Roles of VWA1 and Rac2 in compensatory and decompensatory responses via FGF9/FGFR3 and p38 MAPK signaling pathways in condylar chondrocytes under distinct mechanical stress.

BACKGROUND/PURPOSE: Few studies paid attention to compensatory and decompensatory responses of condylar cartilage under different mechanical conditions and the underlying mechanism. MATERIALS AND METHODS: Compensatory and decompensatory models were established. In vivo compensatory (0.5 mm occlusal elevation) and decompensatory (1.5 mm elevation) models were established in rats using zirconia occlusal plates. Parallel in vitro models subjected condylar chondrocytes to physiological (6%) or pathological (18%) cyclic tensile strain (CTS). Pivotal candidates that mediate the states of compensation and decompensation were screened through proteomic analysis, and validated through qRT-PCR, Western blot analyses, immunohistochemistry, and Alcian blue staining. RESULTS: Compensatory phenotypes dominated in 0.5 mm iOVD and 6% CTS groups, characterized by upregulated VWA1 expression and FGF9/FGFR3 pathway activation. Conversely, decompensation markers prevailed in 1.5 mm iOVD and 18% CTS groups, showing Rac2 elevation and p38 MAPK pathway induction. Further validation revealed that Vwa1 silencing attenuated compensatory responses under 6% CTS, while exogenous FGF9 restored them. Conversely, Vwa1 overexpression mitigated decompensation under 18% CTS, an effect nullified by FGFR3 inhibition. Rac2 knockdown reduced decompensatory responses to 18% CTS, whereas p38 MAPK activation reinstated these effects. Rac2 overexpression exacerbated decompensation under 6% CTS, reversible via p38 MAPK inhibition. CONCLUSION: VWA1 can modulate compensatory responses in condylar cartilage via regulating FGF9/FGFR3 signaling pathway, while Rac2 can mediate decompensatory responses via the modulation of p38 MAPK signaling pathway, which provide prospects for developing precise diagnostic and therapeutic strategies for temporomandibular joint osteoarthritis (TMJOA). CLINICAL TRIAL NUMBER: Not applicable.