{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T19:42:42Z","timestamp":1775936562455,"version":"3.50.1"},"posted":{"date-parts":[[2025,3,1]]},"group-title":"Molecular Biology","reference-count":74,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,1]],"date-time":"2025-03-01T00:00:00Z","timestamp":1740787200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Fibrosis in systemic sclerosis\/scleroderma (SSc) is characterized by the progressive accumulation and persistence in multiple organs of pathologic fibroblasts whose contractile properties and exuberant secretion of collagens promote tissue stiffness and scarring. Identifying a tractable mechanism for inactivating and possibly clearing these ultimate effector cells of fibrosis, conventionally termed myofibroblasts (MFs), represents an appealing therapeutic strategy for patients with SSc. This can be accomplished by their phenotypic dedifferentiation, a process known to be promoted by generation of the intracellular second messenger cyclic AMP (cAMP). Notably, however, the abilities of SSc fibroblasts derived from different tissues to generate cAMP \u2013 and dedifferentiate in response to it \u2013 have never been directly characterized or compared. Here we compared these two processes in lung and skin MFs derived from patients with SSc. While directly increasing intracellular cAMP induced comparable dedifferentiation of lung and skin SSc MFs, dedifferentiation in response to the well-recognized cAMP stimulus prostaglandin E\n                  <jats:sub>2<\/jats:sub>\n                  (PGE\n                  <jats:sub>2<\/jats:sub>\n                  ) was diminished or absent in MFs from skin as compared to lung, in part due to differences in the expression of its target G protein-coupled receptors (GPCRs). Importantly, treatment with a phosphodiesterase 4 inhibitor rescued the dedifferentiating effects of PGE\n                  <jats:sub>2<\/jats:sub>\n                  in skin SSc MFs. Finally, both cAMP-mediated and direct pharmacologic inhibition of the MAPK p38\u03b1 promoted dedifferentiation of lung and skin SSc MFs. We conclude that activation of the cAMP pathway and its subsequent inhibition of p38\u03b1 dedifferentiates SSc MFs from both lung and skin, and may thus represent a therapeutic strategy to alleviate multi-organ fibrosis in SSc.\n                <\/jats:p>","DOI":"10.1101\/2025.02.26.640163","type":"posted-content","created":{"date-parts":[[2025,3,1]],"date-time":"2025-03-01T23:30:20Z","timestamp":1740871820000},"source":"Crossref","is-referenced-by-count":0,"title":["Distinct cAMP regulation in scleroderma lung and skin myofibroblasts governs their dedifferentiation via p38\u03b1 inhibition"],"prefix":"10.64898","author":[{"given":"Jared D.","family":"Baas","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6504-2496","authenticated-orcid":false,"given":"John","family":"Varga","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, University of Michigan Medical School, Ann Arbor, Michigan, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6750-6407","authenticated-orcid":false,"given":"Carol","family":"Feghali-Bostwick","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Medical University of South Carolina, Charleston, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9768-0262","authenticated-orcid":false,"given":"Marc","family":"Peters-Golden","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3182-9586","authenticated-orcid":false,"given":"Sean M.","family":"Fortier","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026041111464428000_2025.02.26.640163v1.1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI74368"},{"key":"2026041111464428000_2025.02.26.640163v1.2","unstructured":"Varga J . 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