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Gronau, Tobias; Krüger, Karsten; Prein, Carina; Aszodi, Attila; Gronau, Isabel; Iozzo, Renato V.; Mooren, Frank C.; Clausen-Schaumann, Hauke; Bertrand, Jessica; Pap, Thomas; Bruckner, Peter; Dreier, Rita (2017): Forced exercise-induced osteoarthritis is attenuated in mice lacking the small leucine-rich proteoglycan decorin. In: Annals of the Rheumatic Diseases, Vol. 76, Nr. 2: S. 442-449
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Abstract

Objective Interterritorial regions of articular cartilage matrix are rich in decorin, a small leucine-rich proteoglycan and important structural protein, also involved in many signalling events. Decorin sequesters transforming growth factor P (TGFP3), thereby regulating its activity. Here, we analysed whether increased bioavailability of TGF3 in decorin-deficient (Dcn(-/-)) cartilage leads to changes in biomechanical properties and resistance to osteoarthritis (OA). Methods Unchallenged knee cartilage was analysed by atomic force microscopy (AFM) and immunohistochemistry. Active transforming growth factor beta-1 (TGF beta 1) content within cultured chondrocyte supernatants was measured by ELISA. Quantitative realtime (RT)-PCR was used to analyse mRNA expression of glycosaminoglycan (GAG)-modifying enzymes in C28/12 cells following TGFf31 treatment. In addition, OA was induced in Dcn(-/-) and wild-type (WT) mice via forced exercise on a treadmill. Results AFM analysis revealed a strikingly higher compressive stiffness in Dcn(-/-) than in WT cartilage. This was accompanied by increased negative charge and enhanced sulfation of GAG chains, but not by alterations in the levels of collagens or proteoglycan core proteins. In addition, decorin-deficient chondrocytes were shown to release more active TGF beta 1. Increased TGF beta signalling led to enhanced Chstl 1 sulfotransferase expression inducing an increased negative charge density of cartilage matrix. These negative charges might attract more water resulting in augmented compressive stiffness of the tissue. Therefore, decorin-deficient mice developed significantly less OA after forced exercise than WT mice. Conclusions Our study demonstrates that the disruption of decorin -restricted TGF beta signalling leads to higher stiffness of articular cartilage matrix, rendering joints more resistant to OA. Therefore, the loss of an important structural component can improve cartilage homeostasis.