运动刺激的前破骨细胞上的初级纤毛促进骨膜骨形成

摘要(中文译文)

运动对目前药物难以奏效的皮质骨具有深远影响。然而，这些变化背后的机制仍不清楚。本研究表明，髓系前破骨细胞上的机械敏感性初级纤毛在介导运动诱导的骨膜骨形成中发挥关键作用。我们将Cx3cr1-Cre或Ctsk-Cre小鼠与Ift88和/或Kif3a小鼠杂交，构建了在破骨细胞分化不同阶段髓系细胞缺乏初级纤毛的模型。运动后，所有这些小鼠均表现出骨膜骨形成减少和皮质骨尺寸减小。对前破骨细胞初级纤毛的机械刺激可激活Dvl2，抑制组织蛋白酶K（cathepsin K）的产生并防止骨膜蛋白（periostin）降解。由此导致的骨膜蛋白水平升高促进了骨膜骨形成。值得注意的是，抑制组织蛋白酶K可克服运动Cx3cr1-Cre;Ift88小鼠中初级纤毛缺陷的影响，使皮质骨尺寸、骨形成及骨膜骨膜蛋白水平恢复至运动Ift88同窝对照小鼠中所观察到的水平。通过揭示初级纤毛-前破骨细胞-Ctsk-骨膜蛋白轴，本研究为开发增强皮质骨强度的靶向治疗奠定了基础。

Abstract

Exercise profoundly impacts cortical bones that are refractory to current drugs. However, the mechanisms underlying these changes remain unclear. Here we show that mechanosensitive primary cilia on myeloid-lineage preosteoclasts have a critical role in mediating exercise-induced periosteal-bone formation. We crossed Cx3cr1-Cre or Ctsk-Cre mice with Ift88 and/or Kif3a mice to create models that lack primary cilia on myeloid-lineage cells at various stages of osteoclastic differentiation. On exercise, all these mice displayed decreases in periosteal-bone formation and cortical-bone size. Mechanical stimulation of primary cilia on preosteoclasts activated Dvl2, suppressing cathepsin K production and preventing periostin degradation. The resulting elevation of periostin levels promoted periosteal-bone formation. Notably, cathepsin K inhibition overcame the effects of primary cilia deficiency in exercised Cx3cr1-Cre;Ift88 mice, restoring cortical-bone size, bone formation, and periosteal periostin levels to those observed in exercised Ift88 littermates. By uncovering the primary cilia-preosteoclast-Ctsk-periostin axis, this study provides a foundation for developing targeted therapies to enhance cortical-bone strength.

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