Species-specific inflammatory responses of chondrocytes: Toward evidence-based model selection in OA research.

To inform evidence-based osteoarthritis model selection, this study compares inflammatory responses of articular chondrocytes from six species (human, horse, sheep, rabbit, rat, and mouse) under standardized IL-1β and TNF-α stimulation in 2D and 3D culture. Chondrocytes were assessed for viability, proliferation, wound healing, and transcriptomic changes via RT-qPCR and 3'RNA sequencing. Marked interspecies differences were observed in morphology, proliferation, and inflammatory gene activation, with only two genes (SOD2, NFKBIA) conserved across all species. Human, horse, and rat chondrocytes shared pathways including acute phase response, deubiquitination, and class-A/1-GPCR signaling. Species-specific responses included matrix remodeling in horses, rheumatoid arthritis-related pathways in sheep, and mixed inflammatory-regenerative profiles in rats. While no species fully replicates human OA, equine and rat chondrocytes best reflect key aspects of human inflammation. These findings underscore the need for molecular criteria in model selection and advocate for human cell-based models when interspecies differences limit the translational value of animal models.