{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T15:18:05Z","timestamp":1777907885536,"version":"3.51.4"},"reference-count":70,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T00:00:00Z","timestamp":1768867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006108","name":"NIH-National Center for Advancing Translational Sciences","doi-asserted-by":"crossref","award":["R03TR003669-01A1"],"award-info":[{"award-number":["R03TR003669-01A1"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Emory Orthopaedic"},{"name":"Veterans Affairs CReATE Motion Center Award","award":["1I50RX004845-01"],"award-info":[{"award-number":["1I50RX004845-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Joint acidosis is increasingly recognized as an important determinant of cellular behavior in osteoarthritis (OA). Declines in extracellular pH (pHe) occur across cartilage, meniscus, synovium, and subchondral bone, where they influence inflammation, matrix turnover, and pain. Among proton-sensing G protein-coupled receptors, GPR68 responds to the acidic pH range characteristic of human OA joints. The receptor is activated between pH 6.8 and 7.0, couples to Gq\/PLC-MAPK, cAMP-CREB, G12\/13-RhoA-ROCK signaling pathways, and is expressed most prominently in articular cartilage, with additional expression reported in synovium, bone, vasculature, and some neuronal populations. These pathways regulate transcriptional programs relevant to cartilage stress responses, inflammation, and matrix turnover. GPR68 expression is increased in human OA cartilage and aligns with regions of active matrix turnover. We previously reported that pharmacologic activation of GPR68 suppresses IL1\u03b2-induced MMP13 expression in human chondrocytes under acidic conditions, indicating that increased GPR68 expression may represent a microenvironment-responsive, potentially adaptive signaling response rather than a driver of cartilage degeneration. Evidence from intestinal, stromal, and vascular models demonstrates that GPR68 integrates pH changes with inflammatory and mechanical cues, providing mechanistic context, although these effects have not been directly established in most joint tissues. Small-molecule modulators, including the positive allosteric agonist Ogerin and the inhibitor Ogremorphin, illustrate the tractability of GPR68 as a drug target, although no GPR68-directed therapies have yet been evaluated in preclinical models of OA. Collectively, current data support GPR68 as a functionally relevant proton sensor within the acidic OA joint microenvironment.<\/jats:p>","DOI":"10.3390\/genes17010109","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T11:27:58Z","timestamp":1768908478000},"page":"109","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Joint Acidosis and GPR68 Signaling in Osteoarthritis: Implications for Cartilage Gene Regulation"],"prefix":"10.3390","volume":"17","author":[{"given":"Colette","family":"Hyde","sequence":"first","affiliation":[{"name":"Department of Orthopaedics, Emory Musculoskeletal Institute, Emory University, Atlanta, GA 30329, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam","family":"Yung","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Emory Musculoskeletal Institute, Emory University, Atlanta, GA 30329, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan","family":"Taffe","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Emory Musculoskeletal Institute, Emory University, Atlanta, GA 30329, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bhakti","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Emory Musculoskeletal Institute, Emory University, Atlanta, GA 30329, USA"},{"name":"College of Sciences, Georgia Institute of Technology, Atlanta, GA 30332, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nazir M.","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Emory Musculoskeletal Institute, Emory University, Atlanta, GA 30329, USA"},{"name":"Joseph Maxwell Cleland Atlanta VA Medical Center, Decatur, GA 30033, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1016\/S0140-6736(19)30417-9","article-title":"Osteoarthritis","volume":"393","author":"Hunter","year":"2019","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.cbi.2017.06.025","article-title":"Wogonin, a natural flavonoid, intercalates with genomic DNA and exhibits protective effects in IL-1\u03b2 stimulated osteoarthritis chondrocytes","volume":"274","author":"Khan","year":"2017","journal-title":"Chem.-Biol. 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