Elucidation of physiological and pathological function of membrane-bound and soluble RANKL

2020 Fiscal Year Final Research Report

• Project/Area Number: 18H02919
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: The University of Tokyo
• Principal Investigator: Okamoto Kazuo 東京大学, 大学院医学系研究科(医学部), 特任准教授 (00436643)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 骨代謝 / 破骨細胞 / RANKL / 免疫組織 / がん骨転移

Outline of Final Research Achievements

Bone tissue is remodeled by a concerted action of osteoclastic bone resorption and osteoblastic bone formation. RANKL, an essential cytokine for osteoclast differentiation, is synthesized as a membrane-bound molecule, and cleaved into its soluble form by proteases. RANKL is critical for not only bone remodeling but also the immune organ formation. In addition, excess RANKL signal causes abnormal osteoclast activation, resulting in various bone diseases such as osteoporosis and bone metastasis. However, the functional difference between soluble and membrane-bound forms of RANKL has been poorly understood in vivo so far. In the project, we have elucidated in vivo significances of two forms of RANKL by generating mice that selectively lack each RANKL. We have demonstrated that soluble RANKL is dispensable for physiological regulation of bone and immune systems and postmenopausal osteoporosis, and that soluble RANKL has a distinct and pivotal role in bone metastases.

Free Research Field

骨免疫学

Academic Significance and Societal Importance of the Research Achievements

本研究により、可溶型RANKLは生理学的意義は極めて低いものの、腫瘍細胞に直接作用することで、骨への走化性を促して骨転移を誘導することが判明し、がん骨転移における可溶型RANKLの特異機能が明らかとなった。最近、ヒトの乳がん患者において血中の可溶型RANKL濃度が、以後の骨転移発生率と相関するという報告がなされた。可溶型RANKLは骨転移発生率を読み取る血清バイオマーカーとして有用であることが示唆され、がんに対する新たな予防・先制医療の開発に重要な知見をもたらすと考えられる。