oxLDL inhibits differentiation and functional activity of osteoclasts via scavenger receptor-A mediated autophagy and cathepsin K secretion
oxLDL inhibits differentiation and functional activity of osteoclasts via scavenger receptor-A mediated autophagy and cathepsin K secretion
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DOI：
10.1038/s41598-018-29963-w
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发表时间：
2018-08-02
影响因子：
4.6
通讯作者：
Kiyan, Yulia
中科院分区：
文献类型：
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作者：
Dawodu, Damilola;Patecki, Margret;Kiyan, Yulia
破骨细胞的吸收活性对于维持骨稳态是重要的。内源性化合物，如氧化低密度脂蛋白（oxLDL）已被证明干扰这种活动。虽然一些研究已经调查了oxLDL对破骨细胞生成过程的影响，但其潜在机制尚未完全了解。我们在这里表明，-10-25 μ g蛋白质（0.43-1.0 μ M MDA/mg蛋白质）的oxLDL浓度完全阻止了功能性破骨细胞的形成。潜在的机制意味着自噬的抑制，这反过来又导致组织蛋白酶K（CatK）负载的溶酶体囊泡与皱褶边缘膜的融合减少。结果，在oxLDL存在下观察到CatK分泌降低和空泡-ATP酶（v-ATP酶）的再吸收陷窝质子化受损。我们证明清道夫受体A（SR-A）介导oxLDL对破骨细胞生成的作用，并抑制该受体部分挽救oxLDL的作用。总的来说，我们的数据提供了一个深入了解oxLDL对破骨细胞生成的可能机制，表明它不会干扰包装的CatK和v-ATP酶（V-a3）的分泌溶酶体，但抑制这些溶酶体的融合到皱褶的边界。我们的研究结果的相关性表明oxLDL，自噬和破骨细胞生成之间有明显的联系。
Resorptive activity of osteoclasts is important for maintaining bone homeostasis. Endogenous compounds such as oxidized low density lipoprotein (oxLDL) have been shown to disturb this activity. While some studies have investigated the effects of oxLDL on the process of osteoclastogenesis, the underlying mechanism are not fully understood. We show here that oxLDL concentrations of -10-25 mu g protein (0.43-1.0 mu M MDA/mg protein) completely blocked the formation of functional osteoclasts. The underlying mechanism implies an inhibition of autophagy that in turn leads to a decreased fusion of cathepsin K (CatK)-loaded lysosomal vesicles with the ruffled border membrane. As result, a lower secretion of CatK and impaired protonation of the resorption lacunae by vacuolar-ATPase (v-ATPase) is observed in the presence of oxLDL. We demonstrate that scavenger receptor A (SR-A) mediates oxLDL effects on osteoclastogenesis and repressing this receptor partially rescued oxLDL effects. Collectively, our data provides an insight into the possible mechanism of oxLDL on osteoclastogenesis suggesting that it does not perturb the packaging of CatK and v-ATPase (V-a3) in the secretory lysosome, but inhibits the fusion of these lysosomes to the ruffled border. The relevance of our findings suggests a distinct link between oxLDL, autophagy and osteoclastogenesis.