The role of regucalcin in bone homeostasis: involvement as a novel cytokine.

Regucalcin, which was discovered as a calcium-binding protein in 1978, has been demonstrated to play a multifunctional role in the regulation of various tissues and cell types. Regucalcin plays a pivotal role in the regulation of intracellular calcium homeostasis, various enzyme activities, cell signal transduction, nuclear function and gene expression, and cell proliferation and apoptosis. Moreover, regucalcin has been found to play a role in the regulation of bone homeostasis. Overexpression of regucalcin induces bone loss in regucalcin transgenic rats in vivo and deficiency causes osteomalacia in vivo. Regucalcin mRNA and its protein are expressed in rat femoral tissues, bone marrow cells, and osteoblastic cells. Exogenous regucalcin has suppressive effects on the differentiation and mineralization of osteoblastic MC3T3-E1 cells and stimulates osteoclastogenesis in mouse bone marrow culture in vitro. Moreover, regucalcin has been found to suppress osteoblastogenesis and stimulate adipogenesis in the bone marrow culture system in vitro. Regucalcin shows enhancing effects on activation of NF-κB, which is mediated through tumor necrosis factor-α (TNF-α) or the receptor activator of the NF-κB ligand (RANKL) in preosteoblastic cells and preosteoclastic cells. Exogenous regucalcin may play a pivotal role in the regulation of bone homeostasis as a suppressor in osteoblastogenesis and an enhancer in osteoclastogenesis, suggesting its role as a cytokine.