Mechanisms of Disease: the link between RANKL and arthritic bone disease.
Chronic inflammation and bone loss are closely linked pathophysiologic events. The most typical example of inflammatory bone loss is seen in patients with rheumatoid arthritis who develop systemic osteopenia as well as local breakdown of bone in the direct vicinity of inflamed joints. Understanding the mechanisms of arthritic bone degradation is crucial for designing therapies that can specifically protect joints from structural damage. Since osteoclast differentiation and activity are key events in arthritic bone damage, the signals that trigger osteoclastogenesis are potential therapeutic targets. Receptor activator of nuclear factor-kappaB (RANK) is activated by its ligand, RANKL, an essential molecule for osteoclast development: in the absence of RANKL or RANK, osteoclast differentiation from monocyte precursors does not occur. RANKL is expressed on T cells and fibroblasts within the synovial inflammatory tissue of patients with RA and its expression is regulated by proinflammatory cytokines. In animal models of arthritis, blockade of RANKL-RANK interactions, or a genetic absence of RANKL or RANK, protects against joint damage despite the presence of joint inflammation. Therefore, inhibition of RANKL is regarded as a promising future strategy for inhibiting inflammatory bone loss in patients with chronic inflammatory arthritis.
Schett
Georg
G
Medical University of Vienna, Austria. georg.schett@meduniwien.ac.at
Hayer
Silvia
S
Zwerina
Jochen
J
Redlich
Kurt
K
Smolen
Josef S
JS
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000150:complications / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D001851:Bone Diseases, Metabolic / Q000150:complications / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D018450:Disease Progression; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D011379:Prognosis; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D015415:Biomarkers; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D014409:Tumor Necrosis Factor-alpha