A C-Met chemical inhibitor promotes fracture healing through interacting with osteogenic differentiation via the mTORC1 pathway

C-Met 化学抑制剂通过 mTORC1 通路与成骨分化相互作用促进骨折愈合

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作者:Rongliang Wang, Xingquan Xu, Yixuan Li, Jiawei Li, Chen Yao, Rui Wu, Qing Jiang, Dongquan Shi

Abstract

Currently, HGF/C-Met signaling inhibitors are being investigated to determine if they are useful for enhancing progenitor cell differentiation into osteoblasts, and one of them, BMS-777607, has been utilized to treat osteoporosis and bone loss in several types of diseases. However, whether BMS-777607 could be a potential treatment during fracture healing remains elusive. Here, we examined the therapeutic effects of BMS-777607 on bone fracture healing in a mouse model. In vivo radiological analysis showed that fractures treated with BMS-777607 exhibited accelerated osteotylus formation during the early stage of bone healing. Thereafter, the Safranin O staining evaluation indicated that the structure of the external callus in the Treatment group was larger than that in the Vehicle group at week 2. Furthermore, cellular proliferation of MC3T3-E1 was not significantly affected by low concentrations of BMS-777607. In addition, stimulation of osteoblast differentiation and mineralization was a result of BMS-777607 inducing the expression of Runx2 and Col1, and this osteogenic ability, at least in part, was mediated through the mammalian target of rapamycin complex 1 (mTORC1) signaling in vitro. Conclusively, BMS-777607 has been identified as a therapeutic agent to improve bone formation during fracture healing, and its osteogenic effects on osteoblast differentiation were mediated via the mTORC1 signaling pathway.

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