Osteoclast-secreted CTHRC1 in the coupling of bone resorption to formation
Sunao Takeshita, … , Masako Ito, Kyoji Ikeda
Sunao Takeshita, … , Masako Ito, Kyoji Ikeda
Published August 1, 2013
Citation Information: J Clin Invest. 2013;123(9):3914-3924. https://doi.org/10.1172/JCI69493.
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Research Article Bone biology

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

Abstract

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.

Authors

Sunao Takeshita, Toshio Fumoto, Kazuhiko Matsuoka, Kyoung-ae Park, Hiroyuki Aburatani, Shigeaki Kato, Masako Ito, Kyoji Ikeda

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Figure 6

Impaired coupling function in osteoclast-specific Cthrc1 KO mice.

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Impaired coupling function in osteoclast-specific Cthrc1 KO mice. (A) ...
(A) Cthrc1, Acp5, Calcr, and Ctsk expression at baseline and after RANKL injection in Cthrc1fl/fl control and ΔOC mice, determined by quantitative RT-PCR. Values were normalized for Gapdh. n = 4. (B) Impaired recovery of 3D BV at 8 weeks after RANKL injection in ΔOC versus Cthrc1fl/fl control mice. Mice were sacrificed at 10 days and 8 weeks after RANKL injections, and 3D-determined BV relative to tissue volume was determined. Representative μCT images at 8 weeks are also shown. Scale bars: 1 mm. n = 8. (C) Urinary CTX excretion was assessed 1 day before (–1) and 2 and 4 days after RANKL injections. Data are normalized for creatinine (Cr). n = 5. (D) Bone histomorphometric analysis was performed at 10 days after RANKL injections. Osteoblast surface (Ob.S), osteoblast number (Ob.N), osteoid surface, and bone formation rate were corrected for bone surface. n = 8. (E) Serum osteocalcin (Ocn) concentrations were determined 10 days after RANKL injections (n = 8). *P < 0.05; **P < 0.01; ***P < 0.001.