EPC-derived exosomes promote osteoclastogenesis through LncRNA-MALAT1

Abstract

Bone repair involves bone resorption through osteoclastogenesis and the stimulation of neovascularization and osteogenesis by endothelial progenitor cells (EPCs). However, the role of EPCs 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 (BMMs) 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 BMMs in a mouse bone fracture model in vivo. We found that EPCs cultured with BMMs secreted exosomes into the medium and, compared with EPCs, exosomes had a higher expression level of LncRNA-MALAT1. We confirmed that LncRNA-MALAT1 directly binds to miR-124 to negatively control miR-124 activity. Moreover, overexpression of miR-124 could reverse the migration and osteoclastic differentiation of BMMs induced by EPC-derived exosomes. A dual-luciferase reporter assay indicated that the integrin ITGB1 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 BMMs alone. Overall, our results suggest that EPC-derived exosomes can promote bone repair by enhancing recruitment and differentiation of osteoclast precursors through LncRNA-MALAT1.

Keywords: ITGB1; LncRNA-MALAT1; bone marrow-derived macrophages; bone repair; endothelial progenitor cells; miR-124; osteoclastogenesis.