Mechanism of EC-EXOs-Derived THBS3 Targeting CD47 to Regulate BMSCs Differentiation to Ameliorate Bone Loss

Abstract

With the continuous increase of the elderly population and the deepening of population ageing in China, osteoporosis has gradually become one of the significant public health problems. Elucidating the pathophysiological mechanisms that induce osteoporosis and identifying more effective therapeutic targets is of great clinical significance. In this study, in vitro experiments demonstrated that endothelial cell exosomes (EC-EXOs) promoted osteogenic and inhibited adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Aged and ovariectomy (OVX)-induced osteoporosis mice models injected with EC-EXOs confirmed that EC-EXOs delayed bone loss. Proteomic analysis revealed a key protein regulating the differentiation of BMSCs. Expression of THBS3 was significantly higher in EC-EXOs than in Human microvascular endothelial cells (HMEC-1). In vitro and in vivo experiments further validated that THBS3 promoted BMSCs' osteogenic differentiation, inhibited their adipogenic differentiation, and retarded bone loss. Computational biology analysis found that CD47 is a downstream target and potentially functional receptor in BMSCs that bind to THBS3. THBS3 treatment of BMSCs down-regulated the expression of CD47 in in vitro experiments. The aged/OVX models further confirmed that EC-EXOs can regulate the differentiation of BMSCs and delay the process of bone loss via the THBS3–CD47 axis. CD47 antibody may be a potential therapeutic agent for treating ageing-associated bone loss.

Keywords

ageing / bone marrow mesenchymal stem cells / CD47 antibody / osteogenic differentiation / osteoporosis / thrombospondin-3 / vascular endothelial cell exosomes

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2025 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.