Inactivation of autophagy ameliorates glucocorticoid-induced and ovariectomy-induced bone loss
Inactivation of autophagy ameliorates glucocorticoid-induced and ovariectomy-induced bone loss
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DOI：
10.1136/annrheumdis-2015-207240
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发表时间：
2016-06-01
影响因子：
27.4
通讯作者：
Distler, Joerg H. W.
中科院分区：
文献类型：
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作者：
Lin, Neng-Yu;Chen, Chih-Wei;Distler, Joerg H. W.
目的近年来研究发现，自噬调控破骨细胞的活性和分化。在这里，我们的目的是探讨自噬抑制的影响，作为一种潜在的治疗方法，用于治疗骨质疏松症的临床前models.Methods全身性骨丢失诱导小鼠糖皮质激素和卵巢切除术（OVX）。自噬通过自噬相关基因7（Atg 7）的条件失活和氯喹（CQ）处理来靶向。通过microCT评估骨密度。通过破骨细胞生成和骨吸收测定分析自噬在破骨细胞生成中的作用。结果与Atg 7（fl/fl）同窝小鼠相比，Atg 7（fl/fl）_x_LysM-Cre小鼠单核细胞中Atg 7的选择性缺失减轻了糖皮质激素诱导的和OVX诱导的破骨细胞分化和骨丢失。通过CQ治疗对自噬的药理学抑制抑制了糖皮质激素诱导的破骨细胞生成并保护小鼠免受骨丢失。类似地，自噬的失活保护小鼠免受OVX诱导的骨丢失。抑制自噬导致破骨细胞分化减少，破骨细胞标志物如NFATc 1、抗酒石酸酸性磷酸酶、OSCAR和组织蛋白酶K的表达降低，体外骨吸收减弱。与此相反，成骨细胞的分化没有受到影响的抑制自噬。结论药理学或遗传失活的自噬改善糖皮质激素诱导和OVX诱导的骨丢失抑制破骨细胞生成。这些发现可能对骨质疏松症的治疗有直接的翻译意义，因为自噬抑制剂如CQ已经在临床上使用。
Objectives Autophagy has recently been shown to regulate osteoclast activity and osteoclast differentiation. Here, we aim to investigate the impact of autophagy inhibition as a potential therapeutic approach for the treatment of osteoporosis in preclinical models.Methods Systemic bone loss was induced in mice by glucocorticoids and by ovariectomy (OVX). Autophagy was targeted by conditional inactivation of autophagyrelated gene 7 (Atg7) and by treatment with chloroquine (CQ). Bone density was evaluated by microCT. The role of autophagy on osteoclastogenesis was analysed by osteoclastogenesis and bone resorption assays. The quantification of receptor activator of nuclear factor kappa B ligand and osteoprotegerin proteins in cocultures was performed using ELISA whereas that of osteoclast and osteoblast differentiation markers was by qPCR.Results Selective deletion of Atg7 in monocytes from Atg7(fl/fl)_x_LysM-Cre mice mitigated glucocorticoid-induced and OVX-induced osteoclast differentiation and bone loss compared with Atg7(fl/fl) littermates. Pharmacological inhibition of autophagy by treatment with CQ suppressed glucocorticoid-induced osteoclastogenesis and protected mice from bone loss. Similarly, inactivation of autophagy shielded mice from OVX-induced bone loss. Inhibition of autophagy led to decreased osteoclast differentiation with lower expression of osteoclast markers such as NFATc1, tartrate-resistant acid phosphatase, OSCAR and cathepsin K and attenuated bone resorption in vitro. In contrast, osteoblast differentiation was not affected by inhibition of autophagy.Conclusions Pharmacological or genetic inactivation of autophagy ameliorated glucocorticoid-induced and OVX-induced bone loss by inhibiting osteoclastogenesis. These findings may have direct translational implications for the treatment of osteoporosis, since inhibitors of autophagy such as CQ are already in clinical use.