Regulation of MMP-3 expression and secretion by the chemokine eotaxin-1 in human chondrocytes

Pin-Zhir Chao,Chao-Wen Cheng,Yung-Feng Lin,Chien-Ho Chen,Ming-Shium Hsieh

doi:10.1186/1423-0127-18-86

Pin-Zhir Chao, Chao-Wen Cheng + Show 3 more

Open Access

https://doi.org/10.1186/1423-0127-18-86

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Abstract

BackgroundOsteoarthritis (OA) is characterized by the degradation of articular cartilage, marked by the breakdown of matrix proteins. Studies demonstrated the involvement of chemokines in this process, and some may potentially serve as diagnostic markers and therapeutic targets; however, the underlying signal transductions are not well understood.MethodsWe investigated the effects of the CC chemokine eotaxin-1 (CCL11) on the matrix metalloproteinase (MMP) expression and secretion in the human chondrocyte cell line SW1353 and primary chondrocytes.ResultsEotaxin-1 significantly induced MMP-3 mRNA expression in a dose-dependent manner. Inhibitors of extracellular signal-regulated kinase (ERK) and p38 kinase were able to repress eotaxin-1-induced MMP-3 expression. On the contrary, Rp-adenosine-3',5'-cyclic monophosphorothioate (Rp-cAMPs), a competitive cAMP antagonist for cAMP receptors, and H-89, a protein kinase A (PKA) inhibitor, markedly enhanced eotaxin-1-induced MMP-3 expression. These results suggest that MMP-3 expression is specifically mediated by the G protein-coupled eotaxin-1 receptor activities. Interestingly, little amount of MMP-3 protein was detected in the cell lysates of eotaxin-1-treated SW1353 cells, and most of MMP-3 protein was in the culture media. Furthermore we found that the eotaxin-1-dependent MMP-3 protein secretion was regulated by phospholipase C (PLC)-protein kinase C (PKC) cascade and c-Jun N-terminal kinase (JNK)/mitogen-activated protein (MAP) kinase pathways. These data indicate a specific regulation of MMP-3 secretion also by eotaxin-1 receptor activities.ConclusionsEotaxin-1 not only induces MMP-3 gene expression but also promotes MMP-3 protein secretion through G protein-coupled eotaxin-1 receptor activities. Chemokines, such as eotaxin-1, could be a potential candidate in the diagnosis and treatment of arthritis.

Highlights

Osteoarthritis (OA) is characterized by the degradation of articular cartilage, marked by the breakdown of matrix proteins
Eotaxin-1 induces matrix metalloproteinase (MMP)-3 gene expression and protein secretion in human chondrocytes In our previous study, we found that eotaxin-1 is overexpressed in OA patients [13]
In the present study, we demonstrated that MMP-3 expression in SW1353 chondrosarcoma cells and primary chondrocytes was obviously induced by eotaxin-1 at 30 and 10 ng/ml, respectively (Figure 1A and 1B)

Summary

Introduction

Osteoarthritis (OA) is characterized by the degradation of articular cartilage, marked by the breakdown of matrix proteins. Osteoarthritis (OA) is a chronic degenerative joint disease characterized by degradation of articular cartilage and inflammation of the synovium [1,2]. Chondrocytes, the only cells found in cartilage, can produce interleukin (IL)-1b that induces the expression of MMPs, aggrecanases, and other catabolic proteins [5,6]. IL-1b induces the production of the CC chemokines, such as monocyte chemoattractant protein 1 (MCP-1) and regulated upon activation of normal T cell expression and secretion (RANTES), and promotes inflammation [10,11]. It was shown that chondrocytes respond to MCP-1 and RANTES by releasing MMP-3 and N-acetyl-b-D-glucosaminidase, contributing to cartilage matrix degradation [12]. Recent study demonstrated elevated level of eotaxin-1 in the cells of rheumatoid arthritis (RA) patients before disease onset [14]

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