs resulted in decreased Akt activation and increased FoxO1 activity during osteoclastogenesis. In conclusion, HDAC2 activates Akt thus suppresses FoxO1 transcription results in enhanced osteoclastogenesis. Our data imply the potential value of HDAC2 as a new target in regulating osteoclast differentiation and function. [ABSTRACT FROM AUTHOR]

Cordycepin was previously reported to have anti-tumor, anti-inflammatory and anti-oxidant activity. However, the potential role of cordycepin in bone metabolism and cell biology of osteoclasts remains unclear. In our study, we focused on the in vitro effects of cordycepin on osteoclastogenesis and its in vivo effects in ovariectomized (OVX) mice. Osteoclast differentiation, formation and fusion were evaluated by Tartrate-resistant acid phosphatase (TRAP) stain, focal adhesion stain and fusion assay, respectively. Osteoclastic bone resorption was evaluated by pit formation assay. Reactive oxygen species (ROS) generation and removal were detected by the ROS assay. OVX mice were orally administered with 10 mg/kg of cordycepin daily for four weeks. In vitro results revealed that cordycepin inhibited receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation, formation, fusion and bone resorption activity. We further proved that cordycepin treatments scavenged the generation of ROS, upregulated interferon regulatory factor 8 (IRF-8) and suppressed the activity of nuclear factor of activated T cells c1 (NFATc1) during osteoclastogenesis. In vivo results indicated cordycepin prevents bone loss, rescues bone microarchitecture, and restores bone mineralization in OVX mice. Our observations strongly suggested that cordycepin is an efficient osteoclast inhibitor and hold potential therapeutic value in preventing bone loss among postmenopausal osteoporosis patients. [ABSTRACT FROM AUTHOR]

Completely repairing of damaged cartilage is a difficult procedure. In recent years, the use of tissue engineering approach in which scaffolds play a vital role to regenerate cartilage has become a new research field. Investigating the advances in biological cartilage scaffolds has been regarded as the main research direction and has great significance for the construction of artificial cartilage. Native biological materials and synthetic polymeric materials have their advantages and disadvantages. The disadvantages can be overcome through either physical modification or biochemical modification. Additionally, developing composite materials, biomimetic materials, and nanomaterials can make scaffolds acquire better biocompatibility and mechanical adaptability. [ABSTRACT FROM AUTHOR]

Chondrogenic differentiation of mesenchymal stem cells (MSCs) is accurately regulated by essential transcription factors and signaling cascades. However, the precise mechanisms involved in this process still remain to be defined. MicroRNAs (miRNAs) regulate various biological processes by binding target mRNA to attenuate protein synthesis. To investigate the mechanisms for miRNAs-mediated regulation of chondrogenic differentiation, we identified that miR-145 was decreased during transforming growth factor beta 3 (TGF-&bgr;3)-induced chondrogenic differentiation of murine MSCs. Subsequently, dual-luciferase reporter gene assay data demonstrated that miR-145 targets a putative binding site in the 39-UTR of SRYrelated high mobility group-Box gene 9 (Sox9) gene, the key transcription factor for chondrogenesis. In addition, overexpression of miR-145 decreased expression of Sox9 only at protein levels and miR-145 inhibition significantly elevated Sox9 protein levels. Furthermore, over-expression of miR-145 decreased mRNA levels for three chondrogenic marker genes, type II collagen (Col2a1), aggrecan (Agc1), cartilage oligomeric matrix protein (COMP), type IX collagen (Col9a2) and type XI collagen (Col11a1) in C3H10T1/2 cells induced by TGF-b3, whereas anti-miR-145 inhibitor increased the expression of these chondrogenic marker genes. Thus, our studies demonstrated that miR-145 is a key negative regulator of chondrogenic differentiation by directly targeting Sox9 at early stage of chondrogenic differentiation. [ABSTRACT FROM AUTHOR]

Interstitial cells of Cajal (ICCs) in gastrointestinal tract are specialized cells serving as pacemaker cells. The origin of ICCs is currently not fully characterized. In this work, we aimed to study whether bone marrow-derived cells (BMDCs) could contribute to the origin of ICCs in the muscular plexus of small intestine using GFP-C57BL/6 chimeric mice.Engraftment of BMDCs in the intestine was investigated for GFP expression. GFP positive bone marrow mononuclear cells reached a proportion of 95.65%±3.72% at different times in chimerism. Donor-derived cells distributed widely in all the layers of the gastrointestinal tract. There were GFP positive BMDCs in the myenteric plexus, which resembled characteristics of ICCs, including myenteric location, c-Kit positive staining, and ramifiedmorphology. Donor-derived ICCs in themyenteric plexus contributed to a percentage ranging 9.25% ± 4.9% of all the ICCs in the myenteric plexus. In conclusion, here we described that donor-derived BMDCs might differentiate into gastrointestinal ICCs after radiation injury, which provided an alternative source for the origin of the ICCs in the muscular plexus of adult intestine. These results further identified the plasticity of BMDCs and indicated therapeutic implications of BMDCs for the gastrointestinal dysmotility caused by ICCs disorders. [ABSTRACT FROM AUTHOR]

The article presents a study which evaluates the effect of a novel recombinant protein of fibronectin III7-10/cadherin 11 Extracellular cadherin (EC) 1-2 (rFN/CDH) on cell adhesion and differentiation. It demonstrates that rFN/CDH has improved the performance of the two osoteogenic markers such as the osteocalcin messenger RNA expression and alkaline phosphatase activity. It suggests that rFN/CDH can process an enhanced dual biofunctionality in osteoblastic adhesion and differentiation.

Bone marrow mesenchymal stem cells (MSCs) are ideal target cells for cell transplantation and tissue engineering. We investigated their biological characteristics and differentiation mediated by different methods. It is important to study the short-term fate of labeled allogeneic MSCs after subcutaneous implantation in rabbits in order to provide insights into the application of allogeneic MSCs for tissue regeneration. Mesenchymal stem cells were labeled by two different methods in vitro and then were incubated with gelatin sponge. Autologous MSCs-Gelatin constructs and allogeneic MSCs-Gelatin constructs were subcutaneously implanted into 32 rabbits. The constructs were analyzed for the survival and migration of labeled MSCs at day 3, week 1, 3, and 5 post-implantation. EGFP was successfully expressed following transfection of MSCs with the retroviral vector pLEGFP-N1. In addition, EGFP-MSCs can be functionally induced into osteocytes, chondrocytes, and adipocytes in conditioned media. By weeks 3 after implantation, the labeled cells distributed extensively on the surface of gelatin sponge and gradually integrated into host tissues. EGFP-labeled MSCs were observed under fluorescence microscopy and BrdU-expressing cells were detected with immunohistochemical stain in allogeneic or autologous MSCs-Gelatin constructs during the initial five weeks after implantation. It is a simple and reliable way to trace the changes of MSCs in vivo by EGFP in cell transplantation and gene therapy. Allogeneic rabbit MSCs can survive for at least 5 weeks after subcutaneous implantation and maintain a strong ability of migration, indicating that allogeneic MSCs are of certain value in clinical application for temporary replacement. [ABSTRACT FROM AUTHOR]