Role of osteoclasts in bone resorption of arthritis

Rheumatoid arthritis is characterized by chronic inflammation and the destrucion of cartilage and bone. Whereas investigations on the molecular pathways of chronic inflammation have lead to the identification of TNF-alpha and IL-1 as central mediators of arthritis, the pathogenesis of bone destruction in rheumatoid arthritis is still elusive. Several points of evidence point to the role of osteoclasts in local and systemic bone resorption of arthritis, however, other studies favour an invasive growth of synovial inflammatory tissue as the major cause for bone erosion. This project is to clarify if osteoclasts are necessary to give arthritis its erosive features. Mice transgenic for human tumor necrosis factor (TNF)-alpha will serve as an animal model of a destructive arthritis. This model has many similarities of human rheumatoid arthritis and is characterized by a spontaneous onset of a polyarticular and symetrical arthritis leading to a progressive destruction of cartilage and bone. To identify the role of osteoclasts in TNF-triggered joint destruction, osteoclast differentiation and/or function will be inhibited pharmacologically by either bisphosphonates and/or osteoprotegerin, an inhibitor of osteoclast differentiation. In addition, crossing of TNF-transgenic mice with mice knocked out of c-fos, which have defects in osteoclast formation and thus lack any mature osteoclast should give insights in the role of osteoclasts in TNF- triggered arthritis. For control purposes, TNF-transgenic mice will also be crossed with mice knocked out for JNK1 and p38 which display a normal osteoclast differentiation. Beside the analysis of local bone changes during arthritis also systemic bone changes will be assessed. Bone architecture, bone density and bone resorption and formation will be studied in untreated and treated wild type and TNF-transgenic mice. Also the three knock out models will be subject of such studies. This model provides the opportunity to analyse the basis of inflammation-triggered systemic bone loss and define the effects of TNF-alpha and molecules for osteoclast differentiation such as RANKL in systemic bone resorption Destruction of cartilage and bone is major cause of progressive disability in patients with rheumatoid arthritis. This project should thus help to understand the pathophysiology of bone erosion in arthritis and point to new therapeutic strategies to prevent it.