Sclerostin's role in bone's adaptive response to mechanical loading.
Sclerostin's role in bone's adaptive response to mechanical loading.
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DOI：
10.1016/j.bone.2016.10.008
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发表时间：
2017-03
期刊：
影响因子：
4.1
通讯作者：
Price JS
中科院分区：
文献类型：
--
作者：
Galea GL;Lanyon LE;Price JS
机械载荷是骨量和结构的主要功能决定因素，骨细胞在将机械信号转化为（重新）建模响应中起关键作用。虽然确切的机制仍不清楚，Wnt信号通路组分，特别是抗成骨经典Wnt抑制剂Sost/sclerostin，在调节骨对负荷的适应性反应中发挥重要作用。负荷产生的菌株的增加下调骨细胞sclerostin的表达，而减少的菌株，如废用，与增加sclerostin的生产和骨丢失。然而，尽管sclerostin上调似乎是废用性骨丢失所必需的，但sclerostin在对负荷的成骨反应中的作用更为复杂。虽然不能下调sclerostin的小鼠不会在负荷下获得骨，但Sost敲除小鼠对负荷的成骨反应增强。骨细胞的感觉和骨负荷相关的刺激到sclerostin表达的变化的分子机制仍不清楚，但包括几个，潜在的相互关联，涉及骨膜蛋白/整联蛋白，前列腺素，雌激素受体，钙/NO和Igf信号传导的信号级联。解读机械环境中的变化调节sclerostin产生的机制可能会导致治疗策略的发展，这些策略可以逆转废用性和年龄相关性骨质疏松症的骨骼结构退化特征，并增强骨骼对负荷的功能适应。通过增强个体疗法（例如硬化蛋白抗体）发挥作用的背景的成骨潜力，可以预防和逆转骨质疏松症的年龄相关的骨骼结构退化特征。骨细胞sclerostin表达的负荷相关变化空间预测随后的成骨反应。急性sclerostin下调不足以对负荷产生最大的成骨反应。不能抑制硬化蛋白会妨碍负荷后的骨获得。sclerostin缺乏可防止废用性骨丢失。硬化蛋白影响成骨环境，其中负荷作为其缺失增强功能适应。
Mechanical loading is the primary functional determinant of bone mass and architecture, and osteocytes play a key role in translating mechanical signals into (re)modelling responses. Although the precise mechanisms remain unclear, Wnt signalling pathway components, and the anti-osteogenic canonical Wnt inhibitor Sost/sclerostin in particular, play an important role in regulating bone's adaptive response to loading. Increases in loading-engendered strains down-regulate osteocyte sclerostin expression, whereas reduced strains, as in disuse, are associated with increased sclerostin production and bone loss. However, while sclerostin up-regulation appears to be necessary for the loss of bone with disuse, the role of sclerostin in the osteogenic response to loading is more complex. While mice unable to down-regulate sclerostin do not gain bone with loading, Sost knockout mice have an enhanced osteogenic response to loading. The molecular mechanisms by which osteocytes sense and transduce loading-related stimuli into changes in sclerostin expression remain unclear but include several, potentially interlinked, signalling cascades involving periostin/integrin, prostaglandin, estrogen receptor, calcium/NO and Igf signalling. Deciphering the mechanisms by which changes in the mechanical environment regulate sclerostin production may lead to the development of therapeutic strategies that can reverse the skeletal structural deterioration characteristic of disuse and age-related osteoporosis and enhance bones' functional adaptation to loading. By enhancing the osteogenic potential of the context in which individual therapies such as sclerostin antibodies act it may become possible to both prevent and reverse the age-related skeletal structural deterioration characteristic of osteoporosis. Loading-related changes in osteocyte sclerostin expression spatially predict subsequent osteogenic responses. Acute sclerostin down-regulation is not sufficient for maximal osteogenic responses to loading. Inability to suppress sclerostin precludes bone gain following loading. Lack of sclerostin prevents bone loss in disuse. Sclerostin influences the osteogenic context in which loading acts as its deletion enhances functional adaptation.