Hydrogen sulfide: a new regulator of osteoclastogenesis?
Hydrogen sulfide: a new regulator of osteoclastogenesis?
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DOI：
10.1161/atvbaha.114.303072
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发表时间：
2014
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影响因子：
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通讯作者：
M. Kurabayashi
中科院分区：
文献类型：
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作者：
M. Kurabayashi
这些结果代表了对RANKL诱导的破骨细胞生成调节的理解的潜在突破。然而，尚不清楚H2S如何对RANKL刺激的RAW 264发挥其骨细胞生成作用。7个细胞。以往的研究表明，H2S是一种重要的内源性血管活性因子，可保护动脉免受动脉粥样硬化损伤，包括炎症、内皮功能障碍、血管SMC增殖和迁移。H2S的抗动脉粥样硬化作用归因于其抗氧化作用，因为用H2S供体处理CSE缺乏的致动脉粥样硬化饮食喂养的小鼠导致氧化应激降低。19考虑到这些数据，Itou等人暗示H2S的血管保护作用有助于响应H2S供体GYY 4137加速破骨细胞分化。Itou et al关于H2S对破骨细胞分化的影响的发现似乎得到了先前几项研究的支持，这些研究表明，抗氧化剂谷胱甘肽的细胞内水平升高可增强破骨细胞发育和骨陷窝形成，谷胱甘肽合成的特异性抑制剂L-丁硫氨酸-（S，R）-亚砜亚胺的谷胱甘肽耗竭可抑制RANKL刺激的RAW 264中的破骨细胞生成。7个细胞。20然而，有几项研究对这一假设提出了挑战;巨噬细胞中产生的活性氧对破骨细胞分化至关重要21;给予抗氧化剂完全防止了卵巢切除小鼠的骨丢失22;并且RANKL诱导的破骨细胞分化所必需的几种信号传导组分被活性氧类激活，包括肿瘤坏死因子受体相关因子6，核因子κB、c-Fos、活化细胞核因子、p38促分裂原活化蛋白激酶、c-Jun N-末端激酶、细胞外信号调节激酶和NADPH氧化酶。23这些争议可以通过氧化应激或抗氧化剂防御的变化引起的氧化还原转变根据细胞氧化还原状态对细胞功能发挥其双峰效应的概念来调和。因此，推测RANKL诱导的破骨细胞分化的稳健性依赖于前体细胞的氧化还原状态是有趣的，该氧化还原状态由CSE产生的H2S调节。显然，需要额外的工作，以确定是否H2S的生产或CSE的活动是在体内破骨细胞分化牵连。此外，还有待确定破骨细胞对H2S的反应是否在骨和脉管系统之间受到差异调节。尽管骨质疏松和血管钙化之间的关系一直被称为钙化悖论，但其确切的分子机制仍不清楚。令人欣慰的是，钙悖论不仅是因为钙从骨转移到动脉壁，而且可能是因为成骨细胞和破骨细胞对骨和动脉之间的氧化应激的不同反应。24过去，许多研究强调了RANK/RANKL/OPG轴对两种组织之间钙化的明显相反调节的重要作用。8-15 Itou等人的报告为破骨细胞分化的调节机制带来了新的视角，并可能为确定预防和治疗血管钙化的有希望的靶点开辟新的途径。
These results represent a potential breakthrough in the understanding of the modulation of RANKL-induced osteoclastogenesis. However, it is not clear how H2S exerts its osteoclestogenic effects on RANKL-stimulated RAW264. 7 cells. Previous studies have demonstrated that H2S is an important endogenous vasoactive factor that protects arteries from atherosclerotic damage, including inflammation, endothelial dysfunction, vascular SMC proliferation, and migration. 17, 18 The antiatherogenic effects of H2S have been ascribed to its antioxidant effect because treatment of CSE-deficient, atherogenic diet–fed mice with an H2S donor resulted in decreased oxidative stress. 19 Taking these data into consideration, Itou et al alluded that the vasoprotective effect of H2S contributes to the acceleration of osteoclast differentiation in response to the H2S donor GYY4137. The finding of Itou et al of the effects of H2S on osteoclast differentiation seems to be supported by several previous studies demonstrating that increased intracellular levels of the antioxidant glutathione enhance osteoclast development and bone pit formation, and glutathione depletion by L-buthionine-(S, R)-sulfoximine, a specific inhibitor of glutathione synthesis, inhibits osteoclastogenesis in RANKL-stimulated RAW264. 7 cells. 20 Nevertheless, there have been several studies challenging this hypothesis; reactive oxygen species produced in macrophages are essential for osteoclast differentiation21; the administration of antioxidants completely prevented bone loss in ovariectomized mice22; and several signaling components essential for RANKL-induced osteoclast differentiation are activated by reactive oxygen species, including tumor necrosis factor receptor–associated factor 6, nuclear factor κB, c-Fos, nuclear factor of activated cells, p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and NADPH oxidase. 23 These controversies would be reconciled by the notion that redox shift caused by the change in oxidative stress or antioxidant defense exerts its bimodal effects on cellular function depending on the cellular redox status. Thus, it is intriguing to speculate that the robustness of RANKL-induced osteoclast differentiation is dependent on the redox state of precursor cells that is regulated by H2S generated by CSE.What are the potential clinical implications of this study? Clearly, additional work is required to determine whether H2S production or CSE activity is implicated in osteoclast differentiation in vivo. Moreover, it is yet to be determined whether osteoclast response to H2S is differentially regulated between bone and vasculature. Although the relationship between osteoporosis and vascular calcification has long been known as calcification paradox, its precise molecular mechanism remains unclear. It is reassuring that calcium paradox is not merely because of calcium shift from bone to artery wall but is likely because of the differential response of both osteoblasts and osteoclasts to oxidative stress between bone and artery. 24 In the past, many studies have highlighted the important role for RANK/RANKL/OPG axis for the apparently opposite regulation of calcification between 2 tissues. 8–15 The report by Itou et al brings a new perspective to the regulatory mechanisms of osteoclast differentiation and may open new avenues to the identification of a promising target for the prevention and treatment of vascular calcification.