The TNF-family molecule receptor activator of nuclear factor kappa B (NFκB) ligand (RANKL) (OPGL, TRANCE, ODF) and its receptor activator of NFκB (RANK) are key regulators of bone remodeling and regulate T cell/dendritic cell communications, and lymph node formation. Moreover, RANKL and RANK are expressed in mammary gland epithelial cells and control the development of a lactating mammary gland during pregnancy. Genetically, RANKL and RANK are essential for the development and activation of osteoclasts and bone loss in response to virtually all triggers tested. Inhibition of RANKL function via the natural decoy receptor osteoprotegerin (OPG, TNFRSF11B) prevents bone loss in postmenopausal osteoporosis and cancer metastases. Importantly, RANKL appears to be the pathogenetic principle that causes bone and cartilage destruction in arthritis, and OPG treatment prevents bone loss at inflamed joints and has partially beneficial effects on cartilage destruction in all arthritis models studied so far. Modulation of these systems provides a unique opportunity to design novel therapeutics to inhibit bone loss and crippling in arthritis.
Abbreviations:AdA adjuvant-induced arthritis, NFκB nuclear factor kappa B, OPG osteoprotegerin, RANKL receptor activator of NFκB ligand, RANK receptor activator of NFκB
Morphogenesis and remodeling of bone involve the synthesis of bone matrix by osteoblasts and the coordinate resorption of bone by osteoclasts [1]. It has been estimated that approximately 10% of the total bone mass in humans is being remodeled per year. Osteoblasts and osteoclasts arise from distinct cell lineages and maturation processes, ie, osteoclasts arise from mesenchymal stem cells while osteoclasts differentiate from hematopoietic monocyte/macrophage precursors [2]. Imbalances between osteoclast and osteoblast activities can arise from a wide variety of hormonal changes or perturbations of inflammatory and growth factors, resulting in skeletal abnormalities characterized by decreased (osteoporosis) or increased (osteopetrosis) bone mass. Increased osteoclast activity is seen in many osteopenic disorders, including postmenopausal osteoporosis, Paget disease, lytic bone metastases, or rheumatoid arthritis, leading to increased bone resorption and crippling bone damage [3].