Femur Shape Changes in Prg4‐Deficient Mice: Morphological Insights Into Joint Well‐Being

Many studies have reported on the role of Proteoglycan-4 (PRG4, aka lubricin) in the reduction of friction between cartilage surfaces with a specific focus on chondroprotection within the joint. Disruption of the Prg4 gene in humans and mice leads to premature joint failure, hallmarked by synovial hyperplasia and premature articular cartilage fibrillation. Our group has published extensively using Prg4 knockout mice and has consistently noticed variable distal femoral morphology in these animals when compared to Prg4^+/+ wild-types (WT). This prompted us to undertake a quantitative study examining joint element size and shape to elucidate if this phenotype was consistent in a larger sample size. High-resolution X-ray microscopy (XRM) images were obtained from WT and Prg4^-/- mice between 8- and 36 weeks of age. We then employed geometric morphometrics to characterize mouse femora shape changes, which were correlated to cross-sectional histological findings. We find that Prg4^-/- femora vary in size and shape compared to WT controls; distal femora in Prg4^-/- mice are enlarged, extended (anteroposterior) and narrower (mediolateral), with the largest regional deviations being traced to the trochlear groove, epicondyles, and medial condyle. Additionally, quantifiable changes in condylar articular cartilage thickness were associated with abnormal compressive biomechanical properties. Collectively, these data suggest that PRG4 loss extends beyond joint homeostasis and critically impacts joint morphology.