Department of Stomatology, College and Hospital of Stomatology, Jilin University, Changchun 130021, China.
Department of Orthodontics, College of Dentistry, University of Florida, Gainesville, FL 32610, USA.
Biomolecules. 2019 Jan 9;9(1):17. doi: 10.3390/biom9010017.
Osteoclasts are cells of the hematopoietic lineage that are specialized to resorb bone. In osteoclasts, the actin cytoskeleton engages in at least two unusual activities that are required for resorption. First, microfilaments form a dynamic and structurally elaborate actin ring. Second, microfilaments bind vacuolar H⁺-ATPase (V-ATPase) and are involved in forming the V-ATPase-rich ruffled plasma membrane. The current review examines these two specialized functions with emphasis on the identification of new therapeutic opportunities. The actin ring is composed of substructures called podosomes that are interwoven to form a cohesive superstructure. Studies examining the regulation of the formation of actin rings and its constituent proteins are reviewed. Areas where there are gaps in the knowledge are highlighted. Microfilaments directly interact with the V-ATPase through an actin binding site in the B2-subunit of V-ATPase. This binding interaction is required for ruffled membrane formation. Recent studies show that an inhibitor of the interaction blocks bone resorption in pre-clinical animal models, including a model of post-menopausal osteoporosis. Because the unusual actin-based resorption complex is unique to osteoclasts and essential for bone resorption, it is likely that deeper understanding of its underlying mechanisms will lead to new approaches to treat bone disease.
破骨细胞是造血谱系中的细胞，专门负责吸收骨骼。在破骨细胞中，肌动蛋白细胞骨架至少参与两种对吸收必不可少的异常活动。首先，微丝形成一个动态的、结构复杂的肌动蛋白环。其次，微丝与液泡 H⁺-ATP 酶（V-ATPase）结合，并参与形成富含 V-ATPase 的皱襞质膜。本综述重点研究了这两种特殊功能，并强调了新的治疗机会。肌动蛋白环由称为皱襞足的亚结构组成，这些亚结构交织在一起形成一个有凝聚力的超结构。对研究肌动蛋白环及其组成蛋白形成的调控的研究进行了回顾。突出了知识空白的领域。微丝通过 V-ATPase 的 B2 亚基中的一个肌动蛋白结合位点直接与 V-ATPase 相互作用。这种结合相互作用对于皱襞膜的形成是必需的。最近的研究表明，这种相互作用的抑制剂可以阻断包括绝经后骨质疏松症在内的临床前动物模型中的骨吸收。因为这种不寻常的基于肌动蛋白的吸收复合物是破骨细胞所特有的，并且对骨吸收是必不可少的，所以深入了解其潜在机制很可能会为治疗骨病提供新的方法。
