Shedding New Light on The Role of ανβ3 and α5β1 Integrins in Rheumatoid Arthritis

Abstract

ανβ3 and α5β1 are essential glycoproteins involved in the pathogenesis of rheumatoid arthritis (RA). Understanding of the role these integrins play in disease have been analyzed via description of cells-expressing ανβ3 and α5β1 and their mediators to trigger inflammation. ανβ3 and α5β1 facilitate cells-ECM and cell-cell communication, producing pro-inflammatory factors. Pro-inflammatory factors are essential for the building of undesirable new blood vessels termed angiogenesis which can further lead to destruction of bones and joints. Despite many attempts to target these glycoproteins, there are still some problems, therefore, there is still interest in understanding the synergistic role these integrins play in the pathogenesis of RA. The purpose of this review is to gain insights into the biological effects of ανβ3 and α5β1 in synovial tissues that are relevant to pathogenesis and therapy of RA.

Keywords: angiogenesis; antagonist; integrin; rheumatoid arthritis; α5β1; αvβ3.

Figure 1

Classification of integrins. Integrins are divided into RGD binding receptors and non-RGD binding receptors. RGD binding receptors include αvβ1, αvβ3, αvβ5, αvβ6, αvβ8, αllbβ3, α5β1 and α8β1. Non-RGD binding receptors include collagen binding receptors (α1β1, α2β1, α10β1 and α11β1), laminin binding receptors (α3β1, α6β1, α6β4 and α7β1) and leukocyte binding receptors (αEβ7, α4β1, α4β7, α9β1, αDβ2, αLβ2, αMβ2 and αXβ2).

Figure 2

The role of αvβ3 and α5β1 in the development of RA. ECM proteins communication with cells-expressed αvβ3 and α5β1 as well as between αvβ3 and α5β1 of synovial cells, inducing bone and cartilage destruction. Fibroblasts-expressed αvβ3 and α5β1 secrete cytokines that induce MMPs production by chondrocytes, also fibroblasts activate B cells and T cells. αvβ3 and α5β1-expressed macrophages promote fibroblasts activation and secretion their cytokines. αvβ3 and α5β1-expressed T cells induce secretion of macrophages cytokines via IL-15 and IL-17. Neutrophils-expressed αvβ3 and α5β1 induce a group of pro-inflammatory cytokines, chemokines and MMPs. Osteoclasts express only αvβ3. αvβ3 enhances osteoclasts proliferation and bone resorption.

Figure 3

Role of αvβ3 and α5β1 in RA joint angiogenesis. Joint hyperplasia resulted from accumulated of synovial cells and their secretions, leading to extensive hypoxia. Hypoxia conditions lead to HIF-1 release, which is recognized as a stimulator of angiogenic growth factors (VEGF, FGF-2 and PDGF). The growth factors induce αvβ3 and α5β1 over-expression on endothelial cells (ECs), smooth muscle cells (SMCs) and platelets. Up-regulated αvβ3 and α5β1 activate production of pro-inflammatory cytokines that mediate ECs and SMCs migration and proliferation and platelets activation. These events entrain new vascularization.