The unique molecular signature of TMJ as compared to the knee, demonstrates its susceptibility to osteoarthritis.

Osteoarthritis (OA) is a debilitating joint disease that affects millions of people worldwide, with prominent effects on the temporomandibular joints (TMJs) and knee. Despite its prevalence, TMJ-OA remains understudied. This study investigated the transcriptional signature of the TMJ compared to that of the knee and explored transcriptional differences in the medial and superficial layers of TMJ-OA. TMJ and knee tissue samples were collected from 6-month-old C57BL/6 J mice. TMJ superficial and medial layer cartilage from goats were collected, separated, and treated with interleukin (IL)-1β. All samples were subjected to bulk RNA sequencing, followed by differential expression and gene-set enrichment analyses. A total of 4031 protein-coding genes were identified that were 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 OA biomarkers (Mmp13, Postn, and Col1a1) were more highly expressed in the TMJ, indicating higher vulnerability to OA development. IL-1β treatment of goat TMJ chondrocytes mimicked the natural TMJ-OA-like transcriptional changes and immune responses, which are also observed in a rabbit TMJ-OA model. These results validated the in vitro goat TMJ-OA model. The IL-1β-treated goat TMJ medial cartilage layer was enriched with OA-associated transcription factors, senescence genes, and epigenetic regulators. This study demonstrated the unique transcriptomic signature of the TMJ compared to that of the knee, identifying differential vulnerabilities to OA- and pain-related genes. These findings provide valuable insights into the molecular mechanisms and therapeutic target selection for TMJ-OA treatment.