Pharmacology & Therapeutics ( IF 13.5 ) Pub Date : 2021-08-12 , DOI: 10.1016/j.pharmthera.2021.107965 Eijiro Jimi 1 , Hiroaki Honda 2 , Ichiro Nakamura 3
p130 Crk-associated substrate (Cas) functions as an adapter protein and plays important roles in certain cell functions, such as cell proliferation, spreading, migration, and invasion. Furthermore, it has recently been reported to have a new function as a mechanosensor. Since bone is a tissue that is constantly under gravity, it is exposed to mechanical stress. Mechanical unloading, such as in a microgravity environment in space or during bed rest, leads to a decrease in bone mass because of the suppression of bone formation and the stimulation of bone resorption. Osteoclasts are multinucleated bone-resorbing giant cells that recognize bone and then form a ruffled border in the resorption lacuna. p130Cas is a molecule located downstream of c-Src that is important for the formation of a ruffled border in osteoclasts. Indeed, osteoclast-specific p130Cas-deficient mice exhibit osteopetrosis due to osteoclast dysfunction, similar to c-Src-deficient mice. Osteoblasts subjected to mechanical stress induce both the phosphorylation of p130Cas and osteoblast differentiation. In osteocytes, mechanical stress regulates bone mass by shuttling p130Cas between the cytoplasm and nucleus. Oral squamous cell carcinoma (OSCC) cells express p130Cas more strongly than epithelial cells in normal tissues. The knockdown of p130Cas in OSCC cells suppressed the cell growth, the expression of receptor activator of NF-κB ligand, which induces osteoclast formation, and bone invasion by OSCC. Taken together, these findings suggest that p130Cas might be a novel therapeutic target molecule in bone diseases, such as osteoporosis, rheumatoid arthritis, bone loss due to bed rest, and bone invasion and metastasis of cancer.
中文翻译:
p130Cas在调节骨代谢中的独特作用
p130 Crk 相关底物 (Cas) 作为衔接蛋白发挥作用,在某些细胞功能中发挥重要作用,例如细胞增殖、扩散、迁移和侵袭。此外,最近有报道称它具有作为机械传感器的新功能。由于骨骼是一种不断受到重力作用的组织,因此它会受到机械应力。机械卸载,例如在太空中的微重力环境中或在卧床休息期间,由于抑制骨形成和刺激骨吸收而导致骨量减少。破骨细胞是多核的骨吸收巨细胞,可识别骨,然后在吸收空腔中形成褶皱边界。p130Cas 是一种位于 c-Src 下游的分子,对破骨细胞中褶皱边界的形成很重要。确实,破骨细胞特异性 p130Cas 缺陷小鼠由于破骨细胞功能障碍而表现出骨质硬化症,类似于 c-Src 缺陷小鼠。受到机械应力的成骨细胞诱导 p130Cas 的磷酸化和成骨细胞分化。在骨细胞中,机械应力通过在细胞质和细胞核之间穿梭 p130Cas 来调节骨量。口腔鳞状细胞癌 (OSCC) 细胞比正常组织中的上皮细胞更强烈地表达 p130Cas。OSCC 细胞中 p130Cas 的敲低抑制了 OSCC 细胞的生长、诱导破骨细胞形成的 NF-κB 配体受体激活剂的表达和骨侵袭。综上所述,这些发现表明 p130Cas 可能是治疗骨质疏松症、类风湿性关节炎、卧床休息引起的骨质流失等骨病的新型治疗靶分子,