title: Negative Regulators of JAK/STAT Signaling in Rheumatoid Arthritis and Osteoarthritis.
abstract: Elevated levels of pro-inflammatory cytokines are generally thought to be responsible for driving the progression of synovial joint inflammation in rheumatoid arthritis (RA) and osteoarthritis (OA). These cytokines activate several signal transduction pathways, including the Janus kinase/Signal Transducers and Activators of Transcription (JAK/STAT), Stress-Activated/Mitogen-Activated Protein Kinase (SAPK/MAPK) and phosphatidylinositol-3-kinase/Akt/mechanistic target of rapamycin (PI3K/Akt/mTOR) pathways which regulate numerous cellular responses. However, cytokine gene expression, matrix metalloproteinase gene expression and aberrant immune cell and synoviocyte survival via reduced apoptosis are most critical in the context of inflammation characteristic of RA and OA. Negative regulation of JAK/STAT signaling is controlled by Suppressor of Cytokine Signaling (SOCS) proteins. SOCS is produced at lower levels in RA and OA. In addition, gaining further insight into the role played in RA and OA pathology by the inhibitors of the apoptosis protein family, cellular inhibitor of apoptosis protein-1, -2 (c-IAP1, c-IAP2), X (cross)-linked inhibitor of apoptosis protein (XIAP), protein inhibitor of activated STAT (PIAS), and survivin (human) as well as SOCS appears to be a worthy endeavor going forward.
authors.affiliation: Department of Medicine, Division of Rheumatic Diseases, Case Western Reserve University School of Medicine, University Hospitals Cleveland Medical Center, Foley Medical Building, 2061 Cornell Road, Room 207, Cleveland, OH 44106-5076, USA. cjm4@cwru.edu.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Malemud
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D019902:Chondrocytes / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism*; D010003:Osteoarthritis / Q000378:metabolism*; D011485:Protein Binding; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D051034:Inhibitor of Apoptosis Proteins; D050791:STAT Transcription Factors; D053612:Janus Kinases
keywords: apoptosis; arthritis; chondrocytes