Load regulates bone formation and Sclerostin expression through a TGFβ-dependent mechanism.
Load regulates bone formation and Sclerostin expression through a TGFβ-dependent mechanism.
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DOI：
10.1371/journal.pone.0053813
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Alliston T
中科院分区：
文献类型：
--
作者：
Nguyen J;Tang SY;Nguyen D;Alliston T
骨骼不断适应不断变化的生理和生物需求。成骨细胞、破骨细胞和骨细胞合作整合这些物理和生化信号以维持骨稳态。虽然TGFβ作用于所有这三种细胞类型以维持骨稳态，但其参与骨适应机械负荷的程度尚不清楚。在这里，我们研究了TGFβ通路在负荷诱导的骨形成中的作用以及骨抑制剂的机械敏感性拮抗剂Sclerostin的调节。我们发现，机械负荷迅速抑制骨细胞中TGFβ通路的净活性，导致关键下游效应物Smad2和Smad3的磷酸化和活性降低。TGFβ敏感性的丧失损害了骨对机械负荷的合成代谢反应，表明TGFβ信号传导的机械敏感性调节对于负荷诱导的骨形成至关重要。此外，对TGFβ的敏感性是硬化蛋白的机械敏感性调节所必需的，其由TGFβ以Smad3依赖性方式诱导。总之，我们的研究结果表明，物理因素通过TGFβ途径调节硬化蛋白表达和新骨沉积来维持骨稳态。
Bone continually adapts to meet changing physical and biological demands. Osteoblasts, osteoclasts, and osteocytes cooperate to integrate these physical and biochemical cues to maintain bone homeostasis. Although TGFβ acts on all three of these cell types to maintain bone homeostasis, the extent to which it participates in the adaptation of bone to mechanical load is unknown. Here, we investigated the role of the TGFβ pathway in load-induced bone formation and the regulation of Sclerostin, a mechanosensitive antagonist of bone anabolism. We found that mechanical load rapidly represses the net activity of the TGFβ pathway in osteocytes, resulting in reduced phosphorylation and activity of key downstream effectors, Smad2 and Smad3. Loss of TGFβ sensitivity compromises the anabolic response of bone to mechanical load, demonstrating that the mechanosensitive regulation of TGFβ signaling is essential for load-induced bone formation. Furthermore, sensitivity to TGFβ is required for the mechanosensitive regulation of Sclerostin, which is induced by TGFβ in a Smad3-dependent manner. Together, our results show that physical cues maintain bone homeostasis through the TGFβ pathway to regulate Sclerostin expression and the deposition of new bone.
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