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 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 relaxininduced 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.

Relationship of Relaxin Hormone and Thumb Carpometacarpal Joint Arthritis

“…The effect of relaxin to increase expression of MMPs has been shown previously in vitro in fibrochondrocytes cultured from the temporomandibular joint [23,29]. We noted a correlation between serum relaxin and MMP-1, suggesting a potential connection with binding to relaxin receptors in the ligament with subsequent upregulation of MMP-1 transcription.…”

Effects of human relaxin on orthodontic tooth movement and periodontal ligaments in rats

“…26 Relaxin has been immunolocalized on PDL fibers and cranial sutures in both male and female mice.26 Moreover, there is a link between relaxin, matrix metalloproteinases, and matrix degradation; relaxin was found to induce degradative mediators in the nonreproductive, fibrocartilaginous synovial discs of temporomandibular joints. 30 In an effort to discern the effect of relaxin on bone metabolism, we found relaxin to increase tumor necrosis factor-and interleukin-1β secretion in supernatants from peripheral blood mononuclear cells. 31 Based on this, relaxin might have effects on osteoclastic behavior resulting in increased bone resorption, but there is no direct evidence for this effect.…”

Relaxin: Antifibrotic Properties and Effects in Models of Disease

“…42 In limited studies, relaxin has also been shown to inhibit glycosaminoglycan content (which is known to play a role in tissue hydration) in fibrocartilaginous joints. 43 …”