Single-cell transcriptional atlas reveals distinct immune-chondrocyte crosstalk mechanisms in temporomandibular joint osteoarthritis induced by different types of occlusal disorder.

Temporomandibular joint (TMJ) osteoarthritis (OA) is a progressive degenerative disease in which the intricate mechanisms of the condyle cartilage damage are yet to be disclosed. A detailed characterization of cellular composition and signal networks involved in the pathogenesis is in need. This study, for the first time, identified chondrocytes heterogeneity and subchondral immune microenvironments based on single-cell transcriptomes of the mouse mandibular condyle, and provided insights into the cellular and signaling basis of the homeostasis of the condyle and pathogenesis of TMJOA by healthy-to-diseased comparisons. The differentially expressed gene pattern distinguished 8 chondrocyte subsets and 9 immune cell types in the condyle. Close interactions were found between these cell populations, with enhanced communication between chondrocytes and immune cell subsets in the condyles subjected to anterior premature contact (APC) model or unilateral anterior crossbite (UAC) model. The single-cell transcriptomic changes suggested predominant roles of neutrophils in immune-chondrocyte interactions in these occlusal disorder models. Neutrophils-derived TNF-α signaling was inferred to be the most greatly enhanced information flow in the condyle of the APC model, while increased Thbs1-Sdc4 signaling in mediating neutrophils-to-chondrocytes interactions was indicated in the UAC-model condyle, with predominant BSP signaling. Interfering in these signaling by drug administration demonstrated therapeutic potential for the APC- or UAC-induced TMJOA.