Osteoclast-secreted CTHRC1 in the coupling of bone resorption to formation

• Published in: The Journal of clinical investigation Vol. 123; no. 9; pp. 3914 - 3924
• Main Authors: Takeshita, Sunao, Fumoto, Toshio, Matsuoka, Kazuhiko, Park, Kyoung-ae, Aburatani, Hiroyuki, Kato, Shigeaki, Ito, Masako, Ikeda, Kyoji
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.09.2013
• Subjects: 3T3-L1 Cells; Animals; Biomedical research; Bone resorption; Bone Resorption - metabolism; Calcium - pharmacology; Cell Differentiation; Cells, Cultured; Dentin; Durapatite - pharmacology; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Extracellular Matrix Proteins - secretion; Female; Gene expression; Gene Expression Regulation; Genetic aspects; Grants; Hydroxyapatite; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Osteoclasts (Biology); Osteoclasts - secretion; Osteogenesis; Physiological aspects; Proteins; Science
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci69493

Bone remodeling is characterized by the sequential, local tethering of osteoclasts and osteoblasts and is key to the maintenance of bone integrity. While bone matrix-mobilized growth factors, such as TGF-β, are proposed to regulate remodeling, no in vivo evidence exists that an osteoclast-produced molecule serves as a coupling factor for bone resorption to formation. We found that CTHRC1, a protein secreted by mature bone-resorbing osteoclasts, targets stromal cells to stimulate osteogenesis. Cthrc1 expression was robustly induced when mature osteoclasts were placed on dentin or hydroxyapatite, and also by increasing extracellular calcium. Cthrc1 expression in bone increased in a high-turnover state (such as that induced by RANKL injections in vivo), but decreased in conditions associated with suppressed bone turnover (such as with aging and after alendronate treatment). Targeted deletion of Cthrc1 in mice eliminated Cthrc1 expression in bone, whereas its deficiency in osteoblasts did not exert any significant effect. Osteoclast-specific deletion of Cthrc1 resulted in osteopenia due to reduced bone formation and impaired the coupling process after resorption induced by RANKL injections, impairing bone mass recovery. These data demonstrate that CTHRC1 is an osteoclast-secreted coupling factor that regulates bone remodeling.