Bone repair involves bone resorption through osteoclastogenesis and the stimulation of neovascularization and osteogenesis by endothelial progenitor cells ( EPC s). However, the role of EPC s in osteoclastogenesis is unclear. In this study, we assess the effects of EPC ‐derived exosomes on the migration and osteoclastic differentiation of primary mouse bone marrow‐derived macrophages ( BMM s) in vitro using immunofluorescence, western blotting, RT ‐ PCR and Transwell assays. We also evaluated the effects of EPC ‐derived exosomes on the homing and osteoclastic differentiation of transplanted BMM s in a mouse bone fracture model in vivo. We found that EPC s cultured with BMM s secreted exosomes into the medium and, compared with EPC s, exosomes had a higher expression level of Lnc RNA ‐ MALAT 1. We confirmed that Lnc RNA ‐ MALAT 1 directly binds to miR‐124 to negatively control miR‐124 activity. Moreover, overexpression of miR‐124 could reverse the migration and osteoclastic differentiation of BMM s induced by EPC ‐derived exosomes. A dual‐luciferase reporter assay indicated that the integrin ITGB 1 is the target of miR‐124. Mice treated with EPC ‐derived exosome‐ BMM co‐transplantations exhibited increased neovascularization at the fracture site and enhanced fracture healing compared with those treated with BMM s alone. Overall, our results suggest that EPC ‐derived exosomes can promote bone repair by enhancing recruitment and differentiation of osteoclast precursors through Lnc RNA ‐ MALAT 1.
Background/Aims: Bone resorption mediated by osteoclasts plays an important role in bone healing. Endothelial progenitor cells (EPCs) promote bone repair by stimulating neovascularization and osteogenesis. However, the role of EPCs in osteoclast formation and function is not well defined. The aim of this study was to elucidate mechanisms of EPCs in osteoclast formation and function. Methods: In this study, we examined the effects of EPCs on the proliferation, migration and osteoclastic differentiation of primary mouse bone marrow-derived macrophages (BMMs) in a co-culture system in vitro. We also evaluated the effects of EPC co-transplantation on the homing and osteoclastic differentiation of transplanted BMMs in a mouse bone fracture model in vivo. The technology of immunofluorescence, immunohistochemical, western blot, Rt-PCR, cell co-culture and Transwell were used in this study. Results: EPCs secreted TGF-β1 in the EPC-BMM co-culture medium and increased Talin-1 expression in the co-cultured BMMs. Treatment with a TGF-β1 neutralizing antibody or Talin-1 silencing in BMMs completely inhibited BMM osteoclastic differentiation in the co-culture system. These results indicated that the osteoclastogenic effects of EPCs were mediated by TGF-β1-mediated Talin-1 expression in BMMs. In the femur fracture model, BMMs co-transplanted with EPCs exhibited enhanced engraftment into the fracture site and osteoclastic differentiation compared with those transplanted alone. Mice treated with EPC-BMM co-transplantation exhibited increased neovascularization at the fracture site and accelerated fracture healing compared with those treated with BMMs alone. Conclusion: Taken together, the results suggest that EPCs can promote bone repair by enhancing recruitment and differentiation of osteoclast precursors.
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