BACKGROUND: Postmenopausal female individuals are disproportionately affected by knee osteoarthritis (KOA), experiencing earlier onset and more severe pathology compared to their male counterparts. Despite this clinical disparity, the molecular mechanisms underlying female-specific vulnerability remain poorly defined. OBJECTIVE: To evaluate the mechanistic role of relaxin-2 in postmenopausal KOA. DESIGN: This was a translational research study that evaluated relaxin-2 using an in vitro postmenopausal human KOA chondrocyte culture model and in silico network medicine simulation. SETTING: Research laboratory. SPECIMENS: KOA chondrocytes isolated from a 67-year-old postmenopausal female human donor. INTERVENTIONS: Female KOA chondrocytes were treated with varying relaxin-2 concentrations (control: 0 pg/mL, low: 0.496 pg/mL, medium: 49.6 pg/mL, and high: 4960 pg/mL; n = 5-7/group), with doses based on previously reported physiologic serum levels for pre- and postmenopausal female individuals. MAIN OUTCOME MEASURE(S): 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-13 MMP-13, 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-Activated Receptor Gamma Coactivator 1-alpha PGC-1α). RESULTS: Relaxin-2 increased Col2 at low and medium concentrations (p .05). In silico analysis revealed that postmenopausal female individuals exhibit a fibrotic transcriptomic signature and that mitochondrial function is regulated by relaxin-2 in fibrotic chondrocytes. Computational analyses were validated experimentally, with TOMM20 and SDHA elevated at all relaxin-2 concentrations (p < .05), whereas PGC-1α was reduced at high concentration (p < .05). CONCLUSIONS: These findings demonstrate that relaxin-2 reprograms fibrotic osteoarthritic chondrocytes toward a healthier, less fibrotic state by restoring mitochondrial function.
Katz et al. (Sun,) studied this question.