Differences in male and female mice in a model of early osteoarthritis

Osteoarthritis is a prevalent musculoskeletal disease characterised by joint degeneration and pain. Over the age of 50, women are twice as likely to develop osteoarthritis than men. Given the importance of biological sex in osteoarthritis, we compared early osteoarthritis in male and female mice.

We induced osteoarthritis via surgical destabilisation of the medial meniscus and cartilage scratch (DCS) on 10-week-old male and female mice (n=8). Two weeks after induction we characterised joint parameters via microCT and histology, and pain behaviours by dynamic weight bearing (DWB). We ovariectomised (OVX) 8-week-old females (n=10) and induced osteoarthritis at 11 weeks old. We assessed for pain behaviours via DWB and von Frey testing. Contralateral and ipsilateral dorsal root ganglion (DRG) of male, female sham OVX and female OVX were dissected and processed for gene expression RNAseq analysis.

Male mice showed 31.2 ± 4.5% increase in subchondral bone osteoclerosis while female mice showed a minimal 4.42 ± 6.23 % change in subchondral bone (P < 0.001). There were no significant differences in cartilage damage, synovitis or osteophytogenesis. Males loaded their osteoarthritic leg less than the contralateral (paired t-test P < 0.01), which indicates discomfort. None of the female mice or OVX female mice showed this change in loading. Female OVX mice showed a decrease in mechanical withdrawal threshold in the osteoarthritic leg (0.3 ± 0.12) when compared to the contralateral leg (0.5 ± 0.24, P < 0.05). There were no significant changes in DRG gene expression when comparing osteoarthritic to contralateral side in any of the groups. Female DRG show downregulation of genes involved neuron projection guidance and calcium ion transmembrane transport when compared to males. Female OVX mice showed an upregulation of lymphocyte development pathways when compared to female sham OVX DRG.
The main differences observed in early osteoarthritis between male and female mice resided in the bone and display of pain. Female mice in general have a slower bone modelling rate, which here translates into lower subchondral osteosclerosis. Interestingly, female mice did not display differential pain behaviours compared to male mice, which could be related to the gene expression changes observed in the DRG.