ECTS2013 Poster Presentations Chondrocytes and cartilage (20 abstracts)
Decrypting TGFβ signaling in age-induced osteoarthritis
Amaya Garcia de Vinuesa 1 , Esmeralda Blaney-Davidson 2 , Gonzalo Sanchez-Duffhues 1 , Arjan van Caam 2 , Elly Vitters 2 , Ingrid Meulenbelt 1 , Marie Jose Goumans 1 , Peter van der Kraan 2 & Peter ten Dijke 1
1Leiden University Medical Center, Leiden, The Netherlands; 2Nijmegen Medical Centre, The Radboud University, Nijmegen, The Netherlands.
Destruction of the articular cartilage is the major feature of Osteoarthritis (OA). Ageing is the primary risk factor, but how ageing results in OA is still an enigma. In OA, articular chondrocytes degrade their own matrix, while in healthy articular cartilage they preserve it.
Transforming growth factor β (TGFβ) is a central regulator of chondrocyte proliferation, differentiation and extracellular matrix production. Deregulation of TGFβ signaling has been implicated in OA and other cartilage diseases. TGFβ can play both protective and deleterious roles in the articular cartilage, which can be explained by the fact that TGFβ can signal via the TGFβ type 1 receptor ALK5, but also via ALK1. Activated ALK1 induces the phosphorylation of intracellular effectors Smad1/5/8, while ALK5 signals via Smad2/3 resulting in opposite chondrocyte responses. In ageing and OA cartilage the ratio ALK1/ALK5 is increased, leading to preferential activation of the Smad1/5/8 signaling pathway, which mediates the expression of matrix metallo-proteinase 13 (MMP13), which is the most potent cartilage-degrading enzyme, contributing to the degradation of the cartilage.
In an attempt to find novel druggable targets that modulate the TGFβ signaling pathway, we have monitored the expression of a number of TGFβ superfamily members and their extracellular regulators in three experimental mouse models: i) C57Bl/6; ii) STR/ort mouse strains, that spontaneously develop OA during ageing; and iii) DMM-inducible OA model, by destabilization of the medial meniscus. Importantly, the mRNA expression of a number of TGFβ family members was strikingly modified towards the onset of OA. Our results point out several members of the TGFβ signaling pathway as important novel candidates that could be implicated in the changes observed on chondrocytes during age-induced OA and their potential use as therapeutic tools and early diagnostic biomarkers.
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ISSN 2052-1219 (online)
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