title: Relaxin's induction of metalloproteinases is associated with the loss of collagen and glycosaminoglycans in synovial joint fibrocartilaginous explants.
abstract: Diseases of specific fibrocartilaginous joints are especially common in women of reproductive age, suggesting that female hormones contribute to their etiopathogenesis. Previously, we showed that relaxin dose-dependently induces matrix metalloproteinase (MMP) expression in isolated joint fibrocartilaginous cells. Here we determined the effects of relaxin with or without beta-estradiol on the modulation of MMPs in joint fibrocartilaginous explants, and assessed the contribution of these proteinases to the loss of collagen and glycosaminoglycan (GAG) in this tissue. Fibrocartilaginous discs from temporomandibular joints of female rabbits were cultured in medium alone or in medium containing relaxin (0.1 ng/ml) or beta-estradiol (20 ng/ml) or relaxin plus beta-estradiol. Additional experiments were done in the presence of the MMP inhibitor GM6001 or its control analog. After 48 hours of culture, the medium was assayed for MMPs and the discs were analyzed for collagen and GAG concentrations. Relaxin and beta-estradiol plus relaxin induced the MMPs collagenase-1 and stromelysin-1 in fibrocartilaginous explants--a finding similar to that which we observed in pubic symphysis fibrocartilage, but not in articular cartilage explants. The induction of these proteinases by relaxin or beta-estradiol plus relaxin was accompanied by a loss of GAGs and collagen in joint fibrocartilage. None of the hormone treatments altered the synthesis of GAGs, suggesting that the loss of this matrix molecule probably resulted from increased matrix degradation. Indeed, fibrocartilaginous explants cultured in the presence of GM6001 showed an inhibition of relaxin-induced and beta-estradiol plus relaxin-induced collagenase and stromelysin activities to control baseline levels that were accompanied by the maintenance of collagen or GAG content at control levels. These findings show for the first time that relaxin has degradative effects on non-reproductive synovial joint fibrocartilaginous tissue and provide evidence for a link between relaxin, MMPs, and matrix degradation.
authors.affiliation: University of California, San Francisco, USA. sheema@hotmail.com
authors.forename: Tabassum
authors.initials: T
authors.lastname: Naqvi
authors.forename: Trang T
authors.initials: TT
authors.lastname: Duong
authors.forename: Gihan
authors.initials: G
authors.lastname: Hashem
authors.forename: Momotoshi
authors.initials: M
authors.lastname: Shiga
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhang
authors.forename: Sunil
authors.initials: S
authors.lastname: Kapila
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects* / Q000378:metabolism; D003094:Collagen / Q000378:metabolism*; D017364:Collagenases / Q000096:biosynthesis / Q000235:genetics; D004151:Dipeptides / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D051445:Fibrocartilage / Q000187:drug effects* / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism*; D007719:Knee Joint / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000096:biosynthesis* / Q000235:genetics; D009924:Organ Culture Techniques; D009928:Organ Specificity; D011631:Pubic Symphysis / Q000378:metabolism; D011817:Rabbits; D012065:Relaxin / Q000008:administration & dosage / Q000494:pharmacology*; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism; D013704:Temporomandibular Joint / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D004151:Dipeptides; D016326:Extracellular Matrix Proteins; D006025:Glycosaminoglycans; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D019715:Tissue Inhibitor of Metalloproteinase-1; D004958:Estradiol; D012065:Relaxin; D003094:Collagen; D017364:Collagenases; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3