Department of Bone and Joint Disease, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.
J Clin Invest. 2013 Sep;123(9):3914-24. doi: 10.1172/JCI69493. Epub 2013 Aug 1.
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.
骨重塑的特征是破骨细胞和成骨细胞的顺序、局部连接，是维持骨完整性的关键。虽然骨基质动员的生长因子（如 TGF-β）被认为可以调节重塑，但目前还没有体内证据表明破骨细胞产生的分子可作为骨吸收到形成的偶联因子。我们发现，成熟的破骨细胞分泌的 CTHRC1 蛋白可靶向基质细胞来刺激成骨。当成熟的破骨细胞置于牙本质或羟磷灰石上时，或通过增加细胞外钙时，CTHRCl 的表达会被强烈诱导。在高转换状态下（如体内 RANKL 注射诱导的状态），骨中 Cthrc1 的表达增加，但在与骨转换受抑制相关的条件下（如衰老和阿伦膦酸盐治疗后），其表达减少。在小鼠中靶向敲除 Cthrc1 会消除骨中 Cthrc1 的表达，而其在成骨细胞中的缺失则没有任何显著影响。破骨细胞特异性敲除 Cthrc1 会导致骨量减少，原因是骨形成减少，以及 RANKL 注射诱导的吸收后偶联过程受损，从而损害骨量的恢复。这些数据表明，CTHRCl 是一种破骨细胞分泌的偶联因子，可调节骨重塑。
