{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T11:16:42Z","timestamp":1789039002320,"version":"build-2803163510"},"reference-count":99,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:00:00Z","timestamp":1760572800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the NIH\u2014National Center for Advancing Translational Sciences","award":["R03TR003669-01A1"],"award-info":[{"award-number":["R03TR003669-01A1"]}]},{"name":"the Veterans Affairs CReATE Motion Center Award","award":["1I50RX004845-01"],"award-info":[{"award-number":["1I50RX004845-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Osteoarthritis (OA) lacks disease-modifying therapies, in part because key features of the joint microenvironment remain underappreciated. One such feature is localized acidosis, characterized by sustained reductions in extracellular pH within the cartilage, meniscus, and the osteochondral interface despite near-neutral bulk synovial fluid. We synthesize current evidence on the origins, sensing, and consequences of joint acidosis in OA. Metabolic drivers include hypoxia-biased glycolysis in avascular cartilage, cytokine-driven reprogramming in the synovium, and limits in proton\/lactate extrusion (e.g., monocarboxylate transporters (MCTs)), with additional contributions from fixed-charge matrix chemistry and osteoclast-mediated acidification at the osteochondral junction. Acidic niches shift proteolysis toward cathepsins, suppress anabolic control, and trigger chondrocyte stress responses (calcium overload, autophagy, senescence, apoptosis). In the nociceptive axis, protons engage ASIC3 and sensitize TRPV1, linking acidity to pain. Joint cells detect pH through two complementary sensor classes: proton-sensing GPCRs (GPR4, GPR65\/TDAG8, GPR68\/OGR1, GPR132\/G2A), which couple to Gs, Gq\/11, and G12\/13 pathways converging on MAPK, NF-\u03baB, CREB, and RhoA\/ROCK; and proton-gated ion channels (ASIC1a\/3, TRPV1), which convert acidity into electrical and Ca2+ signals. Therapeutic implications include inhibition of acid-enabled proteases (e.g., cathepsin K), pharmacologic modulation of pH-sensing receptors (with emerging interest in GPR68 and GPR4), ASIC\/TRPV1-targeted analgesia, metabolic control of lactate generation, and pH-responsive intra-articular delivery systems. We outline research priorities for pH-aware clinical phenotyping and imaging, cell-type-resolved signaling maps, and targeted interventions in \u2018acidotic OA\u2019 endotypes. Framing acidosis as an actionable component of OA pathogenesis provides a coherent basis for mechanism-anchored, locality-specific disease modification.<\/jats:p>","DOI":"10.3390\/cells14201605","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T12:17:02Z","timestamp":1760617022000},"page":"1605","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Joint Acidosis and Acid-Sensing Receptors and Ion Channels in Osteoarthritis Pathobiology and Therapy"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6023-8198","authenticated-orcid":false,"given":"William N.","family":"Martin","sequence":"first","affiliation":[{"name":"Department of Orthopaedics, Emory Musculoskeletal Institute, Emory University, Atlanta, GA 30329, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colette","family":"Hyde","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Emory Musculoskeletal Institute, Emory University, Atlanta, GA 30329, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Yung","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Emory Musculoskeletal Institute, Emory University, Atlanta, GA 30329, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Taffe","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Emory Musculoskeletal Institute, Emory University, Atlanta, GA 30329, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajay","family":"Premkumar","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Emory Musculoskeletal Institute, Emory University, Atlanta, GA 30329, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pallavi","family":"Bhattaram","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Emory Musculoskeletal Institute, Emory University, Atlanta, GA 30329, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hicham","family":"Drissi","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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Li, H.Z., Liang, X.Z., Sun, Y.Q., Jia, H.F., Li, J.C., and Li, G. 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