Ogerin mediated inhibition of TGF-β(1) induced myofibroblast differentiation is potentiated by acidic pH
Transforming growth factor beta (TGF-β) 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...
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| description | Transforming growth factor beta (TGF-β) 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-β 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-β induced myofibroblast differentiation in a dose dependent manner. This occurs at the transcriptional level without inhibition of canonical TGF-β induced SMAD signaling. Ogerin induces PKA dependent CREB phosphorylation, a marker of Gαs pathway activation. The ability of Ogerin to inhibit both basal and TGF-β induced collagen gene transcription, and induction of Gαs 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 Gαs 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. |
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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-β 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-β induced myofibroblast differentiation in a dose dependent manner. This occurs at the transcriptional level without inhibition of canonical TGF-β induced SMAD signaling. Ogerin induces PKA dependent CREB phosphorylation, a marker of Gαs pathway activation. The ability of Ogerin to inhibit both basal and TGF-β induced collagen gene transcription, and induction of Gαs 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 Gαs 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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0271608</identifier><identifier>PMID: 35901086</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Allosteric properties ; Benzyl Alcohols ; Biology and Life Sciences ; Cell Differentiation ; Collagen ; Consent ; Cyclic AMP response element-binding protein ; Differentiation ; Disease ; Extracellular matrix ; FDA approval ; Fibroblasts ; Fibroblasts - metabolism ; Fibrosis ; G protein-coupled receptors ; Growth factors ; Humans ; Hydrogen-Ion Concentration ; Idiopathic Pulmonary Fibrosis - pathology ; Lung - pathology ; Lung diseases ; Medicine and Health Sciences ; Myofibroblasts - metabolism ; Ovarian cancer ; Ovarian carcinoma ; pH effects ; Phosphorylation ; Physiology ; Proteins ; Protons ; Pulmonary fibrosis ; Receptors ; Receptors, G-Protein-Coupled - metabolism ; Scars ; Signaling ; Smad protein ; Transforming Growth Factor beta - metabolism ; Transforming Growth Factor beta - pharmacology ; Transforming growth factor-b ; Triazines</subject><ispartof>PloS one, 2022-07, Vol.17 (7), p.e0271608</ispartof><rights>2022 Bell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2022 Bell et al 2022 Bell et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-e61ffd24900d6bbea372cfc7566813bb393222e3c7971c574623ce0c4b412d0a3</citedby><cites>FETCH-LOGICAL-c526t-e61ffd24900d6bbea372cfc7566813bb393222e3c7971c574623ce0c4b412d0a3</cites><orcidid>0000-0001-7197-5057 ; 0000-0002-5767-8264</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9333254/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9333254/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,725,778,782,862,883,2098,2917,23853,27911,27912,53778,53780,79355,79356</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35901086$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Feghali-Bostwick, Carol</contributor><creatorcontrib>Bell, Tyler J</creatorcontrib><creatorcontrib>Nagel, David J</creatorcontrib><creatorcontrib>Woeller, Collynn F</creatorcontrib><creatorcontrib>Kottmann, R Mathew</creatorcontrib><title>Ogerin mediated inhibition of TGF-β(1) induced myofibroblast differentiation is potentiated by acidic pH</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Transforming growth factor beta (TGF-β) 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-β 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-β induced myofibroblast differentiation in a dose dependent manner. This occurs at the transcriptional level without inhibition of canonical TGF-β induced SMAD signaling. Ogerin induces PKA dependent CREB phosphorylation, a marker of Gαs pathway activation. The ability of Ogerin to inhibit both basal and TGF-β induced collagen gene transcription, and induction of Gαs 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 Gαs 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.</description><subject>Allosteric properties</subject><subject>Benzyl Alcohols</subject><subject>Biology and Life Sciences</subject><subject>Cell Differentiation</subject><subject>Collagen</subject><subject>Consent</subject><subject>Cyclic AMP response element-binding protein</subject><subject>Differentiation</subject><subject>Disease</subject><subject>Extracellular matrix</subject><subject>FDA approval</subject><subject>Fibroblasts</subject><subject>Fibroblasts - metabolism</subject><subject>Fibrosis</subject><subject>G protein-coupled receptors</subject><subject>Growth factors</subject><subject>Humans</subject><subject>Hydrogen-Ion Concentration</subject><subject>Idiopathic Pulmonary Fibrosis - pathology</subject><subject>Lung - pathology</subject><subject>Lung diseases</subject><subject>Medicine and Health Sciences</subject><subject>Myofibroblasts - metabolism</subject><subject>Ovarian cancer</subject><subject>Ovarian carcinoma</subject><subject>pH effects</subject><subject>Phosphorylation</subject><subject>Physiology</subject><subject>Proteins</subject><subject>Protons</subject><subject>Pulmonary fibrosis</subject><subject>Receptors</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Scars</subject><subject>Signaling</subject><subject>Smad protein</subject><subject>Transforming Growth Factor beta - metabolism</subject><subject>Transforming Growth Factor beta - pharmacology</subject><subject>Transforming growth factor-b</subject><subject>Triazines</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNp1UstuFDEQtBCIhMAfIBiJCxxmsd1jz84FCUXkIUXKJZwtPzdezY4HezbS_hYfkm9KLzuJkgMn291dVV3tJuQjowsGLfu-Tts86H4xpsEvKG-ZpMtX5Jh1wGvJKbx-dj8i70pZUypgKeVbcgSio4wu5TGJ1yuf41BtvIt68q6Kw200cYppqFKobs7P6vu_X9k3jLutxfxml0I0OZlel6lyMQSf_TAheA-JpRrTdHhjsdlV2kYXbTVevCdvgu6L_zCfJ-T32a-b04v66vr88vTnVW0Fl1PtJQvB8aaj1EljvIaW22BbIeWSgTGAnjj3YNuuZVa0jeRgPbWNaRh3VMMJ-XzgHftU1DylorjsBJoHClhxeahwSa_VmONG551KOqp_gZRXSucp2t4rbIlpFNLCmkZ4jv2IFkXQNee0s8j1Y1bbGpyhRetZ9y9IX2aGeKtW6U51AMBFgwRfZoKc_mx9mf7TcnOosjmVkn14UmBU7dfhEaX266DmdUDYp-fdPYEe_x8eAOnVtOU</recordid><startdate>20220728</startdate><enddate>20220728</enddate><creator>Bell, Tyler J</creator><creator>Nagel, David J</creator><creator>Woeller, Collynn F</creator><creator>Kottmann, R Mathew</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0001-7197-5057</orcidid><orcidid>https://orcid.org/0000-0002-5767-8264</orcidid></search><sort><creationdate>20220728</creationdate><title>Ogerin mediated inhibition of TGF-β(1) induced myofibroblast differentiation is potentiated by acidic pH</title><author>Bell, Tyler J ; Nagel, David J ; Woeller, Collynn F ; Kottmann, R Mathew</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-e61ffd24900d6bbea372cfc7566813bb393222e3c7971c574623ce0c4b412d0a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Allosteric properties</topic><topic>Benzyl Alcohols</topic><topic>Biology and Life Sciences</topic><topic>Cell Differentiation</topic><topic>Collagen</topic><topic>Consent</topic><topic>Cyclic AMP response element-binding protein</topic><topic>Differentiation</topic><topic>Disease</topic><topic>Extracellular matrix</topic><topic>FDA approval</topic><topic>Fibroblasts</topic><topic>Fibroblasts - 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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-β 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-β induced myofibroblast differentiation in a dose dependent manner. This occurs at the transcriptional level without inhibition of canonical TGF-β induced SMAD signaling. Ogerin induces PKA dependent CREB phosphorylation, a marker of Gαs pathway activation. The ability of Ogerin to inhibit both basal and TGF-β induced collagen gene transcription, and induction of Gαs 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 Gαs 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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>35901086</pmid><doi>10.1371/journal.pone.0271608</doi><orcidid>https://orcid.org/0000-0001-7197-5057</orcidid><orcidid>https://orcid.org/0000-0002-5767-8264</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Allosteric properties Benzyl Alcohols Biology and Life Sciences Cell Differentiation Collagen Consent Cyclic AMP response element-binding protein Differentiation Disease Extracellular matrix FDA approval Fibroblasts Fibroblasts - metabolism Fibrosis G protein-coupled receptors Growth factors Humans Hydrogen-Ion Concentration Idiopathic Pulmonary Fibrosis - pathology Lung - pathology Lung diseases Medicine and Health Sciences Myofibroblasts - metabolism Ovarian cancer Ovarian carcinoma pH effects Phosphorylation Physiology Proteins Protons Pulmonary fibrosis Receptors Receptors, G-Protein-Coupled - metabolism Scars Signaling Smad protein Transforming Growth Factor beta - metabolism Transforming Growth Factor beta - pharmacology Transforming growth factor-b Triazines |
| title | Ogerin mediated inhibition of TGF-β(1) induced myofibroblast differentiation is potentiated by acidic pH |
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