Bone and the Unfolded Protein Response: In Sickness and in Health.
Bone and the Unfolded Protein Response: In Sickness and in Health.
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DOI：
10.1007/s00223-023-01096-x
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发表时间：
2023-07
影响因子：
4.2
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中科院分区：
文献类型：
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成骨细胞和破骨细胞的分化和最佳功能取决于健康蛋白质组的合成和维持。这些骨骼细胞的分泌能力受损和/或改变是大多数骨骼疾病的主要驱动因素。内质网（ER）协调膜的折叠和成熟，以及在富含钙和氧化的细胞器小生境中以高速率分泌蛋白质。三种ER膜蛋白监测ER中蛋白质加工的保真度，并启动称为未折叠蛋白质反应（UPR）的复杂信号级联，以修复其管腔中错误折叠蛋白质的积累，这种情况称为ER应激。UPR有助于微调，扩大和/或修改细胞蛋白质组，特别是在专门的分泌细胞，以匹配不断变化的生理线索和代谢需求。然而，已知由于慢性ER应激导致的UPR的持续激活加速细胞死亡并驱动几种疾病的病理生理学。越来越多的证据表明，ER应激和异常的UPR可能导致骨骼健康不良和骨质疏松症的发展。因此，靶向UPR不同组分的小分子治疗剂可能对开发与骨骼相关的新型治疗方式产生影响。本文综述了UPR在骨细胞中作用的复杂性，在骨骼生理学和骨质疏松性骨丢失的背景下，并强调需要未来的机制研究，以开发新的UPR治疗，减轻不良骨骼结果。
Differentiation and optimal function of osteoblasts and osteoclasts are contingent on synthesis and maintenance of a healthy proteome. Impaired and/or altered secretory capacity of these skeletal cells is a primary driver of most skeletal diseases. The endoplasmic reticulum (ER) orchestrates the folding and maturation of membrane as well as secreted proteins at high rates within a calcium rich and oxidative organellar niche. Three ER membrane proteins monitor fidelity of protein processing in the ER and initiate an intricate signaling cascade known as the Unfolded Protein Response (UPR) to remediate accumulation of misfolded proteins in its lumen, a condition referred to as ER stress. The UPR aids in fine-tuning, expanding and/or modifying the cellular proteome, especially in specialized secretory cells, to match everchanging physiologic cues and metabolic demands. Sustained activation of the UPR due to chronic ER stress, however, is known to hasten cell death and drive pathophysiology of several diseases. A growing body of evidence suggests that ER stress and an aberrant UPR may contribute to poor skeletal health and the development of osteoporosis. Small molecule therapeutics that target distinct components of the UPR may therefore have implications for developing novel treatment modalities relevant to the skeleton. This review summarizes the complexity of UPR actions in bone cells in the context of skeletal physiology and osteoporotic bone loss, and highlights the need for future mechanistic studies to develop novel UPR therapeutics that mitigate adverse skeletal outcomes.