Session Type: Poster Session D
Session Time: 9:00AM-11:00AM
Background/Purpose: Angiogenesis plays a key role in the progression of rheumatoid arthritis (RA), but the mechanisms regulating this process are not fully elucidated. EMMPRIN is a multi-functional protein that can induce the expression of matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF), which are pro-angiogenic. Tofacitinib, a small molecule inhibitor of Janus Kinase (JAK) 1 and JAK3, in use for treatment of RA, has been shown to inhibit production of cytokines. However, its effects on angiogenesis, and specifically on EMMPRIN expression and activity, are not yet clear.
Methods: To determine the effects of Tofacitinib on the expression of EMMPRIN, MMP-9 and VEGF, as well as on the expression of the anti-angiogenic proteins endostatin and thrombospondin-1 (Tsp-1).
Results: The co-culture increased the secretion of MMP-9 and VEGF compared to the single culture of HT1080 cells (by 1.5-fold and 1.4-fold respectively, p< 0.05) and decreased the secretion of endostatin and Tsp-1 (by ~45%, p< 0.05); however, EMMPRIN secretion was unaffected. Tofacitinib significantly inhibited the secretion of EMMPRIN, VEGF and MMP-9 (by 16%, 39%, 29% respectively, p< 0.01), whereas secretion of endostatin, but not of Tsp-1, was increased (1.7-fold, p=0.0074). The ratio between VEGF and endostatin, a measure of the overall angiogenic potential, was reduced by 54% by the addition of Tofacitinib (p=0.0005). Likewise, CM from the co-cultured cells after incubation with Tofacitinib demonstrated reduction (12.7%, p=0.0441) in the ability of endothelial cells to migrate and to form closed lumens (17%, p=0.0002).
Conclusion: We suggest that the interactions between monocytes and fibroblasts lead to an angiogenic switch, as they enhance pro-angiogenic factors and decrease anti-angiogenic mediators. Tofacitinib reversed these effects by enhancing endostatin secretion and reducing the accumulation of EMMPRIN, VEGF and MMP-9. Thus, the inhibitory effect of tofacitinib on angiogenesis may contribute to its efficacy in treating inflammatory arthritis.
To cite this abstract in AMA style:Zisman D, Rahat M, Simanovich E, Mellins E, Haddad A, Gazitt T, Feld J, Rahat M. Tofacitinib Inhibits Angiogenesis Through Its Opposite Effects on Pro- and Anti-angiogenic Factors [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/tofacitinib-inhibits-angiogenesis-through-its-opposite-effects-on-pro-and-anti-angiogenic-factors/. Accessed November 26, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tofacitinib-inhibits-angiogenesis-through-its-opposite-effects-on-pro-and-anti-angiogenic-factors/