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Despite this clinical disparity, the molecular mechanisms underlying female\u2010specific vulnerability remain poorly defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To evaluate the mechanistic role of relaxin\u20102 in postmenopausal KOA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>This was a translational research study that evaluated relaxin\u20102 using an in vitro postmenopausal human KOA chondrocyte culture model and in silico network medicine simulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Setting<\/jats:title>\n                    <jats:p>Research laboratory.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Specimens<\/jats:title>\n                    <jats:p>KOA chondrocytes isolated from a 67\u2010year\u2010old postmenopausal female human donor.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interventions<\/jats:title>\n                    <jats:p>\n                      Female KOA chondrocytes were treated with varying relaxin\u20102 concentrations (control: 0\u2009pg\/mL, low: 0.496\u2009pg\/mL, medium: 49.6\u2009pg\/mL, and high: 4960\u2009pg\/mL;\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20095\u20107\/group), with doses based on previously reported physiologic serum levels for pre\u2010 and postmenopausal female individuals.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main Outcome Measure(s)<\/jats:title>\n                    <jats:p>Effects were evaluated by immunofluorescence analysis of chondrogenicity markers (type II collagen [Col2], aggrecan [ACAN]), fibrotic markers (type I collagen [Col1], type III collagen [Col3]), extracellular matrix degradation markers (matrix metalloproteinase\u201013 [MMP\u201013], A Disintegrin And Metalloproteinase with Thrombospondin Motifs 4 [ADAMTS4]), and mitochondrial integrity and function markers (translocase of the outer mitochondrial membrane 20 [TOMM20], Succinate Dehydrogenase Subunit A [SDHA], Peroxisome Proliferator\u2010Activated Receptor Gamma Coactivator 1\u2010alpha [PGC\u20101\u03b1]).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Relaxin\u20102 increased Col2 at low and medium concentrations (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.05), with the Col2\/Col1 ratio highest at the low dose relaxin\u20102. MMP\u201013 expression was greatest for the medium compared to the control (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u2009.73), low (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u2009.002), and high relaxin\u20102 concentrations (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u2009.005), whereas ACAN and ADAMTS4 showed no differences across concentrations (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&gt;\u2009.05). In silico analysis revealed that postmenopausal female individuals exhibit a fibrotic transcriptomic signature and that mitochondrial function is regulated by relaxin\u20102 in fibrotic chondrocytes. Computational analyses were validated experimentally, with TOMM20 and SDHA elevated at all relaxin\u20102 concentrations (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.05), whereas PGC\u20101\u03b1 was reduced at high concentration (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.05).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings demonstrate that relaxin\u20102 reprograms fibrotic osteoarthritic chondrocytes toward a healthier, less fibrotic state by restoring mitochondrial function.<\/jats:p>\n                  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