{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T14:26:34Z","timestamp":1790519194019,"version":"4.1.0"},"reference-count":51,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2018,8,23]],"date-time":"2018-08-23T00:00:00Z","timestamp":1534982400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["26461459"],"award-info":[{"award-number":["26461459"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2018,10]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Apelin\/\n                      <jats:styled-content style=\"fixed-case\">APJ<\/jats:styled-content>\n                      signaling has been determined to regulate cardiac and arterial fibrosis and to be involved in the pathogenesis of pulmonary arterial hypertension. Our objective was to elucidate the role of apelin in skin fibrosis in systemic sclerosis (\n                      <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>\n                      c).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Expression of apelin\/\n                      <jats:styled-content style=\"fixed-case\">APJ<\/jats:styled-content>\n                      in normal and\n                      <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>\n                      c fibroblasts was compared. Effects of small interfering\n                      <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>\n                      depletion and the addition of apelin in fibroblasts were analyzed. The effect of apelin injections on bleomycin\u2010induced dermal fibrosis in mice was investigated. We analyzed the effects of the biased agonist of\n                      <jats:styled-content style=\"fixed-case\">APJ<\/jats:styled-content>\n                      ,\n                      <jats:styled-content style=\"fixed-case\">MM<\/jats:styled-content>\n                      07, on skin fibrosis in vitro and in vivo.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The expression of apelin in\n                      <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>\n                      c fibroblasts was significantly lower than that in normal fibroblasts. Serum apelin levels were negatively correlated with the modified Rodnan skin thickness score in\n                      <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>\n                      c patients. Stimulation with transforming growth factor \u03b21 (\n                      <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\n                      \u03b21) inhibited apelin expression in fibroblasts, suggesting that activation of\n                      <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\n                      \u03b21 signaling in\n                      <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>\n                      c might be responsible for reduced apelin expression in\n                      <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>\n                      c fibroblasts. Small interfering\n                      <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>\n                      depletion of apelin from fibroblasts significantly enhanced fibrosis\u2010related gene expression, and treatment with apelin protein significantly inhibited\n                      <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\n                      \u03b21 signaling in fibroblasts. Administration of apelin significantly inhibited bleomycin\u2010induced dermal fibrosis in mice. We demonstrated that\n                      <jats:styled-content style=\"fixed-case\">MM<\/jats:styled-content>\n                      07 had greater potential than apelin to inhibit fibrosis in vivo and in vitro.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Collectively,\n                      <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\n                      \u03b21 signaling and apelin signaling may counteract each other in the fibrotic process of\n                      <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>\n                      c. Inhibitory regulation of\n                      <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\n                      \u03b21\u2010induced skin fibrosis by apelin\/\n                      <jats:styled-content style=\"fixed-case\">APJ<\/jats:styled-content>\n                      signaling may be involved in the pathogenesis of\n                      <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>\n                      c and could be a therapeutic target for fibrosis in\n                      <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>\n                      c patients.\n                    <\/jats:p>\n                  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