Institute of Physiological Chemistry, Dresden University of Technology, Dresden, Germany.
J Bone Miner Res. 2012 Oct;27(10):2085-96. doi: 10.1002/jbmr.1670.
Bone remodeling involves tightly regulated bone-resorbing osteoclasts and bone-forming osteoblasts. Determining osteoclast function is central to understanding bone diseases such as osteoporosis and osteopetrosis. Here, we report a novel function of the F-actin binding and regulatory protein SWAP-70 in osteoclast biology. F-actin ring formation, cell morphology, and bone resorption are impaired in Swap-70(-/-) osteoclasts, whereas the expression of osteoclast differentiation markers induced in vitro by macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL) remains unaffected. Swap-70(-/-) mice develop osteopetrosis with increased bone mass, abnormally dense bone, and impaired osteoclast function. Ectopic expression of SWAP-70 in Swap-70(-/-) osteoclasts in vitro rescues their deficiencies in bone resorption and F-actin ring formation. Rescue requires a functional pleckstrin homology (PH) domain, known to support membrane localization of SWAP-70, and the F-actin binding domain. Transplantation of SWAP-70-proficient bone marrow into Swap-70(-/-) mice restores osteoclast resorption capacity in vivo. The identification of the role of SWAP-70 in promoting osteoclast function through modulating membrane-proximal F-actin rearrangements reveals a new pathway to control osteoclasts and bone homeostasis.
骨重塑涉及受严格调控的骨吸收破骨细胞和骨形成成骨细胞。确定破骨细胞的功能对于理解骨质疏松症和骨质硬化症等骨骼疾病至关重要。在这里，我们报告了 F-肌动蛋白结合和调节蛋白 SWAP-70 在破骨细胞生物学中的一个新功能。SWAP-70(-/-)破骨细胞中的 F-肌动蛋白环形成、细胞形态和骨吸收受损，而巨噬细胞集落刺激因子 (M-CSF) 和核因子-κB 配体 (RANKL) 体外诱导的破骨细胞分化标志物的表达不受影响。SWAP-70(-/-)小鼠发生骨质硬化症，骨量增加，骨密度异常增加，破骨细胞功能受损。体外异位表达 SWAP-70 可挽救 SWAP-70(-/-)破骨细胞在骨吸收和 F-肌动蛋白环形成方面的缺陷。挽救需要一个功能齐全的pleckstrin 同源 (PH) 结构域，该结构域已知支持 SWAP-70 的膜定位，以及 F-肌动蛋白结合结构域。将具有 SWAP-70 功能的骨髓移植到 SWAP-70(-/-)小鼠中可恢复体内破骨细胞的吸收能力。SWAP-70 调节膜近端 F-肌动蛋白重排以促进破骨细胞功能的作用的确定揭示了一种控制破骨细胞和骨稳态的新途径。
