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Excess glucocorticoid administration impairs osteogenic activities, which raises the risk of osteoporotic disorders. Epigenetic methylation of DNA and histone regulates the lineage commitment of progenitor cells. This study was undertaken to delineate the actions of histone lysine demethylase 6a (UTX) with regard to the glucocorticoid impediment of osteogenic differentiation. Osteogenic progenitor cells responded to supraphysiological glucocorticoid by elevating CpG dinucleotide methylation proximal to transcription start sites within Runx2 and osterix promoters and Wnt inhibitor Dickkopf-1 (Dkk1) expression concomitant with low UTX expression. 5′-Aza-deoxycystidine demethylation of Runx2 and osterix promoters abolished the glucocorticoid inhibition of mineralized matrix accumulation. Gain of UTX function attenuated the glucocorticoid-induced loss of osteogenic differentiation, whereas UTX silencing escalated adipogenic gene expression and adipocyte formation. UTX sustained osteogenic gene transcription through maintaining its occupancy to Runx2 and osterix promoters. It also mitigated the trimethylation of histone 3 at lysine 27 (H3K27me3), which reduced H3K27me3 enrichment to Dkk1 promoter and thereby lowered Dkk1 transcription. Modulation of β-catenin and Dkk1 actions restored UTX signaling in glucocorticoid-stressed cells. In vivo, UTX inhibition by exogenous methylprednisolone and GSK-J4 administration, an effect that disturbed H3K27me3, β-catenin, Dkk1, Runx2, and osterix levels, exacerbated trabecular microarchitecture loss and marrow adiposity. Taken together, glucocorticoid reduction of UTX function hindered osteogenic differentiation. Epigenetic hypomethylation of osteogenic transcription factor promoters and H3K27 contributed to the UXT alleviation of Dkk1 transcription and osteogenesis in glucocorticoid-stressed osteogenic progenitor cells. Control of UTX action has an epigenetic perspective of curtailing glucocorticoid impairment of osteogenic differentiation and bone mass. Key messages: [ABSTRACT FROM AUTHOR]

Purpose: MicroRNAs (miRNAs) are associated with various pathologic conditions and can serve as diagnostic or therapeutic biomarkers. This study tried to identify the differentially expressed miRNAs to predict the possible pathomechanisms involved in osteonecrosis of the femoral head (ONFH).Methods: We compared the peripheral blood miRNAs in 46 patients with ONFH and 85 healthy controls by microarray and droplet digital polymerase chain reaction (ddPCR). Putative interacted networks between the differentially responded miRNAs were analyzed by web-based bioinformatics prediction tools.Results: Microarray identified 51 differentially expressed miRNAs with at least twofold change (upregulation in 34 and downregulation in 17), and the results were validated by ddPCR using six selected miRNAs. Bioinformatics genetic network analysis focusing on the six miRNAs found the upregulated miR-18a and miR-19a are associated with angiogenesis after induction of ischemia; the upregulated miR-138-1 can inhibit osteogenic differentiation of mesenchymal stem cells; the most targeted genes, p53 and SERBP1, are associated with hypoxia and hypofibrinolysis.Conclusions: This study combined the miRNA analysis with the bioinformatics and predicts that hypoxia, inhibited osteogenesis of stem cells, and dysregulated angiogenesis might be orchestrated through the miRNA interacting circuits in the pathogenesis of ONFH. [ABSTRACT FROM AUTHOR]

Subchondral bone deterioration and osteophyte formation attributable to excessive mineralization are prominent features of end-stage knee osteoarthritis (OA). The cellular events underlying subchondral integrity diminishment remained elusive. This study was undertaken to characterize subchondral mesenchymal stem cells (SMSCs) isolated from patients with end-stage knee OA who required total knee arthroplasty. The SMSCs expressed surface antigens CD29, CD44, CD73, CD90, CD105, and CD166 and lacked CD31, CD45, and MHCII expression. The cell cultures exhibited higher proliferation and greater osteogenesis and chondrogenesis potencies, whereas their population-doubling time and adipogenic lineage commitment were lower than those of bone marrow MSCs (BMMSCs). They also displayed higher expressions of embryonic stem cell marker OCT3/4 and osteogenic factors Wnt3a, β-catenin, and microRNA-29a (miR-29a), concomitant with lower expressions of joint-deleterious factors HDAC4, TGF-β1, IL-1β, TNF-α, and MMP3, in comparison with those of BMMSCs. Knockdown of miR-29a lowered Wnt3a expression and osteogenic differentiation of the SMSCs through elevating HDAC4 translation, which directly regulated the 3′-untranslated region of HDAC4. Likewise, transgenic mice that overexpressed miR-29a in osteoblasts exhibited a high bone mass in the subchondral region. SMSCs in the transgenic mice showed a higher osteogenic differentiation and lower HDAC4 signaling than those in wild-type mice. Taken together, high osteogenesis potency existed in the SMSCs in the osteoarthritic knee. The miR-29a modulation of HDAC4 and Wnt3a signaling was attributable to the increase in osteogenesis. This study shed an emerging light on the characteristics of SMSCs and highlighted the contribution of SMSCs in the exacerbation of subchondral integrity in end-stage knee OA. Key messages: [ABSTRACT FROM AUTHOR]

Articular cartilage integrity loss is a prominently deleterious feature of osteoarthritis (OA). The mechanistic underlying the development of OA warrants characterization. Heat shock proteins (HSPs), members of the chaperone family, reportedly orchestrate tissue homeostasis and remodeling in response to detrimental stress. This study was undertaken to characterize the biological role of HSP60 in the pathogenesis of OA knee. Articular specimens from OA knee patients displayed severe articular damage histopathology concomitant with low HSP60 concentrations in cartilage and synovial fluid compared to non-OA patients. In vitro, a gain of HSP60 signaling counteracted the IL-1β-mediated suppression of mitochondrial biogenesis, chondrogenic transcription factor SOX9, and cartilage matrix expression of human chondrocytes cultures. Transgenic mice that overexpressed human HSP60 (TgHSP60) had higher chondrocyte proliferation and thicker articular cartilage than wild-type mice. In collagenase-induced OA knees, analyses of CatWalk, 2-deoxyglucose-probed fluorescence imaging, and μCT revealed that affected knees of TgHSP60 mice showed minor footprint irregularity, joint inflammation, and osteophyte formation. HSP60 overexpression also alleviated the histopathology of cartilage damage, synovial hypervascularization, and macrophage infiltration within joint lesions. Intra-articular administration of exogenous HSP60 ameliorated the pathogenesis of cartilage deterioration, synovitis, and osteophyte accumulation, thereby improving gait profiles of the collagenase-injured knees. HSP60 signaling maintains SOX9 levels by attenuating SOX9 hyper-ubiquitination of affected joints. Taken together, HSP60 deficiency in articular compartments was relevant to OA knee incidence. Sustained HSP60 signaling is favorable to mitigate the progression of OA. This study highlights the joint-anabolic actions of HSP60 and provides perspective on its therapeutic potential for OA. Key messages: [ABSTRACT FROM AUTHOR]

Intensive fibrosis in the glomerular microenvironment is a prominent feature of diabetic nephropathy. Cannabinoid receptor 1 (CB1R) reportedly mediates diabetes-induced renal injury. However, studies on the molecular events underlying CB1R promotion of renal dysfunction are limited. This study is undertaken to investigate whether CB1R signaling via Ras or PPARγ pathway regulates mesangial fibrosis in diabetic kidneys. In streptozotocin-induced diabetic rats, hyperglycemia induced glomerular hypertrophy and fibrosis in association with increased IL-1β, fibronectin, and CB1R expressions and reduced PPARγ2 signaling. CB1R transgenic mice gained kidney weight, and renal glomeruli strongly displayed IL-1β and fibrotic matrices. Disruption of CB1R by antisense oligonucleotides or inverse agonist AM251 restored PPARγ2 signaling and reduced the promotional effects of hyperglycemia on the expression of fibrogenic transcription factor c-Jun, inflammation regulator SOCS3, proinflammatory cytokines, and accumulation of fibrotic matrix. PPARγ agonist rosiglitazone reduced the hyperglycemia-mediated enhancement of CB1R signaling, inflammation, and glomerular fibrosis in diabetic animals. In vitro, CB1R antagonism restored PPARγ2 action and reduced the promotional effects of high glucose on Ras, ERK, c-Jun, SOCS3 signaling, IL-1β, and fibronectin expression in renal mesangial cells. Activation of PPARγ2 reduced the high glucose-induced CB1R expression in mesangial cells. Taken together, CB1R signaling contributes to the hyperglycemia disturbance of PPARγ2 signaling and increases inflammatory cytokine secretion and fibrotic matrix deposition in renal glomeruli. CB1R mediates the hyperglycemia-induced inflammation and fibrosis in mesangial cells by regulating Ras, ERK, and PPARγ2 signaling. CB1R blockade has a therapeutic potential to reduce the deleterious actions of hyperglycemia on renal glomerular integrity. Key message: [ABSTRACT FROM AUTHOR]

Purpose: This study investigated the effects of extracorporeal shockwave therapy (ESWT) on the subchondral bone and articular cartilage in the initiation of osteoarthritis of the knee in rats. Methods: Anterior cruciate ligament transected (ACLT) osteoarthritis (OA) rat knee model was used in this study. Twenty-seven male Sprague-Dawley rats were divided into three groups. The control group underwent sham surgery without ACLT and received no ESWT. The ACLT group underwent ACLT, but received no ESWT. The ACLT plus ESWT group underwent ACLT and received ESWT immediately after surgery. The evaluation parameters included radiograph, bone mineral density, serum levels of cartilage oligometric protein and osteocalcin, and urinary concentration of C-telopeptide of type II collagen (CTX-II), and histomorphological examination. Results: At 12 weeks, OA of the knee was radiographically verified in the ACLT group, but very subtle changes were noticed in the control and the ACLT plus ESWT groups. On articular cartilage, the ACLT group showed significant increases in cartilage degradation and chondrocyte apoptosis compared to the control and ACLT plus ESWT groups. The ACLT plus ESWT group demonstrated significant decrease in the cartilage degradation and an increase in chondrocyte activity comparable to the control. In subchondral bone, the ACLT group showed a significant decrease in bone remodeling as compared to the control and ACLT plus ESWT groups. The ACLT plus ESWT group showed significant improvement in bone remodeling comparable to the control. Conclusion: Extracorporeal shockwave therapy shows chondroprotective effect associated with improvement in subchondral bone remodeling in the initiation of ACLT OA knee model in rats. [ABSTRACT FROM AUTHOR]

The median overall survival (OS) of some head and neck malignancies, such as head and neck squamous cell carcinoma (HNSCC), with metastatic lesions was only 12 months. Whether aggressive pulmonary metastasectomy (PM) improves survival is controversial. Patients with primary head and neck malignancy undergoing PM were enrolled. Clinical outcomes were compared among different histological types. Whole-exome sequencing was used for matched pulmonary metastatic samples. The genes where genetic variants have been identified were sent for analysis by DAVID, IPA, and STRING. Forty-nine patients with primary head and neck malignancies were enrolled. Two-year postmetastasectomy survival (PMS) rates of adenoid cystic carcinoma, thyroid carcinoma, nasopharyngeal carcinoma, and HNSCC were 100%, 88.2%, 71.4%, and 59.2%, respectively (P = 0.024). In HNSCC, the time to distant metastasis was an independent predictive factor of the efficacy of PM. Several pathways, such as branched-chain amino acid (BCAA) consumption, were significantly associated with the progression of HNSCC [P < 0.001, fold enrichment (FE) = 5.45]. Moreover, metabolism-associated signaling pathways also seemed to be involved in cancer metastasis. Histological types and time to distant metastasis were important factors influencing the clinical outcomes of PM. For HNSCC, metabolic-associated signaling pathways were significantly associated with tumor progression and distant metastasis. Future validations are warranted. [ABSTRACT FROM AUTHOR]