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.
Keywords: BMS-777607; C-Met inhibitor; Fracture healing; Osteoblast differentiation; mTORC1.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.