Oral Presentation ANZBMS-MEPSA-ANZORS 2022

Sex differences in a pre-clinical model of injury-induced osteoarthritis (#95)

Sasha Gonzales-malcolm 1 , Carina Blaker 2 , Christopher Little 2 , Sanaa Zaki 1
  1. Sydney School of Veterinary Science, University of Sydney, Camperdown, NSW, Australia
  2. The Kolling Institute of Medical Research, St Leonards, NSW, Australia

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Background: Osteoarthritis (OA) is a complex heterogeneous joint disease. Prevalence is higher in women who also suffer worse symptoms than men. However, despite well-established sex differences most pre-clinical research is conducted in males. Consequently, the female OA animal model phenotype is poorly defined. We investigated differences in male and female OA severity and progression in a well-established murine model of post-injury OA to better characterise the female phenotype in this model.

Methods: Male and female 10-week C57BL6 mice had unilateral anterior cruciate ligament rupture (ACLR) to induce knee OA or sub-critical injury. Tactile allodynia, local hyperalgesia and hindlimb weight distribution (HLWD) were measured at baseline and week-1/-2/-4/-8/-16. Joints were harvested week-4/-8/-16 post-injury. Joint-wide histopathology was quantified by scoring articular cartilage (AC), synovium, subchondral bone (SCB), menisci & osteophyte/enthesophyte pathology. Associations between different histology scores were determined using Kendall’s tau-b partial correlation coefficients.

Results: Both males and females developed allodynia, mechanical-hyperalgesia and altered HLWD. Sex differences were only observed in sub-critical injury mice. Despite similar pain, sex differences were identified in the measured histopathology outcomes in ACLR mice. Males had worse OA pathology than females for AC damage and proteoglycan loss at week-8 and 16. Osteochondral and meniscus damage was worse in males. In contrast, females demonstrated greater anterior meniscus bone formation (week-8) and posterior pannus (week-16). There were no significant sex differences for SBC sclerosis, osteophyte and enthesophyte formation. Sex-specific tissue pathology correlations were observed predominantly in females; positive correlations between posterior joint fibrosis and proteoglycan loss (r=0.52) and SCB sclerosis (r=0.60), whole joint AC damage and pannus (r=0.55), and posterior joint AC damage and SCB sclerosis (r=0.77).

Conclusions:These findings define the female phenotype of an established OA model and suggest the mechanisms driving OA joint pathology are sex-specific, thus highlighting the current ‘sex’ gap in pre-clinical OA research.