Regulation of osteoclast function via Rho-Pkn3-c-Src pathways

Background: Wnt signaling pathways are largely divided into the beta-catenin-dependent canonical pathway and beta-catenin-independent non-canonical pathways. The roles of Wnt signaling in bone metabolism have been extensively investigated. We previously attempted to clarify the roles of Wnt-non-canonical signaling in bone resorption and demonstrated that Wnt5a-receptor tyrosine kinase-like orphan receptor 2 (Ror2) signaling promoted osteoclast differentiation by enhancing RANK expression in osteoclast precursor cells. However, the roles of Wnt5a-Ror2 signaling in osteoclast function remain unclear. Highlight: Trabecular bone mass was significantly greater in osteoclast-specific Ror2-deficient (Ror2(Delta OCL/Delta OCL)) mice than in control mice due to the decreased bone-resorbing activity of osteoclasts. Wnt5a-Ror2 signaling activated Rho in osteoclasts via dishevelled-associated activator of morphogenesis 2 (Daam2). The expression of protein kinase N3 (Pkn3), a Rho effector, increased during osteoclast differentiation. Trabecular bone mass was significantly greater in Pkn3-deficient mice than in wild-type mice due to the decreased bone-resorbing activity of osteoclasts. Pkn3 bound to c-Src and Pyk2 in a Wnt5a-Ror2 signaling-dependent manner, thereby enhancing the kinase activity of c-Src in osteoclasts. The binding of Pkn3 to c-Src was essential for the bone-resorbing activity of osteoclasts. Conclusion: Wnt5a-Ror2 signaling promotes the bone-resorbing activity of osteoclasts by activating the Daam2-Rho-Pkn3-c-Src pathways. Pkn3 inhibitors, therefore, have potential as therapeutic agents for osteoporosis and bone destruction in inflammatory diseases. (C) 2019 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved.