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 β-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 β-estradiol (20 ng/ml) or relaxin plus β-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 β-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 β-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 β-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.
Highlights
In certain sites in and around joints, ligaments and tendons subjected to complex tensile and compressive loading specialize into fibrocartilaginous tissues [1,2,3] containing types I and II collagens and cartilage-specific proteoglycans
Relaxin and β-estradiol induce collagenase-1 and stromelysin-1 in temporomandibular joint (TMJ) disc explants Explanted discs constitutively expressed collagenase-1 (MMP-1) (Fig. 1a, lane 1), and the expression of this proteinase was increased by exposure to relaxin alone or to βestradiol plus relaxin (Fig. 1a, lanes 3 and 4)
Because the gelatinolytic enzymes were inhibited by 1,10-phenanthroline (Fig. 1b, lane 5), these proteinases were characterized as matrix metalloproteinase (MMP), most probably procollagenase-1 and active collagenase-1
Summary
In certain sites in and around joints, ligaments and tendons subjected to complex tensile and compressive loading specialize into fibrocartilaginous tissues [1,2,3] containing types I and II collagens and cartilage-specific proteoglycans. These tissues include specific regions of the metacarpophalangeal ligament and the deep flexor tendon, the temporomandibular joint (TMJ) disc, and the pubic symphysis. The relative contribution of matrix synthesis and degradation to these relaxin-mediated changes is not clear, collagen loss through increased proteolysis has been suggested [4], and studies in relaxin-knockout mice have implicated increased collagenase activity [11].
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