2. Academic Validation
  3. RKIP regulates bone marrow macrophage differentiation to mediate osteoclastogenesis and H-type vessel formation

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

  • Nat Commun. 2025 Aug 15;16(1):7604. doi: 10.1038/s41467-025-62972-8.
Zeyu Zheng # 1 2,  Siyue Tao # 1 2,  Jiayan Jin # 1 2,  Yansong Li 3,  Liya Dai 4,  Zhaobo Huang 1 2,  Yihao Zhao 1 2,  Bao Huang 1 2,  Saijilafu 5,  Wenlong Lin 6,  Xiaojian Wang 6,  Mengrui Wu 7,  Jian Chen 8 9 10,  Fengdong Zhao 11 12 13 14
Affiliations

Affiliations

  • 1 Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China.
  • 3 School of Medicine, Hangzhou Normal University, Hangzhou, China.
  • 4 Department of Ultrasound, Lishui Central Hospital, Lishui, China.
  • 5 School of Medicine, Hangzhou City University, Hangzhou, China.
  • 6 Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
  • 7 Department of Cell and Developmental Biology, College of Life Sciences, Zhejiang University, Hangzhou, China. mengruiwu@zju.edu.cn.
  • 8 Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. chenjian-bio@zju.edu.cn.
  • 9 Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China. chenjian-bio@zju.edu.cn.
  • 10 Department of Wound Healing, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. chenjian-bio@zju.edu.cn.
  • 11 Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. zhaofengdong@zju.edu.cn.
  • 12 Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China. zhaofengdong@zju.edu.cn.
  • 13 School of Medicine, Hangzhou City University, Hangzhou, China. zhaofengdong@zju.edu.cn.
  • 14 Department of Wound Healing, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. zhaofengdong@zju.edu.cn.
  • # Contributed equally.
PMID: 40817102 DOI: 10.1038/s41467-025-62972-8
Abstract

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.

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