Article Text
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 β (TGFβ), thereby regulating its activity. Here, we analysed whether increased bioavailability of TGFβ 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 β-1 (TGFβ1) content within cultured chondrocyte supernatants was measured by ELISA. Quantitative real-time (RT)-PCR was used to analyse mRNA expression of glycosaminoglycan (GAG)-modifying enzymes in C28/I2 cells following TGFβ1 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 TGFβ1. Increased TGFβ signalling led to enhanced Chst11 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 TGFβ 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.
- Chondrocytes
- Knee Osteoarthritis
- Cytokines
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Footnotes
Handling editor Tore K Kvien
Contributors TG, PB and RD incepted and designed the experiments, analysed the data and prepared the manuscript. Experimental work was performed by TG, KK, CP and IG with contributions from AA, FCM, HC-S, JB and TP. RVI provided Dcn–/– animals. The manuscript was approved by all authors.
Funding The D-Board project has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement No. 305815 (TP). The work was also supported by grants from the German Research Foundation: SFB492 (RD project B18, PB project A2) and FOR 2407 (AA, CP, HCS). CP and HCS also acknowledge financial support from the Bavarian State Ministry for Science and Education through the Forschungsschwerpunkt “Herstellung und biophysikalische Charakterisierung von dreidimensionalen Geweben—CANTER”.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.