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 G_s, G_q/11, and G_12/13 pathways converging on MAPK, NF-κB, 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 ‘acidotic OA’ endotypes. Framing acidosis as an actionable component of OA pathogenesis provides a coherent basis for mechanism-anchored, locality-specific disease modification.

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 IL1β-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.