Loss of chemerin prevents ovariectomy-induced osteoporosis in mice through intraosseous vascular remodeling

Abstract

Chemerin, an adipocyte-secreted adipokine, can regulate bone resorption and bone formation and is a promising therapy for postmenopausal osteoporosis. However, the effect of endogenous chemerin on intraosseous vascular remodeling in postmenopausal osteoporosis remains unclear. In this study, we investigated the effect of chemerin on osteogenesis formation and intraosseous vascular remodeling in ovariectomized Rarres2 knockout (Rarres2^−/−) mice. The results showed that the bone mineral density (BMD) and volume score, trabecular thickness, cortical thickness, bone formation marker BALP and osteocalcin, and angiogenesis markers CD31 and EMCN significantly increased in ovariectomized Rarres2^−/− mice. Furthermore, the expression of biomarkers to osteoblasts (β-catenin and Runx2) and angiogenesis markers (VEGF-A, Noggin, and Ang-1) significantly increased in the bone tissue of ovariectomized Rarres2^−/− mice, as well as in bone marrow stromal cells and primary intraosseous vascular endothelial cells of Rarres2^−/− mice. Conversely, treatment with chemerin significantly inhibited expression of biomarkers for osteoblasts and angiogenesis markers in bone marrow stromal cells and primary intraosseous vascular endothelial cells of Rarres2^−/− mice. More importantly, the supernatants of the primary intraosseous vascular endothelial cells of the Rarres2^−/− mice could promote the osteogenic differentiation effect of BMSCs, which could be blocked by treating with the chemerin recombinant protein. These data indicate that endogenous chemerin has an inhibitory effect on intraosseous vascular formation as well as osteoblast differentiation and proliferation in ovariectomy-induced osteoporosis mice. Chemerin effectively promoted postmenopausal osteoporosis development, which is associated with the involvement of chemerin in the reduction of microcirculation within the skeleton.