Adipose-derived CLEC3B promotes osteogenesis through a CLEC3B–IGFBP4-related paracrine axis associated with mitochondrial adaptation in postmenopausal osteoporosis

Abstract Postmenopausal osteoporosis (PMOP) develops within a complex metabolic milieu, but the adipose-derived cues that regulate osteoblast function are not fully defined. Here, plasma ELISA analysis showed preferential elevation of circulating C-type lectin domain family 3 member B (CLEC3B) in the high-BMI PMOP subgroup. CLEC3B was enriched in adipose tissue and negatively regulated by estradiol. In vivo , adipose-targeted overexpression of Clec3b increased trabecular bone mass and promoted osteoblast-associated bone formation without markedly altering osteoclast-related parameters. To investigate the underlying mode of action, we used an adipocyte–osteoblast conditioned-medium model. Conditioned medium from Clec3b -overexpressing adipocytes promoted osteogenic differentiation of primary calvarial osteoblasts, whereas conditioned medium from Clec3b -silenced adipocytes produced the opposite effect. Adipocyte transcriptomic analysis nominated Igfbp4 as a secretome-associated candidate reduced after Clec3b overexpression. Recombinant insulin-like growth factor-binding protein 4 (IGFBP4) reduced the increases in osteogenic gene expression, RUNX2 abundance, and matrix deposition induced by Clec3b -enriched conditioned medium. In parallel, recombinant IGFBP4 (rIGFBP4) partially attenuated the associated changes in mitochondrial superoxide-related fluorescence, intracellular oxidative fluorescence, mitochondrial membrane potential, and PINK1/PRKN-related signaling. Collectively, the data are consistent with a model whereby adipose-derived CLEC3B promotes osteogenesis through a CLEC3B–IGFBP4-related paracrine axis associated with mitochondrial adaptation in osteoblasts. These findings define a testable adipose-to-bone signaling mechanism relevant to osteoblast dysfunction in PMOP. Graphical Abstract Proposed adipose-to-bone CLEC3B–IGFBP4-related paracrine axis associated with mitochondrial adaptation in osteoblasts. • Plasma CLEC3B is preferentially elevated in high-BMI PMOP. • Adipose-targeted Clec3b overexpression promotes trabecular bone accrual. • Adipocytic Clec3b overexpression suppresses IGFBP4 and enhances osteogenic differentiation. • The CLEC3B–IGFBP4-related axis is associated with mitochondrial adaptation in osteoblasts.