Skeletal Diseases Genome Research Center, Kyungpook National University Hospital, Daegu, Korea.
J Bone Miner Res. 2011 Mar;26(3):657-65. doi: 10.1002/jbmr.241.
Glucocorticoids (GCs) inhibit the resorptive capacity of the osteoclast by disrupting its cytoskeleton. We find that calpain-6 (Capn6), a unique, nonproteolytic member of its family, is suppressed 12-fold by dexamethasone (DEX) in the bone-degrading cell. While Capn6 abundance parallels commitment of naive bone marrow macrophages (BMMs) to the osteoclast phenotype, its excess or deletion does not affect the cell's differentiation. On the other hand, Capn6 localizes to the sealing zone, and its overexpression promotes osteoclast spreading and large actin ring formation, eventuating in stimulated bone degradation. Conversely, Capn6 knockdown impairs cytoskeletal organization and the cell's resorptive capacity. Capn6 complexes with tubulin, and its absence inhibits microtubule acetylation and stability in the osteoclast. Knockdown of Capn6 also reduces β(3)-integrin subunit protein, another essential regulator of osteoclast cytoskeletal function. Reflecting Capn6 as a target molecule of GCs, microtubule stability and acetylation, as well as the expression of β(3)-integrin protein, are similarly suppressed in DEX-treated osteoclasts. Moreover, overexpression of Capn6 rescues GC-mediated disruption of osteoclast cytoskeleton. Thus Capn6 promotes cytoskeletal organization and microtubule stability in osteoclasts, and its inhibition may mediate the resorption-arresting properties of GCs.
糖皮质激素（GCs）通过破坏破骨细胞的细胞骨架来抑制其吸收能力。我们发现钙蛋白酶-6（Capn6），作为其家族中独特的非蛋白水解成员，在骨降解细胞中被地塞米松（DEX）抑制 12 倍。虽然 Capn6 的丰度与幼稚骨髓巨噬细胞（BMMs）向破骨细胞表型的分化相一致，但它的过量或缺失并不影响细胞的分化。另一方面，Capn6 定位于封闭带，其过表达促进破骨细胞的扩散和大的肌动蛋白环形成，导致刺激的骨降解。相反，Capn6 的敲低会损害细胞骨架的组织和细胞的吸收能力。Capn6 与微管蛋白结合，其缺失抑制破骨细胞中的微管乙酰化和稳定性。Capn6 的敲低还降低了 β(3)-整合素亚基蛋白，这是破骨细胞细胞骨架功能的另一个重要调节因子。反映 Capn6 作为 GCs 的靶分子，微管稳定性和乙酰化以及 β(3)-整合素蛋白的表达在 DEX 处理的破骨细胞中也受到类似的抑制。此外，Capn6 的过表达挽救了 GC 介导的破骨细胞细胞骨架破坏。因此，Capn6 促进破骨细胞中的细胞骨架组织和微管稳定性，其抑制可能介导 GCs 的吸收抑制特性。
