Lubricin maintains temporomandibular joint homeostasis by regulating synovial inflammation.

INTRODUCTION: Temporomandibular joint osteoarthritis (TMJ-OA) is a degenerative joint disease characterized by cartilage degeneration, synovial inflammation, and subchondral bone remodeling, yet its molecular pathogenesis remains poorly understood. In this study, we investigated the role of proteoglycan 4 (Prg4), also known as lubricin, in maintaining temporomandibular joint (TMJ) homeostasis under physiological and pathological conditions, with the aim of exploring its potential for regenerative therapeutic applications. METHODS: Using high-resolution Visium HD spatial transcriptomics, we examined the spatial distribution of Prg4 expression within the TMJ. To model TMJ-OA, surgically induced anterior disc displacement (ADD) was performed in wild-type (WT) and Prg4-knockout (Prg4-KO) mice. In addition, inflammatory stimulation with IL-1β was applied to synovial cells in vitro. Lineage tracing approaches were used to track Prg4-expressing cells under pathological conditions. RESULTS: Spatial transcriptomics revealed that Prg4 expression was highly localized to the posterior synovium of the articular disc, with markedly lower expression in anterior regions. While sham-operated TMJs remained histologically intact, the ADD model resulted in condylar deformation, cartilage degeneration, synovial hyperplasia, and subchondral bone loss-phenotypes that were significantly exacerbated in Prg4-KO mice. Furthermore, IL-1β stimulation increased matrix metalloproteinase expression in Prg4-deficient synovial cells. Lineage tracing demonstrated expansion of Prg4-expressing cells within inflamed synovial tissues in the ADD model. Quantitative analysis revealed that Prg4 expression was transiently increased at 2 weeks after ADD induction and returned to control levels by 8 weeks, indicating a time-dependent regulatory role during inflammation. CONCLUSION: These findings highlight the region-specific and time-dependent function of Prg4 in the TMJ and underscore its critical role in suppressing joint inflammation and degeneration. Importantly, our results suggest that modulation of Prg4 expression or lubricin supplementation could serve as a regenerative therapeutic strategy for preserving TMJ homeostasis and preventing chronic degenerative progression, providing a promising avenue for clinical translation in TMJ-OA treatment.