Calpain function in the differentiation of mesenchymal stem cells.

Calpain is a calcium-activated non lysosomal neutral thiol protease (EC 3.4.22.17) present in a wide variety of eukaryotic cells. Calpain is usually present as an inactive form and is activated by calcium ions and phospholipids. The ability of calpain to alter, by limited proteolysis, the activity or function of numerous cytoskeletal proteins, enzymes, and receptors suggests its involvement in various Ca2+-regulated cellular functions. In this review we focus on the differentiation of mesenchymal stem cells, such as the myoblastic, osteoblastic, chondrocytic, and adipocytic lineages, and the biological significance of calpain in its regulation. Calpain has been implicated in the differentiation of myoblasts through the turnover of glycoproteins. In preosteoblastic cells, calpain is important in mediating the proliferative and prodifferentiating effects of parathyroid hormone and bone morphogenetic proteins. For the differentiation of chondrocytes, calpain is involved in cartilage-matrix mineralization. Furthermore, calpain is required for the differentiation of 3T3-L1 preadipocytes into adipocytes, involving the transcriptional activation of the C/EBP alpha gene and the degradation of the cyclin-dependent kinase inhibitor p27 during the mitotic clonal expansion phase of adipocyte differentiation. We summarize these regulatory effects of calpain on the differentiation of mesenchymal stem cells and speculate on the function and location of calpain in the differentiation processes.