Rgnef regulates bone mass through the activation of RhoA and Rac1

Rho guanine nucleotide exchange factor (Rgnef/p190RhoGEF), a RhoA-specific guanine nucleotide exchange factor, has been implicated in cancer and amyotrophic lateral sclerosis, but little is known about its role in bone. In this study, we investigated the roles of Rgnef in bone metabolism using Rgnef-deficient and overexpressing mice. Compared with littermate wild-type mice, Rgnef-deficient mice had increased bone mass due to lower osteolysis and higher osteogenesis, and Rgnef-overexpressing transgenic mice had the opposite bone phenotype. Rgnef deficiency inhibited osteoclast formation and resorptive function and promoted osteoblast differentiation and mineralization, whereas Rgnef overexpression had the reverse effect. Mechanistically, Rgnef promotes osteoclastogenesis by enhancing the activity of nuclear factor-kappa B (NF-κB), mitogen-activated protein kinases, and AKT through the activation of RhoA and Rac1, and attenuates osteoblastogenesis through the RhoA/Rac1-mediated NF-κB activation. Moreover, Rgnef-deficient mice were protected from bone loss caused by lipopolysaccharide-induced inflammation or ovariectomy. Thus, Rgnef is a crucial regulator of bone metabolism and could serve as a potential new target for treating bone diseases.