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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 Article has an altmetric score of 19

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

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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 2

Regulation of Cthrc1 gene expression.

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Regulation of Cthrc1 gene expression.
 
(A) Cthrc1 mRNA expression was s...
(A) Cthrc1 mRNA expression was strongly induced in osteoclasts cultured on HA. Osteoclasts were cultured on plastic plates, dentin slices, or Osteologic discs composed of HA crystals, and RNAs were prepared. Real-time RT-PCR for Cthrc1 was performed. (B) Increasing extracellular calcium concentrations increased Cthrc1 transcription in osteoclasts on plastic dishes. Osteoclasts were cultured at the indicated CaCl2 concentrations for 24 hours. (C) Alendronate (ALN) inhibited the Cthrc1 expression induced in osteoclasts cultured on dentin or HA. (D) Proton pump inhibitors or calcitonin inhibited Cthrc1 expression. Osteoclasts were cultured on different substrates (plastic plates, dentin slices, or HA discs) in the presence of 100 nM bafilomycin A1 (BM), 1 μM N-ethylmaleimide (NEM), or 1 nM calcitonin (CT). n = 3. *P < 0.05; **P < 0.01; ***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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