Altered TGF-beta function in temporomandibular joint osteoarthritis

Objective: Mice deficient in both biglycan and fibromodulin (bgn/fmod DKO) develop accelerated temporomandibular joint osteoarthritis (TMJ OA). Our goal is to determine the underlying molecular basis for the development of this disease. Because bgn and fmod bind to transforming growth factor-beta (TGF-beta) and TGF-beta plays a critical role in TMJ cartilage maintenance, we hypothesize that TGF-beta function is altered in the bgn/fmod DKO mice. Methods: The TMJ from 12 week-old wildtype (WT) and bgn/fmod DKO mice were fixed and processed for histology. Whole mandibles from 5 week-old WT and bgn/fmod DKO mice were cultured for 24 hours in the presence or absence of 10ng/ml TGF-beta and fixed and processed for histology. TGF-beta expression and programmed cell death (apoptosis) in the condylar chondrocytes were determined by immunohistochemistry and FragEL labeling respectively. Results: TGF-beta immunostaining revealed higher levels of endogenous TGF-beta in the hypertrophic chondrocytes of the mutant TMJ cartilage when compared to WT hypertrophic chondrocytes. FragEL labelling revealed a two-fold increase in levels of apoptosis in the condylar chondrocytes of 12 week-old bgn/fmod DKO mice compared to WT controls. Ex-vivo cultivation of 5 week-old normal and mutant condyles showed no significant difference in apoptosis between the bgn/fmod DKO and WT mice. However, addition of exogenous TGF-beta caused a significant increase in apoptotic condylar chondrocytes in the BGN/FBN DKO mice compared to WT control mice. Conclusion: We show for the first time the combined importance of bgn and fmod in regulating TGF-beta activities in TMJ condylar cartilage. Our observations suggest that the absence of bgn and fmod alter the levels and function of TGF-beta, leading to increased apoptosis in TMJ condylar cartilage. Our data reveals a novel upstream event that may contribute to the pathology and progression of TMJ OA.