Alterations in the self-renewal and differentiation ability of bone marrow mesenchymal stem cells in a mouse model of rheumatoid arthritis

We have used Balb/C Interleukin-1 receptor antagonist knock-out mice, which spontaneously develop RA-like disease in 100% of mice by 20 weeks of age to determine the number of mesenchymal progenitors and their differentiated progeny before, at the start and with progression of the disease.We showed a decrease in the number of mesenchymal progenitors with adipogenic potential and decreased bone marrow adipogenesis before disease onset. This is associated with a decrease in osteoclastogenesis. Moreover, at the onset of disease a significant increase in all mesenchymal progenitors is observed together with a block in their differentiation to osteoblasts. This is associated with accelerated bone loss.Significant changes occur in the BM niche with the establishment and progression of RA-like disease. Those changes may be responsible for aspects of the disease, including the advance of osteoporosis. An understanding of the molecular mechanisms leading to those changes may lead to new strategies for therapeutic intervention.Rheumatoid arthritis (RA) is a systemic autoimmune disease characterised by chronic disruptive polyarthritis. There is no cure for RA and today's treatments aim at achieving the lowest possible level of arthritis disease activity. In the UK alone RA costs the health system around ￡560 million a year, and ￡1.8 billion a year in absence from work. The events preceding the disease and leading to its initiation and progression are unknown. Thus, an understanding of these processes is crucial for the identification of new and more cost-effective treatments and for the move from a manageable to a curable disease.Although the main disease site is the synovium, there is growing evidence that the bone marrow (BM) is actively involved and may even be the primary initiating site of the disease [1]. Abnormalities in both the haemopoietic progenitor cells and the BM stroma have been described [2]. Patients with active RA have been seen to exhibit low frequency and a