Mechanistic Impact of Relaxin-2 on Human Post-Menopausal Knee Osteoarthritis Chondrocytes

Background and/or Objectives: Females are at a higher risk for knee osteoarthritis (KOA) and are likely to experience more symptomatic and severe KOA than males. Relaxin-2, a sex hormone produced in higher levels in females than males, has widespread musculoskeletal effects including cartilage matrix degeneration and anti-fibrotic activity (through regulating mitochondrial integrity) in synovial joints. However, relaxin-2’s mechanistic impact on human chondrocytes and subsequent involvement with KOA remains incompletely characterized. The objective of this work was to analyze relaxin-2’s impact on post-menopausal human KOA chondrocyte phenotype.

Design: This was a translational research study that evaluated relaxin-2 using an in vitro post-menopausal human KOA chondrocyte culture model.

Setting : Academic research laboratory.

Participants : KOA chondrocytes isolated from post-menopausal human.

Interventions: Female KOA chondrocytes were treated with varying relaxin-2 concentrations (control: 0pg/mL, low: 0.496pg/mL, medium: 49.6pg/mL, and high: 4960pg/mL; n=5/group) based on previously reported physiologic serum levels.

Main Outcome Measures: The outcome measures included markers of chondrogenicity (Collagen Type 1 [Col1] and 2 [Col2]), degradation (Matrix Metalloproteinase-13 [MMP-13]), and mitochondrial integrity (Translocase Of Outer Mitochondrial Membrane 20 [TOMM20]) assessed using immunofluorescence.

Results: Treatment with relaxin-2 showed an improvement in chondrocyte phenotype, with the most favorable response to the low relaxin-2 concentration. For the low, medium, and high relaxin-2 concentrations, the Col2/Col1 ratio was 1.9, 1.6, and 1.2 times greater than the control, respectively. MMP13 expression decreased with low (p=0.02) and high (p=0.04) relaxin-2 concentrations compared to the control. Relaxin-2 treatment also preserved mitochondrial integrity, as illustrated by increased TOMM20 expression with low, medium, and high relaxin-2 concentrations compared to the control (p=0.01, p=0.03, and p=0.01, respectively).

Conclusions: Relaxin-2 may reprogram post-menopausal osteoarthritic chondrocytes towards a more youthful state through improving chondrocyte phenotype. These findings suggest that relaxin-2, at physiologic serum levels, could serve as a disease-modifying treatment for KOA by restoring mitochondrial function, and may underlie the therapeutic effects of platelet-rich plasma therapy for osteoarthritis.