Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, United States.
Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, United States.
Elife. 2021 Mar 29;10:e64393. doi: 10.7554/eLife.64393.
The downregulation of sclerostin in osteocytes mediates bone formation in response to mechanical cues and parathyroid hormone (PTH). To date, the regulation of sclerostin has been attributed exclusively to the transcriptional downregulation of the gene hours after stimulation. Using mouse models and rodent cell lines, we describe the rapid, minute-scale post-translational degradation of sclerostin protein by the lysosome following mechanical load and PTH. We present a model, integrating both new and established mechanically and hormonally activated effectors into the regulated degradation of sclerostin by lysosomes. Using a mouse forelimb mechanical loading model, we find transient inhibition of lysosomal degradation or the upstream mechano-signaling pathway controlling sclerostin abundance impairs subsequent load-induced bone formation by preventing sclerostin degradation. We also link dysfunctional lysosomes to aberrant sclerostin regulation using human Gaucher disease iPSCs. These results reveal how bone anabolic cues post-translationally regulate sclerostin abundance in osteocytes to regulate bone formation.
骨细胞中骨硬化蛋白的下调介导了机械刺激和甲状旁腺激素（PTH）对骨形成的反应。迄今为止，骨硬化蛋白的调节仅归因于刺激后数小时基因的转录下调。本研究使用小鼠模型和啮齿动物细胞系，描述了机械负荷和 PTH 作用后，溶酶体对骨硬化蛋白蛋白的快速、分钟级别的翻译后降解。我们提出了一个模型，将新的和已建立的机械和激素激活效应器整合到溶酶体对骨硬化蛋白的调控降解中。使用小鼠前肢机械加载模型，我们发现溶酶体降解或控制骨硬化蛋白丰度的上游机械信号通路的短暂抑制会通过阻止骨硬化蛋白降解来损害随后的负荷诱导的骨形成。我们还使用人类戈谢病 iPSC 将功能失调的溶酶体与异常的骨硬化蛋白调节联系起来。这些结果揭示了骨合成代谢线索如何通过翻译后调节骨细胞中的骨硬化蛋白丰度来调节骨形成。
