title: Pathophysiological mechanisms in osteoarthritis lead to novel therapeutic strategies.
abstract: Osteoarthritis (OA) is a debilitating, progressive disease of diarthrodial joints associated with aging. At the molecular level, OA is characterized by an imbalance between anabolic (i.e. extracellular matrix biosynthesis) and catabolic (i.e. extracellular matrix degradation) pathways in which articular cartilage is the principal site of tissue injury responses. The pathophysiology of OA also involves the synovium in that 'nonclassical' inflammatory synovial processes contribute to OA progression. Chondrocytes are critical to the OA process in that the progression of OA can be judged by the vitality of chondrocytes and their ability to resist apoptosis. Growth factors exemplified by insulin-like growth factor-1, its binding proteins and transforming growth factor-beta contribute to anabolic pathways including compensatory biosynthesis of extracellular matrix proteins. Catabolic pathways are altered by cytokine genes such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) which are upregulated in OA. In addition, IL-1 and TNF-alpha downregulate extracellular matrix protein biosynthesis while concomitantly upregulating matrix metalloproteinase (MMP) gene expression. When MMPs are activated, cartilage extracellular matrix degradation ensues apparently because levels of endogenous cartilage MMP inhibitors cannot regulate MMP activity. Therapeutic strategies designed to modulate the imbalance between anabolic and catabolic pathways in OA may include neutralizing cytokine activity or MMP gene expression or inhibiting signaling pathways which result in apoptosis dependent on mature caspase activity or mitogen-activated protein kinase (MAPK) activity. MAPK activity appears critical for regulating chondrocyte and synoviocyte apoptosis and MMP genes.
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine, and Research Institute of University Hospitals of Cleveland, Ohio 44106-5076, USA. cjm4@po.cwru.edu
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Malemud
authors.forename: Najmul
authors.initials: N
authors.lastname: Islam
authors.forename: Tariq M
authors.initials: TM
authors.lastname: Haqqi
mesh_terms: D000818:Animals; D002356:Cartilage / Q000276:immunology / Q000503:physiopathology*; D006801:Humans; D007596:Joints / Q000276:immunology / Q000503:physiopathology*; D010003:Osteoarthritis / Q000276:immunology / Q000503:physiopathology* / Q000628:therapy*