Department of Orthopedic Surgery, Zhongshan Hospital of Fudan University, Shanghai, China (mainland).
Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Orthopedics and Traumatology, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (mainland).
Med Sci Monit. 2017 Aug 21;23:4034-4040. doi: 10.12659/msm.903432.
BACKGROUND Glucocorticoids (GC) have direct adverse effects on osteocytes, the most abundant bone cell type, and play an important role in osteonecrosis of the femoral head (ONFH). Teriparatide has been reported to be an effective treatment for ONFH. However, the underlying mechanism is unclear. MATERIAL AND METHODS An osteocyte cell line, MLO-Y4, was used under various doses of dexamethasone (Dex) with or without rhPTH (1-34). Cell viability, autophagy, and apoptosis markers and osteocyte characteristic mRNAs were investigated to better understand this phenomenon. RESULTS Induction of apoptosis by Dex was increased in a time- and dose-dependent manner in MLO-Y4 cells. Autophagy markers (LC3-II and Beclin-1) were increased at the low dose of Dex (10^-7 or 10^-6 M) and decreased at the high dose (10^-5 M). In MOL-Y4 cells, rhPTH (1-34) was shown to be protective against Dex-induced apoptosis. The upregulation of LC3-II and Beclin-1 and decreased level of Caspase-3 was observed in the rhPTH (1-34)-treated group compared with the Dex-only-treated group. Furthermore, the changes induced by Dex in osteocytes, such as increased SOST, RANKL, and DMP-1 mRNA level and decreased Destrin mRNA level, were reversed by rhPTH (1-34). A similar result was found in osteocyte-specific proteins sclerostin expression encoded by SOST mRNA, which acted as a bone formation inhibitor. CONCLUSIONS The self-activation of autophagy may be a protective mechanism against apoptosis induced by Dex. The protection effect of rhPTH (1-34) for GC-induced ONFH thus results, at least in part, from enhanced autophagy.
糖皮质激素（GC）对骨细胞（骨细胞是最丰富的骨细胞类型）有直接的不良影响，在股骨头坏死（ONFH）中起重要作用。甲状旁腺素（rhPTH）已被报道为治疗ONFH 的有效方法。然而，其潜在机制尚不清楚。
使用各种剂量的地塞米松（Dex）和/或 rhPTH（1-34）处理成骨细胞系 MLO-Y4。研究细胞活力、自噬和凋亡标志物以及成骨细胞特征性 mRNA，以更好地了解这种现象。
Dex 诱导的 MLO-Y4 细胞凋亡呈时间和剂量依赖性增加。自噬标志物（LC3-II 和 Beclin-1）在低剂量 Dex（10^-7 或 10^-6 M）时增加，而在高剂量（10^-5 M）时减少。在 MOL-Y4 细胞中，rhPTH（1-34）被证明可抵抗 Dex 诱导的凋亡。与单独用 Dex 处理的组相比，rhPTH（1-34）处理组观察到 LC3-II 和 Beclin-1 的上调以及 Caspase-3 水平降低。Dex 诱导的成骨细胞变化，如 SOST、RANKL 和 DMP-1 mRNA 水平增加和 Destrin mRNA 水平降低，也被 rhPTH（1-34）逆转。SOST mRNA 编码的成骨细胞特异性蛋白骨硬化素（sclerostin）的表达也有类似的结果，骨硬化素作为骨形成抑制剂。
自噬的自我激活可能是 Dex 诱导的细胞凋亡的一种保护机制。rhPTH（1-34）对 GC 诱导的 ONFH 的保护作用至少部分是由于自噬增强所致。
