Glucocorticoids and the osteoclast
Glucocorticoids and the osteoclast
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DOI：
10.1196/annals.1402.057
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发表时间：
2007-01-01
期刊：
影响因子：
--
通讯作者：
Teitelbaum, Steven L.
中科院分区：
文献类型：
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作者：
Kim, Hyun-Ju;Zhao, Haibo;Teitelbaum, Steven L.
糖皮质激素（GC）诱导的骨质流失是继发性骨质疏松症最常见的原因，但其发病机制存在争议。GCs在体内明显抑制骨形成，但其影响成骨细胞的方式尚不清楚。由于骨重塑的特点是两种细胞的活动拴在一起，破骨细胞是GCs对成骨细胞作用的潜在调节剂。为了解决这个问题，我们比较了地塞米松对野生型（WT）破骨细胞和来自破骨细胞谱系细胞中GC受体破坏的小鼠的破骨细胞的影响，发现GC处理的WT细胞的骨降解能力受到抑制。地塞米松对骨吸收的抑制作用反映了破骨细胞在M-CSF作用下组织细胞骨架的失败，地塞米松特异性地抑制M-CSF中RhoA、Rac和Vav3的激活，这些细胞分别调节破骨细胞的细胞骨架。在所有情况下，破骨细胞谱系细胞中缺乏GC受体的小鼠不受地塞米松对破骨细胞及其前体的影响。与破骨细胞调节地塞米松的成骨抑制作用一致，GC受体缺陷小鼠免受类固醇抑制骨形成的影响。
Glucocorticoid (GC)-induced bone loss is the most common cause of secondary osteoporosis but its pathogenesis is controversial. GCs clearly suppress bone formation in vivo but the means by which they impact osteoblasts is unclear. Because bone remodeling is characterized by tethering of the activities of the two cells, the osteoclast is a potential modulator of the effect of GCs on osteoblasts. To address this issue we compared the effects of dexamethasone on wild-type (WT) osteoclasts with those derived from mice with disruption of the GC receptor in osteoclast lineage cells and found that the bone-degrading capacity of GC-treated WT cells is suppressed. The inhibitory effect of dexamethasone on bone resorption reflects failure of osteoclasts to organize their cytoskeleton in response to M-CSF Dexamethasone specifically arrests M-CSF activation of RhoA, Rac, and Vav3, each of which regulate the osteoclast cytoskeleton. In all circumstances, mice lacking the GC receptor in osteoclast lineage cells are spared the impact of dexamethasone on osteoclasts and their precursors. Consistent with osteoclasts modulating the osteoblast-suppressive effect of dexamethasone, GC receptor-deficient mice are protected from the steroid's inhibition of bone formation.