Growth hormone, VEGF and FGF: involvement in rheumatoid arthritis.
Adult rheumatoid arthritis (RA), a systemic autoimmune disorder of unknown etiology, is characterized by dysfunctional cellular and humoral immunity, enhanced migration and attachment of peripheral macrophages and pro-inflammatory leukocytes to the synovium and articular cartilage of diarthrodial joints. The progressive destruction of cartilage and bone in RA is a result of elevated pro-inflammatory cytokine gene expression, synovial neovascularization, proteinase-mediated dissolution of articular cartilage matrix and osteoclast-mediated subchondral bone resorption. Juvenile chronic arthritis (JCA) is disease with manifestations similar to adult RA that occurs in childhood. JCA usually causes precocious joint destruction and often also presents with evidence of growth plate anomalies and reduced stature. Three proteins play an integral role in both adult RA and JCA. These are somatotropin (also called pituitary growth hormone (GH)), vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). GH is responsible for regulating long bone growth and skeletal maturation through its capacity to stimulate insulin-like growth factor-I (IGF-1) synthesis by hepatocytes. Mechanisms responsible for growth plate disturbances and short stature in children with JCA include deficient GH production, GH-insensitivity resulting from defects in the GH receptor, suppressed IGF-1 synthesis or neutralization of IGF-1 action by IGF-1 binding proteins (IGFBPs). In addition, GH has also been implicated in perpetuating inflammation and pain in adult RA. VEGF has been shown to be the critical angiogenesis factor responsible for vascular proliferation and blood vessel invasion of the synovial lining membrane in RA. Acidic FGF (FGF-1) and basic FGF (FGF-2) have also been implicated in aberrant synoviocyte proliferation (i.e. synovial hyperplasia) and apoptosis resistance in adult RA.
Malemud
Charles J
CJ
Department of Medicine/Division of Rheumatic Diseases, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, 2061 Cornell Road, Room 207 Cleveland, OH 44106-5076, USA. cjm4@cwru.edu
D000818:Animals; D001171:Arthritis, Juvenile / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D049109:Cell Proliferation; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D013006:Growth Hormone / Q000378:metabolism*; D006801:Humans; D009389:Neovascularization, Pathologic; D013583:Synovial Membrane / Q000098:blood supply / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D042461:Vascular Endothelial Growth Factor A; D005346:Fibroblast Growth Factors; D013006:Growth Hormone