RKIP regulates bone marrow macrophage differentiation to mediate osteoclastogenesis and H-type vessel formation

As central cells involved in osteoimmunology, bone niche macrophages possess diverse functions, and their differentiation fate regulates bone homeostasis. Elucidation of the underlying mechanism involved in macrophage differentiation is important for developing new therapeutic targets for osteoporosis. Here, we show that knocking out Raf kinase inhibitor protein (RKIP), either globally or in macrophages, results in dramatically increased bone mass in mice due to synergistic inhibition of bone resorption and promotion of bone formation. Mechanistically, RKIP knockout inhibits differentiation of macrophages into osteoclasts and promotes their differentiation towards pro-angiogenic subclusters, which enhances formation of H-type vessels. RKIP enhances osteoclastogenesis by interacting with ARHGAP to suppress CDC42 inactivation. Intranuclear RKIP suppresses angiogenic genes expression by bridging the association between HIF-1α and VHL to reduce the protein stability of HIF-1α in macrophages. Furthermore, RKIP deletion or inhibitor rescues ovariectomy (OVX)-induced bone loss in vivo. Collectively, this study provides insights into the different roles of extranuclear or intranuclear RKIP in regulating differentiation of bone niche macrophages and could inform potential therapies for bone homeostasis-related diseases.