Journal
JOURNAL OF BONE AND MINERAL RESEARCH
Volume 35, Issue 1, Pages 167-180Publisher
WILEY
DOI: 10.1002/jbmr.3871
Keywords
BMP2; BONE REGENERATION; MESENCHYMAL STEM CELLS; OSTEOGENESIS; TGF-beta 1; TMEFF1; TRANSCRIPTION
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Funding
- National Natural Science Foundation of China [81772347, 81572123]
- Science and Technology Commission of Shanghai Municipality [15411951100, 16430723500]
- Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support [20161314]
- Shanghai Shen Kang hospital development center [16CR2036B]
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Transforming growth factor-beta 1 (TGF-beta 1) is a key factor in bone reconstruction. However, its pathophysiological role in non-union and bone repair remains unclear. Here we demonstrated that TGF-beta 1 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-beta 1 inhibited BMMSC osteogenesis and attenuated bone regeneration in vivo. Furthermore, different TGF-beta 1 levels exhibited opposite effects on osteogenic differentiation and bone healing. Mechanistically, low TGF-beta 1 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-beta 1 levels. In addition, high TGF-beta 1 doses increased tomoregulin-1 (Tmeff1) levels, resulting in the repression of Bmp2 and bone formation in mice. Treatment with the TGF-beta 1 inhibitor SB431542 significantly rescued BMMSC osteogenesis and accelerated bone regeneration. Our study suggests that high-dose TGF-beta 1 dampens BMMSC-mediated bone regeneration by activating canonical TGF-beta/smad3 signaling and inhibiting Bmp2 via direct and indirect mechanisms. These data collectively show a previously unrecognized mechanism of TGF-beta 1 in bone repair, and TGF-beta 1 is an effective therapeutic target for treating bone regeneration disability. (c) 2019 American Society for Bone and Mineral Research.
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