Apoptosis of Mdm2-deficient osteocytes enhances osteogenesis through TRPM8-enriched apoptotic vesicles

During homeostasis, osteocyte apoptosis is typically associated with bone loss through enhanced osteoclast recruitment and bone resorption. However, whether apoptotic osteocytes also regulate bone formation remains elusive. Here we report that conditional deletion of Mdm2, an E3 ubiquitin ligase regulating cell survival, causes osteocyte apoptosis but paradoxically results in a marked increase in bone mass attributed to up-regulated osteogenic activity. Single-cell RNA sequencing reveals enhanced osteoblastic differentiation of bone marrow mesenchymal stem cells (BMSCs) in conditional knockout mice, with enrichment of cellular calcium related pathways. Mechanistically, apoptotic vesicles (apovs) from Mdm2-deleted osteocytes are engulfed by BMSCs. TRPM8, a calcium channel protein, is enriched in osteocyte-derived apovs and transported into BMSCs, thereby promoting osteoblastic differentiation. Additionally, pharmacological inhibition of TRPM8 attenuates the high bone mass phenotype in conditional knockout mice. Therefore, Mdm2 deletion in osteocytes leads to osteocyte apoptosis, which enhances bone formation through communicating with BMSCs via TRPM8-enriched apovs. Our findings underscore the pivotal role of osteocytes in bone homeostasis and unveil a previously unrecognized mechanism whereby osteocyte apoptosis stimulates osteogenesis through affecting the fate of BMSCs in a TRPM8-mediated paracrine mechanism.