{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:01Z","timestamp":1787028541907,"version":"build-2736575974"},"reference-count":45,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T00:00:00Z","timestamp":1719878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Pfizer Pharmaceuticals, Israel LTD","award":["WI219474"],"award-info":[{"award-number":["WI219474"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Angiogenesis is critical for rheumatoid arthritis (RA) progression. The effects of tofacitinib, a JAK-STAT inhibitor used for RA treatment, on angiogenesis in RA are unclear. We, therefore, evaluated the levels of angiogenic factors in two systems of a human co-culture of fibroblast (HT1080) and monocytic (U937) cell lines treated with tofacitinib and in serum samples from RA patients before and after six months of tofacitinib treatment. Tofacitinib reduced CD147 levels, matrix metalloproteinase-9 (MMP-9) activity, and angiogenic potential but increased endostatin levels and secreted proteasome 20S activity. In vitro, tofacitinib did not change CD147 mRNA but increased miR-146a-5p expression and reduced STAT3 phosphorylation. We recently showed that CD147 regulates the ability of MMP-9 and secreted proteasome 20S to cleave collagen XVIIIA into endostatin. We show here that tofacitinib-enhanced endostatin levels are mediated by CD147, as CD147-siRNA or an anti-CD147 antibody blocked proteasome 20S activity. The correlation between CD147 and different disease severity scores supported this role. Lastly, tofacitinib reduced endostatin\u2019 s degradation by inhibiting cathepsin S activity and recombinant cathepsin S reversed this in both systems. Thus, tofacitinib inhibits angiogenesis by reducing pro-angiogenic factors and enhancing the anti-angiogenic factor endostatin in a dual effect mediated partly through CD147 and partly through cathepsin S.<\/jats:p>","DOI":"10.3390\/ijms25137267","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T12:58:42Z","timestamp":1719925122000},"page":"7267","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Tofacitinib Regulates Endostatin via Effects on CD147 and Cathepsin S"],"prefix":"10.3390","volume":"25","author":[{"given":"Devy","family":"Zisman","sequence":"first","affiliation":[{"name":"Department of Rheumatology, Carmel Medical Center, Haifa 3436212, Israel"},{"name":"Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525422, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7899-9921","authenticated-orcid":false,"given":"Hala","family":"Sabtan","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Carmel Medical Center, Haifa 3436212, Israel"},{"name":"Immunotherapy Laboratory, Carmel Medical Center, Haifa 3436212, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya M.","family":"Rahat","sequence":"additional","affiliation":[{"name":"Immunotherapy Laboratory, Carmel Medical Center, Haifa 3436212, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elina","family":"Simanovich","sequence":"additional","affiliation":[{"name":"Immunotherapy Laboratory, Carmel Medical Center, Haifa 3436212, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"Haddad","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Carmel Medical Center, Haifa 3436212, Israel"},{"name":"Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525422, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8612-2698","authenticated-orcid":false,"given":"Tal","family":"Gazitt","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Carmel Medical Center, Haifa 3436212, Israel"},{"name":"Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525422, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joy","family":"Feld","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Carmel Medical Center, Haifa 3436212, Israel"},{"name":"Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525422, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gleb","family":"Slobodin","sequence":"additional","affiliation":[{"name":"Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525422, Israel"},{"name":"Rheumatology Unit, Bnai Zion Medical Center, Haifa 3339419, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adi","family":"Kibari","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Carmel Medical Center, Haifa 3436212, Israel"},{"name":"Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525422, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muna","family":"Elias","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Carmel Medical Center, Haifa 3436212, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1881-1173","authenticated-orcid":false,"given":"Michal A.","family":"Rahat","sequence":"additional","affiliation":[{"name":"Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525422, Israel"},{"name":"Immunotherapy Laboratory, Carmel Medical Center, Haifa 3436212, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"18001","DOI":"10.1038\/nrdp.2018.1","article-title":"Rheumatoid arthritis","volume":"4","author":"Smolen","year":"2018","journal-title":"Nat. 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