The unique function of p130Cas in regulating the bone metabolism.

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.