Therapeutic potential of cysteine-rich protein 61 in rheumatoid arthritis

Highlights

• Cyr61 is a pro-inflammatory molecule that is able to affect inflammatory responses.

• Cyr61 may be a useful marker of the inflammatory process in RA.

• Cyr61 in the pathogenesis of RA

• Therapeutic implications for targeting Cyr61 in RA

Abstract

Cysteine-rich protein 61 (Cyr61)/CCN1, a product of an immediate early gene, can directly accommodate cell adhesion and migratory processes whilst simultaneously regulating the production of other cytokines and chemokines through paracrine and autocrine feedback loops. This intricate functionality of Cyr61 indicate its important role in targeting components of the infectious or chronic inflammatory disease processes including rheumatoid arthritis (RA). Recent work has focused on the role of Cyr61 in RA. For example, Cyr61 induced proIL-1β production in FLS via the AKT-dependent NF-κB signaling pathway. Moreover, Cyr61-siRNA decreased the levels of matrix metalloproteinase (MMP)-3 and MMP-13, and induced apoptosis in RA-FLS cells. These results indicated that Cyr61 may represent a novel target for the treatment of RA. In this article we will introduce the molecular properties of Cyr61, discuss the function of Cyr61, and the therapeutic potential of modulating the Cyr61 in RA.

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease affecting approximately 1% of people in the developed world (Gibofsky, 2014). It is characterized by joint inflammation, T cell infiltration of the synovium, synovial hyperplasia, neoangiogenesis, involvement of many catabolic cytokines, and progressive destruction of articular cartilage and bone (Mellado et al., 2015). Multiple pro-inflammatory cytokines such as TNF-α, IL-6 involved in RA contribute to the proliferation of synovial tissue and joint erosion and several observations indicate that adipokines affect tissues and cells involved in RA, including synovium, cartilage, bone, and immune cells (Venkatesha et al., 2015). Although the pathogenesis of this disease is poorly understood, accumulating evidence indicates that fibroblast-like synoviocytes (FLS) are important players in all aspects of the pathogenesis of RA (Bartok and Firestein, 2010).

It is well known that CCN proteins are involved in bone homeostasis and that they participate to the cascade of cytokines upon inflammation in fibroblasts of inflamed synovial tissue, osteoclasts and chondrocytes (Jun and Lau, 2011, Chen and Lau, 2009). Therefore, they are likely candidates to contribute to the pathogenesis of RA. Of note, a recent study has demonstrated that cysteine rich 61 (Cyr61, CCN1) play a pivotal role in the pathogenesis of RA (Quan et al., 2011).

Cyr61 is a product of an immediate early gene and functions in regulating cell adhesion and inducing cell migration (Lin et al., 2012). Previously studies demonstrated that the expression of Cyr61, a secreted extracellular matrix (ECM) protein produced by FLS, is stimulated by interleukin-17 (IL-17), and the overexpressed Cyr61 in turn acts to promote FLS proliferation, thus contributing to the hyperplasia of synovial lining cells (Lin et al., 2012, Jie et al., 2015, Zhang et al., 2009). Novel results suggest that in patients with RA, overexpressed Cyr61 is an important mediator in this malicious cycle. In addition, emerging findings picture CCN1 as a putative pro-inflammatory molecule that is able to affect inflammatory responses (Lobel et al., 2012). In addition, Cyr61 regulates a pro-inflammatory genetic program in murine macrophages and could highly induce the expression of cytokines (TNF-α, IL-1α, IL-1β, IL-6 and IL-12β), chemokines (MIP-1α, MCP3, GROa/b and IP10), regulators of oxidative stress and complement (iNOS and C3) and downregulates specific receptors (TLR4 and IL-10Rβ) and anti-inflammatory factors (TGF-β) (Bai et al., 2010, Kular et al., 2011). Collectively, these data suggested that exploring the mechanisms underlying the dysregulation of Cyr61 expression may play a pivotal role in the molecular pathogenesis of RA. In the present review we provide a brief overview of the molecular properties of Cyr61, discuss the Cyr61 involved in signaling pathway, and the therapeutic potential of modulating the Cyr61 in RA.