{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T02:20:27Z","timestamp":1792030827286,"version":"4.4.0"},"reference-count":124,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2022,7,28]],"date-time":"2022-07-28T00:00:00Z","timestamp":1658966400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["2T32ES007026-41"],"award-info":[{"award-number":["2T32ES007026-41"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["P30ES001247"],"award-info":[{"award-number":["P30ES001247"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["T32HL066988"],"award-info":[{"award-number":["T32HL066988"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001003","name":"Boehringer Ingelheim","doi-asserted-by":"publisher","award":["Investigator Initiated Study"],"award-info":[{"award-number":["Investigator Initiated Study"]}],"id":[{"id":"10.13039\/100001003","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Transforming growth factor beta (TGF-\u03b2) induced myofibroblast differentiation is central to the pathological scarring observed in Idiopathic Pulmonary Fibrosis (IPF) and other fibrotic diseases. Our lab has recently identified expression of GPR68 (Ovarian Cancer Gene Receptor 1, OGR1), a pH sensing G-protein coupled receptor, as a negative regulator of TGF-\u03b2 induced profibrotic effects in primary human lung fibroblasts (PHLFs). We therefore hypothesized that small molecule activators of GPR68 would inhibit myofibroblast differentiation. Ogerin is a positive allosteric modulator (PAM) of GPR68, inducing a leftward shift of the dose response curve to proton induced signaling. Using PHLFs derived from patients with both non-fibrotic and IPF diagnoses, we show that Ogerin inhibits, and partially reverses TGF-\u03b2 induced myofibroblast differentiation in a dose dependent manner. This occurs at the transcriptional level without inhibition of canonical TGF-\u03b2 induced SMAD signaling. Ogerin induces PKA dependent CREB phosphorylation, a marker of G\u03b1<jats:sub>s<\/jats:sub> pathway activation. The ability of Ogerin to inhibit both basal and TGF-\u03b2 induced collagen gene transcription, and induction of G\u03b1<jats:sub>s<\/jats:sub> signaling is enhanced at an acidic pH (pH 6.8). Similar findings were also found using fibroblasts derived from dermal, intestinal, and orbital tissue. The biological role of GPR68 in different tissues, cell types, and disease states is an evolving and emerging field. This work adds to the understanding of G\u03b1<jats:sub>s<\/jats:sub> coupled GPCRs in fibrotic lung disease, the ability to harness the pH sensing properties of GPR68, and conserved mechanisms of fibrosis across different organ systems.<\/jats:p>","DOI":"10.1371\/journal.pone.0271608","type":"journal-article","created":{"date-parts":[[2022,7,28]],"date-time":"2022-07-28T18:13:04Z","timestamp":1659031984000},"page":"e0271608","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":16,"title":["Ogerin mediated inhibition of TGF-\u03b2(1) induced myofibroblast differentiation is potentiated by acidic pH"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5767-8264","authenticated-orcid":true,"given":"Tyler J.","family":"Bell","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Nagel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7197-5057","authenticated-orcid":true,"given":"Collynn F.","family":"Woeller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Mathew","family":"Kottmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,7,28]]},"reference":[{"issue":"2","key":"pone.0271608.ref001","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1002\/path.2277","article-title":"Cellular and molecular mechanisms of fibrosis","volume":"214","author":"T.A. Wynn","year":"2008","journal-title":"J Pathol"},{"issue":"3","key":"pone.0271608.ref002","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1172\/JCI31487","article-title":"Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases","volume":"117","author":"T.A. Wynn","year":"2007","journal-title":"The Journal of Clinical Investigation"},{"issue":"8","key":"pone.0271608.ref003","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/nri1412","article-title":"Fibrotic disease and the T(H)1\/T(H)2 paradigm.","volume":"4","author":"T.A. 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