Relaxin Effects on Female Anterior Cruciate Ligament Cells

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Relaxin Effects on Female Anterior Cruciate Ligament Cells

It has been found that the female collegiate athletes with serum relaxin concentrations above 6.0 pg/mL have more than 4 times increased risk for anterior cruciate ligament (ACL) tears. However, the intracellular effect of relaxin on ACL cells has not been elucidated. To elucidated that, a study was conducted.

A study was conducted which was based on the hypotheses that relaxin binding to receptors on female ACL cells result in an increase in matrix metallo-proteinase (MMP) and decreased tissue inhibitor of metallo-proteinase (TIMP) gene expression, decrease in collagen and alpha smooth muscle actin (αSMA) expression, inhibition of transforming growth factor β1 (TGFβ1)–induced fibrosis, and an increase in cyclic adenosine 3',5' monophosphate (cAMP) production and that these changes will not be observed in male ACL cells.

In the trial, ligament cells from ACL tissue were isolated from 7 male and 7 female human donors and expanded in vitro. The cells were incubated with escalating concentrations of relaxin-2 as well as with TGFβ1 or 17β-estradiol in certain groups. Cells were then lysed and analyzed for MMP 1(collagenase-1), MMP3 (stromelysin-1), MMP13 (collagenase-3), TIMP1, type I collagen, type III collagen, and/or αSMA mRNA expression using quantitative real-time polymerase chain reaction. Intracellular cAMP levels were assessed via an enzyme-linked immunoassay.

ACL cells primed with estrogen and treated with 10 ng/mL and 100 ng/mL relaxin illustrated increased MMP1 expression and MMP3 expression. Treatment with 100 ng/mL relaxin decreased αSMA expression. When ACL tissue isolated from female donors with a history of oral contraceptive use was excluded from the analysis, 100 ng/mL of relaxin decreased type I collagen and type III collagen expression in cells primed with estrogen. Relaxin exhibited no significant effect on male-derived ACL cells. ACL cells primed with estrogen and treated with 10 ng/mL and 100 ng/mL relaxin illustrated increased MMP1 expression and MMP3 expression. Treatment with 100 ng/mL relaxin decreased αSMA expression. When ACL tissue isolated from female donors with a history of oral contraceptive use was excluded from the analysis, 100 ng/mL of relaxin decreased type I collagen and type III collagen expression in cells primed with estrogen. Relaxin exhibited no significant effect on male-derived ACL cells.

It was concluded that relaxin-2 significantly up-regulated the intracellular processes in human female ACL cells but no effect was observed in male cells. Increased relaxin MMP and decreased αSMA and type I and III collagen expression, which may act to alter the structural integrity of the ACL tissue over time. Female athletes with higher circulating relaxin levels might be more susceptible to ACL injury.

American Journal of Sports Medicine
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