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

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.