ARHGEF3 Deletion Increase Bone Formation and Suppresses Bone Resorption in Adult Mice

ARHGEF3 (also known as XPLN) is a Rho guanine nucleotide exchange factor that activates RhoA/B. Variants in the ARHGEF3 gene are associated with hip and spine BMD and fracture risk, suggesting ARHGEF3 may play key role in maintaining bone mass. However, the extent to which ARHGEF3 facilitates the anabolic and catabolic effects of RhoA are unclear alongside the down-stream impact on bone mass. We report using knockout mice that ARHGEF3 deletion leads to significant gains in cortical area and moment of inertia, driven by increased periosteal bone formation. Increased periosteal bone formation was attributed to osteocytes' down-regulation of sclerostin and Dkk1 combined with increased Wnt3a and Wnt5a expression. In contrast, endocortical bone formation was reduced in KO mice and attributed to deficits in mineralization despite gains in osteoblast viability and alkaline phosphatase activity. ARHGEF3 deletion also suppressed bone resorption despite no direct effect on osteoclastogenesis. Instead, the decrease in osteoclast numbers and bone resorption in the absence of ARHGEF3 is attributed to decreased M-CSF levels among osteoblasts and osteoblast precursors. Collectively, our findings demonstrate that ARHGEF3 deletion has pro-anabolic and anti-catabolic effects that increase bone mass and may offer a novel target for preventing bone loss in an aging population.