Activation of dimeric glucocorticoid receptors in osteoclast progenitors potentiates RANKL induced mature osteoclast bone resorbing activity
Activation of dimeric glucocorticoid receptors in osteoclast progenitors potentiates RANKL induced mature osteoclast bone resorbing activity
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DOI：
10.1016/j.bone.2016.08.024
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发表时间：
2016-12-01
期刊：
影响因子：
4.1
通讯作者：
Lerner, Ulf H.
中科院分区：
文献类型：
--
作者：
Conaway, H. Herschel;Henning, Petra;Lerner, Ulf H.
糖皮质激素（GC）治疗是继发性骨质疏松症的最大危险因素。致病机制涉及骨吸收最初增加，随后骨形成减少。为了更好地了解 GC 的再吸收活性，我们使用小鼠骨髓巨噬细胞 (BMM) 来确定 GC 是否可以直接调节 RANKL 刺激的破骨细胞形成和/或活性。与之前的研究一致，在塑料孔中进行的实验表明，GC（地塞米松、氢化可的松和泼尼松龙）在 RANKL 刺激破骨细胞生成的初始阶段抑制破骨细胞的数量和大小；然而，在长时间的培养中，观察到细胞凋亡减少，并且随着形成的破骨细胞数量增加（许多破骨细胞面积增加）而逃避GC诱导的抑制。当 BMM 细胞接种在骨切片上时，GC 强烈增强 RANKL 刺激吸收坑的形成和 CTX 的释放，而不影响形成的破骨细胞的数量或大小，也不影响细胞凋亡。刺激小凹形成与破骨细胞寿命的延长或对几种破骨细胞或破骨细胞基因的 mRNA 表达的影响无关。在条件性敲除破骨细胞糖皮质激素受体的小鼠的 BMM 细胞中，地塞米松对 RANKL 诱导的 CTX 释放的增强作用显着减弱，而在 Gem 小鼠的细胞中则完全不存在，Gem 小鼠的细胞在 GC 受体的一个二聚化界面上携带点突变。这些数据表明：1.塑料是用于研究GC对破骨细胞的直接影响的不良介质2.GC可以增强骨吸收而不减少细胞凋亡，以及3.二聚体GC受体刺激RANKL介导的吸收的直接增强。 (C) 2016 爱思唯尔公司保留所有权利。
Glucocorticoid (GC) therapy is the greatest risk factor for secondary osteoporosis. Pathogenic mechanisms involve an initial increase in bone resorption followed by decreased bone formation. To gain a better understanding of the resorptive activity of GCs, we have used mouse bone marrow macrophages (BMM) to determine if GCs can directly modulate RANKL stimulated osteoclast formation and/or activity. In agreement with previous studies, experiments performed in plastic wells showed that GCs (dexamethasone, hydrocortisone, and prednisolone) inhibited osteoclast number and size during the initial phases of RANKL stimulated osteoclastogenesis; however, in prolonged cultures, decreased apoptosis was observed and escape from GC induced inhibition occurred with an enhanced number of osteoclasts formed, many with an increased area. When BMM cells were seeded on bone slices, GCs robustly enhanced RANKL stimulated formation of resorption pits and release of CTX without affecting the number or size of osteoclasts formed and with no effect on apoptosis. Stimulation of pit formation was not associated with increased life span of osteoclasts or an effect on mRNA expression of several osteoclastic or osteoclastogenic genes. The potentiation of RANKL induced CTX release by dexamethasone was significantly less in BMM cells from mice with conditional knockout of the osteoclastic glucocorticoid receptor and completely absent in cells from Gem mice, which carry a point mutation in one dimerizing interface of the GC receptor. These data suggest that: 1. Plastic is a poor medium to use for studying direct effects of GCs on osteoclasts 2. GCs can enhance bone resorption without decreasing apoptosis, and 3. A direct enhancement of RANKL mediated resorption is stimulated by the dimeric GC -receptor. (C) 2016 Elsevier Inc All rights reserved.