Lucy Robinson: Male vs female differences in WNT/β-catenin and pCaMKII signalling in osteoarthritic chondrocytes

<p dir="ltr">Osteoarthritis (OA) is a disabling disease characterised by cartilage loss. Women are more susceptible than men, yet female rodents are largely protected, consequently, all pre-clinical OA drug testing is conducted in males. This is a major limitation as WNT signalling, a key pathway in OA, is sexually dimorphic. Both the canonical and non-canonical e.g. CaMKII (calcium/calmodulin kinase II) WNT pathways can cause OA-like changes in chondrocytes driving cartilage loss, but canonical signalling predominates in rodent models and are the focus of OA drug development. We compared WNT signalling in human OA chondrocytes from females and males (n=11) following knee arthroplasty. Using concentration series of 3 WNT ligands, canonical and non-canonical WNT signalling activity was compared by AlphaLISA and effects on disease-relevant chondrocyte activity determined by RT-qPCR and ELISA. OA chondrocytes from females upregulated both noncanonical CaMKII and canonical signalling in response to WNT ligands whereas males predominantly upregulated canonical signalling. Females responded to lower concentrations of WNT ligands than males, with reduced collagen II expression and increased matrix metalloproteinase 13 following WNT treatment. Conversely MMP13 expression was reduced by WNT treatment in males. WNT signalling differs between male and female OA chondrocytes with potential anti-anabolic, pro-catabolic effects in females but anti-catabolic effects in males. Results from this study suggest male/female specific drug development strategies are required for OA.</p>