Tobias Gronau1,2, Karsten Krüger3, Carina Prein4, Attila Aszodi5, Isabel Gronau2, Renato V Iozzo6, Frank C Mooren3, Hauke Clausen-Schaumann4, Jessica Bertrand1,7, Thomas Pap1, Peter Bruckner2, Rita Dreier2. 1. Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Münster, Germany. 2. Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany. 3. Institute of Sports Medicine, Justus-Liebig University Giessen, Giessen, Germany. 4. Center for Applied Tissue Engineering and Regenerative Medicine (CANTER), Munich University of Applied Sciences and Center for Nanoscience (CeNS), Munich, Germany. 5. Laboratory of Experimental Surgery and Regenerative Medicine, Department of General, Trauma and Reconstruction Surgery, Ludwig-Maximilians-University, Munich, Germany. 6. Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, USA. 7. Department of Orthopaedic Surgery, Otto-von-Guericke University, Magdeburg, Germany.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Authors: Biao Han; Qing Li; Chao Wang; Pavan Patel; Sheila M Adams; Basak Doyran; Hadi T Nia; Ramin Oftadeh; Siyuan Zhou; Christopher Y Li; X Sherry Liu; X Lucas Lu; Motomi Enomoto-Iwamoto; Ling Qin; Robert L Mauck; Renato V Iozzo; David E Birk; Lin Han Journal: ACS Nano Date: 2019-10-01 Impact factor: 15.881
Authors: M Jimena Santos; Soledad Picco; Rodrigo Fernández; M Eugenia Pedreira; Mariano Boccia; Martin Klappenbach; Maria C Krawczyk Journal: IBRO Neurosci Rep Date: 2022-04-21
Authors: Daphney R Chery; Biao Han; Ying Zhou; Chao Wang; Sheila M Adams; Prashant Chandrasekaran; Bryan Kwok; Su-Jin Heo; Motomi Enomoto-Iwamoto; X Lucas Lu; Dehan Kong; Renato V Iozzo; David E Birk; Robert L Mauck; Lin Han Journal: Matrix Biol Date: 2020-11-25 Impact factor: 11.583
Authors: B Han; Q Li; C Wang; P Chandrasekaran; Y Zhou; L Qin; X S Liu; M Enomoto-Iwamoto; D Kong; R V Iozzo; D E Birk; L Han Journal: Osteoarthritis Cartilage Date: 2021-04-27 Impact factor: 7.507
Authors: Selene Pérez-García; Valentina Calamia; Tamara Hermida-Gómez; Irene Gutiérrez-Cañas; Mar Carrión; Raúl Villanueva-Romero; David Castro; Carmen Martínez; Yasmina Juarranz; Francisco J Blanco; Rosa P Gomariz Journal: Int J Mol Sci Date: 2021-06-16 Impact factor: 6.208
Authors: Sarah Dex; Paolo Alberton; Lena Willkomm; Thomas Söllradl; Sandra Bago; Stefan Milz; Mehdi Shakibaei; Anita Ignatius; Wilhelm Bloch; Hauke Clausen-Schaumann; Chisa Shukunami; Matthias Schieker; Denitsa Docheva Journal: EBioMedicine Date: 2017-05-05 Impact factor: 8.143