Raut, R. D.; Choudhury, C.; Chakraborty, A. K.; Singh, H.; Mehra, P.; Gerstenfeld, L.; Almarza, A.; Bais, M. V.

Objectives: Osteoarthritis (OA) is a debilitating joint disease that affects millions of people worldwide, with the temporomandibular joint (TMJ) and knee joint being prominently affected. Despite its prevalence, TMJ-OA remains understudied. This study aimed to investigate the transcriptional signature of the TMJ compared to that of the knee joint and to explore transcriptional differences in the medial and superficial layers of the TMJ-OA. Design: Six-month-old C57BL/6J mice TMJ and knee samples were collected. Goat TMJ superficial and medial layer cartilage was separated and treated with IL-1{beta}. All samples were subjected to bulk RNA sequencing followed by differential expression and gene set enrichment analysis. Results: We identified 4,031 protein-coding genes differentially expressed in the TMJ compared to the knee, with significant enrichment of neuronal system genes and lower enrichment of innate immune system genes. Key osteoarthritis biomarkers such as Mmp13, Postn, and Col1a1 were more highly expressed in the TMJ, indicating a higher vulnerability to OA development. IL-1{beta} treatment in goat TMJ chondrocytes mimicked the natural TMJ-OA-like transcriptional changes and immune responses, which are also observed in the rabbit TMJ-OA model. This validated the in vitro goat TMJ-OA model. The IL-1{beta}-treated goat TMJ medial cartilage layer was enriched in OA-associated transcription factors (TFs), senescence genes, and epigenetic regulators. Conclusion: Our study demonstrated the unique transcriptomic signature of the TMJ compared with the knee joint, highlighting its vulnerability to OA and pain. These findings provide valuable insights into the molecular mechanisms of TMJ and offer a resource for potential therapeutic target selection for TMJ-OA treatment.