Osteoprotegerin-Ligand in osteoporosis, arthritis, and mammary gland development

다국어 초록 (Multilingual Abstract)

The morphogenesis and remodelling of bone requires the synthesis of bone matrix by osteoblasts and its coordinated resorption by osteoclasts. The TNF family molecule Osteoprotegerin-ligand(OPGL; also known as ODF, TRANCE, and RANKL) is a key factor stimulating the differentiation and activation of osteoclasts, and is therefore essential for bone remodelling and calcium mobilization from the bones. Inactivation of the opgl gene in mice results in a complete block in osteoclast development that leads to severe osteopetrosis and a failure in tooth eruption. OPGL exerts its effects on osteoclasts by binding to the TNFR family receptor RANK(receptor activator of NFkB). Osteoprotegerin(OPG) acts as a soluble decoy receptor and competes with RANK for binding to OPGL. The balance between OPGL and OPG levels determines osteoclast activation, skeletal calcium release, and bone remodelling. Abnormalities in the OPGL/RANK/OPG system lead to the increased bone resorption that underlies the bone damage of postmenopausal osteoporosis, Paget's disease, bone loss in metastatic cancers and crippling rheumatoid arthritis.
In mammals, calcium transport from the mother to the fetus and neonates is a vital process to preserve the species. Mothers meet the increased requirements for calcium during pregnancy and lactation by doubling their intestinal calcium absorption and demineralizing their skeletons via activation of bone-resorbing osteoclasts. Recently we demonstrated that OPGL and RANK, the master regulators of skeletal calcium release, are essential for the formation of the lactating mammary gland, the organ required for transmission of maternal calcium to neonates in mammalian species. Moreover, we found that pregnancy hormones induce OPGL expression in mammary epithelial cells and milk protein genes, β-casein and whey acidic protein, are induced by OPGL through C/EBPβ transcriptional factor, thus a mechanism independent of STAT5.