Advances in understanding the genetic basis of rheumatoid arthritis and osteoarthritis: implications for therapy.
Rheumatoid arthritis (RA) and osteoarthritis (OA) are polygenic diseases. Polymorphisms in candidate genes have been studied for possible association with susceptibility to disease development. Aside from HLA polymorphisms, of particular interest are those in genes encoding cytokines, signaling molecules, and enzymes involved in the production and catabolism of oxygen and nitrogen radicals. Cytokines are involved in the modulation of the pathological process and have been the target for novel therapeutic interventions. Evidence for their involvement in RA and OA has been provided from genetic analyses in patient populations as well as from animal models of disease. Intracellular signaling cascades control cellular responses and thus regulate many aspects of the pathology manifested in rheumatic diseases. Deciphering the organization and activity of such signaling pathways in disease is underway. Polymorphisms have been identified in gene promoter regions regulating efficient binding of transcription factors, and in coding regions of genes whose products are involved in signal cascades relevant to RA. Among these are the NF-kappaB pathway, steroid receptors and the p53 tumor suppressor gene. Both reactive oxygen species (ROS) and reactive nitrogen species (RNS) have also been implicated in rheumatic diseases. It is thought that excess, damaging, ROS/RNS may arise from an imbalance between the production and removal of these chemical species. Polymorphisms in genes that encode enzymes involved in either generating or degrading ROS/RNS may contribute to such an imbalance. In the last few years, polymorphisms in such genes have indeed been identified as risk factors for rheumatic diseases.
Chernajovsky
Yuti
Y
Bone and Joint Research Unit, Queen Mary's School of Medicine and Dentistry, Barts and The London, University of London, London, UK. y.chernajovsky@qmul.ac.uk
Winyard
Paul G
PG
Kabouridis
Panagiotis S
PS
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D023281:Genomics / Q000379:methods; D006801:Humans; D010003:Osteoarthritis / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D015398:Signal Transduction / Q000502:physiology
D016207:Cytokines; D005609:Free Radicals