Transforming growth factor‐β1 (TGF‐β1) is a key factor in bone reconstruction. However, its pathophysiological role in non‐union and bone repair remains unclear. Here we demonstrated that TGF‐β1 was highly expressed in both C57BL/6 mice where new bone formation was impaired after autologous bone marrow mesenchymal stem cell (BMMSC) implantation in non‐union patients. High doses of TGF‐β1 inhibited BMMSC osteogenesis and attenuated bone regeneration in vivo. Furthermore, different TGF‐β1 levels exhibited opposite effects on osteogenic differentiation and bone healing. Mechanistically, low TGF‐β1 doses activated smad3, promoted their binding to bone morphogenetic protein 2 (Bmp2) promoter, and upregulated Bmp2 expression in BMMSCs. By contrast, Bmp2 transcription was inhibited by changing smad3 binding sites on its promoter at high TGF‐β1 levels. In addition, high TGF‐β1 doses increased tomoregulin‐1 (Tmeff1) levels, resulting in the repression of Bmp2 and bone formation in mice. Treatment with the TGF‐β1 inhibitor SB431542 significantly rescued BMMSC osteogenesis and accelerated bone regeneration. Our study suggests that high‐dose TGF‐β1 dampens BMMSC‐mediated bone regeneration by activating canonical TGF‐β/smad3 signaling and inhibiting Bmp2 via direct and indirect mechanisms. These data collectively show a previously unrecognized mechanism of TGF‐β1 in bone repair, and TGF‐β1 is an effective therapeutic target for treating bone regeneration disability. © 2019 American Society for Bone and Mineral Research.
MicroRNAs play important roles in osteoporosis and show great potential for diagnosis and therapy of osteoporosis. Previous studies have demonstrated that miR‐146a affects osteoblast (OB) and osteoclast (OC) formation. However, these findings have yet to be identified in vivo, and it is unclear whether miR‐146a is related to postmenopausal osteoporosis. Here, we demonstrated that miR‐146a knockout protects bone loss in mouse model of estrogen‐deficient osteoporosis, and miR‐146a inhibits OB and OC activities in vitro and in vivo. MiR‐146a−/− mice displayed the same bone mass as the wild type (WT) but exhibited a stronger bone turnover than the WT did under normal conditions. Nevertheless, miR‐146a−/− mice showed an increase in bone mass after undergoing ovariectomy (OVX) compared with those subjected to sham operation. OC activities were impaired in the miR‐146a−/− mice exposed to estrogen deficiency, which was diametrically opposite to the enhanced bone resorption ability of WT. Macrophage colony‐stimulating factor (M‐CSF) and receptor activator of NF‐κB ligand (RANKL)/osteoprotegerin (OPG) from a bone microenvironment affect this extraordinary phenomenon. Therefore, our results implicate that miR‐146a plays a key role in estrogen deficiency–induced osteoporosis, and the inhibition of this molecule provides skeleton protection. © 2019 American Society for Bone and Mineral Research.
Long noncoding RNAs (lncRNAs) have emerged as key regulators of cell differentiation and development. However, potential roles for lncRNAs in chondrogenic differentiation have remained poorly understood. Here we identify lncRNA ADAMTS9 antisense RNA 2, ADAMTS9-AS2, which controls the chondrogenic differentiation by acting as a competing endogenous RNA (ceRNA) in human mesenchymal stem cells (hMSCs). We screen out ADAMTS9-AS2 of undifferentiated and differentiated cells during chondrogenic differentiation by microarrays. Suppression or overexpression of lncRNA ADAMTS9-AS2 correlates with inhibition and promotion of hMSC chondrogenic differentiation, respectively. We find that ADAMTS9-AS2 can sponge miR-942-5p to regulate the expression of Scrg1, a transcription factor promoting chondrogenic gene expression. Finally, we confirm the function of ADAMTS9-AS2 to cartilage repair in the absence of transforming growth factor β (TGF-β) in vivo. In conclusion, ADAMTS9-AS2 plays an important role in chondrogenic differentiation as a ceRNA, so that it can be regarded as a therapy target for cartilage repair.
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