COMP and TSP-4: Functional Roles in Articular Cartilage and Relevance in Osteoarthritis.

Kathrin Maly,Andrea Meurer,Enrique Andres Sastre,Frank Zaucke,Eric Farrell

doi:10.3390/ijms22052242

Abstract

Osteoarthritis (OA) is a slow-progressing joint disease, leading to the degradation and remodeling of the cartilage extracellular matrix (ECM). The usually quiescent chondrocytes become reactivated and accumulate in cell clusters, become hypertrophic, and intensively produce not only degrading enzymes, but also ECM proteins, like the cartilage oligomeric matrix protein (COMP) and thrombospondin-4 (TSP-4). To date, the functional roles of these newly synthesized proteins in articular cartilage are still elusive. Therefore, we analyzed the involvement of both proteins in OA specific processes in in vitro studies, using porcine chondrocytes, isolated from femoral condyles. The effect of COMP and TSP-4 on chondrocyte migration was investigated in transwell assays and their potential to modulate the chondrocyte phenotype, protein synthesis and matrix formation by immunofluorescence staining and immunoblot. Our results demonstrate that COMP could attract chondrocytes and may contribute to a repopulation of damaged cartilage areas, while TSP-4 did not affect this process. In contrast, both proteins similarly promoted the synthesis and matrix formation of collagen II, IX, XII and proteoglycans, but inhibited that of collagen I and X, resulting in a stabilized chondrocyte phenotype. These data suggest that COMP and TSP-4 activate mechanisms to protect and repair the ECM in articular cartilage.

Highlights

Articular cartilage consists of an extracellular matrix (ECM) with a unique composition and architecture, providing the biomechanical properties for frictionless motion [1,2,3]
The phosphorylation maximum at 0.1 ng/mL TGF-β1 was weaker than that of cartilage oligomeric matrix protein (COMP) alone. These results show that TSP-4 attenuates TGF-β1 induced Erk1/2 signaling, in contrast to COMP, whose capacity to induce Erk1/2 phosphorylation is suppressed by TGF-β1
We show that the presence and distribution of COMP and TSP-4 are distinguishable, especially in healthy and OA cartilage, both proteins are re-expressed during OA progression

Summary

Introduction

Articular cartilage consists of an extracellular matrix (ECM) with a unique composition and architecture, providing the biomechanical properties for frictionless motion [1,2,3]. Its close family member, thrombospondin-4 (TSP-4), is hardly detectable in healthy cartilage, but its expression increases dramatically in OA cartilage and correlates with disease severity [39] Both proteins have similar structures and binding partners [40,41,42,43,44,45,46], suggesting similar or additive roles in articular cartilage. The present study focuses on the potential of COMP and TSP-4 to promote repopulation of damaged cartilage areas by attracting chondrocytes, stabilizing their phenotype as well as inducing the synthesis and deposition of collagens and proteoglycans. The obtained data will contribute to a better understanding of the functional role of COMP and TSP-4 in articular cartilage, and might help to improve and develop effective therapeutic applications

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