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High‐Dose TGF‐β1 Impairs Mesenchymal Stem Cell–Mediated Bone Regeneration via Bmp2 Inhibition
Author(s) -
Xu Jiajia,
Liu Jinlong,
Gan Yaokai,
Dai Kerong,
Zhao Jingyu,
Huang Mingjian,
Huang Yan,
Zhuang Yifu,
Zhang Xiaoling
Publication year - 2020
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.3871
Subject(s) - bone morphogenetic protein 2 , mesenchymal stem cell , transforming growth factor , bone morphogenetic protein 7 , bone morphogenetic protein , microbiology and biotechnology , transforming growth factor beta , regeneration (biology) , bone healing , stem cell , endocrinology , medicine , cancer research , chemistry , biology , anatomy , in vitro , biochemistry , gene
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.