Osteoarthritis-Related Inflammation Blocks TGF-β's Protective Effect on Chondrocyte Hypertrophy via (de)Phosphorylation of the SMAD2/3 Linker Region.

Nathalie Thielen,Elly Vitters,Renske Wiegertjes,Peter Van Lent,Henk Van Beuningen,Esmeralda Blaney Davidson,Peter Van Der Kraan,Margot Neefjes,Marije Koenders,Fons Van De Loo,Arjan Van Caam,Guus Van Den Akker

doi:10.3390/ijms22158124

Abstract

Osteoarthritis (OA) is a degenerative joint disease characterized by irreversible cartilage damage, inflammation and altered chondrocyte phenotype. Transforming growth factor-β (TGF-β) signaling via SMAD2/3 is crucial for blocking hypertrophy. The post-translational modifications of these SMAD proteins in the linker domain regulate their function and these can be triggered by inflammation through the activation of kinases or phosphatases. Therefore, we investigated if OA-related inflammation affects TGF-β signaling via SMAD2/3 linker-modifications in chondrocytes. We found that both Interleukin (IL)-1β and OA-synovium conditioned medium negated SMAD2/3 transcriptional activity in chondrocytes. This inhibition of TGF-β signaling was enhanced if SMAD3 could not be phosphorylated on Ser213 in the linker region and the inhibition by IL-1β was less if the SMAD3 linker could not be phosphorylated at Ser204. Our study shows evidence that inflammation inhibits SMAD2/3 signaling in chondrocytes via SMAD linker (de)-phosphorylation. The involvement of linker region modifications may represent a new therapeutic target for OA.

Highlights

We showed that there is a link between OA-related inflammation and disturbed transforming growth factor-β (TGF-β) signaling in chondrocytes
Our results indicate that IL-1β and OAScm can stimulate hypertrophy-like differentiation by decreasing TGF-β transcriptional activity
We demonstrate that the inhibition of TGF-β signaling was significantly enhanced when the SMAD3 linker phosphorylation on S213 cannot take place, while inhibition is possibly less pronounced when S204 cannot be phosphorylated

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Osteoarthritis (OA) is characterized by irreversible cartilage breakdown and regarded as a multifactorial disease in which inflammation is involved [1,2]. Synovitis is present in osteoarthritic joints and the production of inflammatory cytokines and chemokines is increased [3,4,5,6]. These pro-inflammatory cytokines, such as Interleukin (IL)-1β can have a direct (negative) effect on cartilage homeostasis [7,8], but can modulate the transforming growth factor-β (TGF-β) signaling [9,10]

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Results

Conclusion