RANKL and RANK as novel therapeutic targets for arthritis.
The TNF-family molecule receptor activator of nuclear factor kappa B (NFkappaB) ligand (RANKL) (OPGL, TRANCE, ODF) and its receptor activator of NFkappaB (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.
Nakashima
Tomoki
T
IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.
Wada
Teiji
T
Penninger
Josef M
JM
D000818:Animals; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000503:physiopathology*; D016723:Bone Remodeling / Q000276:immunology / Q000502:physiology; D002352:Carrier Proteins / Q000502:physiology*; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000502:physiology; D005260:Female; D006023:Glycoproteins / Q000502:physiology*; D006801:Humans; D008024:Ligands; D008297:Male; D010010:Osteoclasts / Q000502:physiology; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor; D012307:Risk Factors; D012680:Sensitivity and Specificity
D018501:Antirheumatic Agents; D002352:Carrier Proteins; D006023:Glycoproteins; D008024:Ligands; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506030:TNFRSF11B protein, human