Implications of Angiogenesis Involvement in Arthritis

Iona J MacDonald, Shan-Chi Liu, Chen-Ming Su, Yu-Han Wang, Chun-Hao Tsai, Chih-Hsin Tang, Iona J MacDonald, Shan-Chi Liu, Chen-Ming Su, Yu-Han Wang, Chun-Hao Tsai, Chih-Hsin Tang

Abstract

Angiogenesis, the growth of new blood vessels, is essential in the pathogenesis of joint inflammatory disorders such as rheumatoid arthritis (RA) and osteoarthritis (OA), facilitating the invasion of inflammatory cells and increase in local pain receptors that contribute to structural damage and pain. The angiogenic process is perpetuated by various mediators such as growth factors, primarily vascular endothelial growth factor (VEGF) and hypoxia-inducible factors (HIFs), as well as proinflammatory cytokines, various chemokines, matrix components, cell adhesion molecules, proteases, and others. Despite the development of potent, well-tolerated nonbiologic (conventional) and biologic disease-modifying agents that have greatly improved outcomes for patients with RA, many remain resistant to these therapies, are only partial responders, or cannot tolerate biologics. The only approved therapies for OA include symptom-modifying agents, such as analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), steroids, and hyaluronic acid. None of the available treatments slow the disease progression, restore the original structure or enable a return to function of the damaged joint. Moreover, a number of safety concerns surround current therapies for RA and OA. New treatments are needed that not only target inflamed joints and control articular inflammation in RA and OA, but also selectively inhibit synovial angiogenesis, while preventing healthy tissue damage. This narrative review of the literature in PubMed focuses on the evidence illustrating the therapeutic benefits of modulating angiogenic activity in experimental RA and OA. This evidence points to new treatment targets in these diseases.

Keywords: angiogenesis; chemokines; cytokines; osteoarthritis; rheumatoid arthritis.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
An illustration of the proinflammatory process underlying rheumatoid arthritis (RA) angiogenesis in synovial fluid. Inflammatory stimulation activates RA osteoblasts and synovial fibroblasts that in turn modulate the expression of growth factors, Toll-like receptors, chemokine receptors, cytokines, matrix metalloproteinases (MMPs) and other mediators that are involved at different stages of angiogenesis. Recruitment of macrophages and T cells from the blood into the inflammatory process ensure the maintenance and progression of angiogenesis.
Figure 2
Figure 2
Specific mechanisms underlying angiogenesis in OA. Chronic, low-grade inflammation in OA is driven by increased expression of pro-angiogenic factors including chemokine receptors, cytokines, growth factors, and other mediators such as advanced glycation end-products (AGEs) and Dickkopf-1 (Dkk-1) entering the synovial fluid, enabling them to erode cartilage and subchondral bone.

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