CD147: The Maverick Triggering the Pathogenesis of Rheumatoid Arthritis

Pictorial representation of RA (http://www.rumatory-arthritis.com/)

Rheumatoid arthritis (RA) is a debilitating chronic autoimmune disorder that leads to the synovial inflammation of joints and surrounding tissues. The clinical prognosis is the irreparable destruction of cartilage, tendon, and bone in affected joints and the disease can progress aggressively, especially without proper treatment.

The source of symptoms is thought to be the aberrant proliferation of a resident joint cell population, termed the synovial cells. The increased proliferation of these cells leads to the formation of an aggressive tissue body called the rheumatoid pannus, which expands into the cartilage and erodes the bone, producing the painful and debilitating effects characteristic of RA. CD147, the extracellular matrix metalloproteinase inducer (EMMPRIN) protein, is expressed at abnormally high levels in the synovial tissues of RA patients and is believed to increase matrix metalloproteinase (MMP) expression by synovial cells. MMP's target and break down a variety of proteins present in joint connective tissues, thus leading to the destruction seen in RA patients (Chen, 2004). Thus, MMP protein levels are thought to reflect disease activity an progression in RA better than levels of other inflammatory signaling molecules (Mahmoud et al., 2005). CD147's ability to increase the expression of MMP’s suggests it could play an important role in RA pathogenesis.

The destructive effects of abnormally CD147 expression may mediate other pathologic features associated with RA as well. Chronic inflammation in these tissues is maintained by angiogenesis, the growth of new blood vessels, through inflammatory cell transport to the synovitis and nutrient cell delivery to the growing pannus. Agiogenic factors thought to be involved in this positive regulation of angiogenesis include vascular endothelial growth factor (VEGF), a protein that triggers growth of blood vessel tissues, and hypoxia inducible factor-1α (HIF-1α), a protein that mediates cellular adaptation to sub-optimal oxygen conditions. Expression of CD147 was found to be positively correlated with VEGF and HIF-1α expression in the synovium of RA patients and experimentally mediated inhibition of CD147 signaling was found to reduce their production significantly. This led researchers to hypothesize CD47 could play an important role in the abnormal angiogenesis observed in the synovium of RA patients, and could promote pannus formation through enhancing local VEGF and HIF-1α expression (Wang et al., 2011).

The SCID mouse co-implantation model of human RA was used to experimentally model the pathologic destruction of cartilage and bone that is mediated in RA patients by activation of the synovium, allowing the role of RA synovial fibroblasts on cartilage destruction to be examined and manipulated directly. When CD147 expression was not disrupted in the grafted synovium, the engrafted tissue was found to control almost 1.2-fold in size, compared to controls and mice who had been treated with C147 inhibitors, in just 9 weeks. This increase in volume was paralleled by an observed increase in vascular density of the grafted tissue, an effect not seen in treatment groups where CD147 signaling was inhibited.

The molecular mechanism underlying CD147's positive effect on VEGF and HIF-1α expression appears to be related to the signaling activities of the PI3K/Akt pathway. A common molecular pathway observed to have widespread roles in biology, the PI3K/Akt pathway can induce local changes in the expression of a variety of genes, including HIF-1α and VEGF. CD147 has been shown to increase activity within this pathway and in this study, experimenters proved that this communication was responsible for the subsequent CD147-induced upregulation of VEGF and HIF-1α expression in an Akt-dependent manner.

Together these experimental results suggest CD147 does not just act as a stimulator of MMP expression in RA, but also as a promoter of angiogenesis through upregulation of HIF-1α and VEGF. Furthermore, the study suggests inhibition of CD147 has strong potential for treating the effects of RA. Currently, Infliximab is considered to be one of the best therapies available for treating the symptoms of RA. However, CD147 inhibition proved to be much more effective than Infliximab at reducing grafted tissue growth and density in SCID mouse model experiments. This suggests CD147 inhibitors have greater potential than Infliximab to induce an anti-angiogenic state and reduce the severity of cartilage and bone destruction mediated by the abnormally activated synovium in individuals suffering from RA. Furthermore, the development of safe and effective CD147 inhibitors could have great applicability to other diseases as well. Recent studies have consistently supported a pathogenic role for CD147 in a variety of tumors and macular degeneration, both through its stimulatory effect on angiogenesis and its role in MMP upregulation (Wang S, Li B, Wang S, Li Y, Li J., 2011). Thus, investing in the development of CD147 inhibitors should be a top priority for pharmaceutical companies, as their applicability could extend to a wide variety of dieseases.

Source Story:

Wang, C., Yao, H., Chen, L., Jia, J., Wang, L., Dai, J., Zheng, Z., Chen, Z. & Zhu, P. (2011). CD147 induces angiogenesis in RA. Arthritis & Rheumatism, [in press].

Additional Sources:

1) Chen PS, Shih YW, Huang HC, Cheng HW. (2011). Diosgenin, a steroidal saponin, inhibits migration and invasion of human prostate cancer PC-3 cells by reducing matrix metalloproteinases expression. PLoS ONE, 6(5):e20164.

2) Chen, Y. (2004). MMP-12, An Old Enzyme Plays a New Role in the Pathogenesis of Rheumatoid Arthritis? Am J Pathol., 165(4), 1069-1070.

3) Mahmoud, RK., El-Anarsy, AK., El-Eishi, HH., Karmal, HM. & El-Saeed, NH. (2005). Matrix metalloproteinases MMP-3 and MMP-1 levels in era and synovial fluids in patients with rheumatoid arthritis and osteoarthritis. Ital J Biochem, 54(3-4), 248-57.

4) Pierer, M., Muller-Ladner, U., Pap, T., Neidhart, M., Gay, RE., & Gay, S. (2003). The SCID mouse model: novel therapeutic targets - lessons from gene transfer. Springe Semin Immunopathol, 25(1), 65-78.

5) Pons M, Cousins SW, Alcazar O, Striker GE, Marin-Castaño ME. (2011). Angiotensin II-induced MMP-2 activity and MMP-14 and basigin protein expression are mediated via the angiotensin II receptor type 1-mitogen-activated protein kinase 1 pathway in retinal pigment epithelium: implications for age-related macular degeneration. Am J Pathol, 178(6), 2665-81.

6) Image taken from “Rumatory Arthritis: How to Conquer Rheumatoid Arthritis” at http://www.rumatory-arthritis.com/