ArticleCell death & disease2022
The proton-activated G protein-coupled receptor GPR4 regulates the development of osteoarthritis via modulating CXCL12/CXCR7 signaling.
Article in Cell death & disease, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 51 citations in OpenAlex.
- The inhibition of lactate/Gpr81 signalling driven by moderate-intensity continuous training protects against osteoarthritis.Experimental & molecular medicine · 2026Article
- Inhibition of GPR4 Ameliorates Neuropathic Pain and Neuronal Ferroptosis via Regulation of Spinal RhoA/YAP Signaling in Rats.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2026Article
- The SDF-1α/CXCR4 axis regulates chondrocyte mitochondrial dynamics via the ERK/AMPKα pathway.Cell communication and signaling : CCS · 2026Article
- Lactate and Acidification: Emerging Metabolic Regulators of Osteoarthritis.Current medical science · 2026Review
- Joint Acidosis and GPR68 Signaling in Osteoarthritis: Implications for Cartilage Gene Regulation.Genes · 2026Review
- Isoquercitrin ameliorates chondrocyte dysfunction in osteoarthritis by targeting AKT1-mediated mitochondrial dynamics regulation.PloS one · 2026Article
- Targeting the CXCL12/CXCR4 pathway by an optimized derivative or EPI-X4 preserves chondrocyte function and offers a novel therapeutic approach in rheumatic diseases.Arthritis research & therapy · 2025Article
- Joint Acidosis and Acid-Sensing Receptors and Ion Channels in Osteoarthritis Pathobiology and Therapy.Cells · 2025Review
- Proteomics and metabolomics studies in pigmented villonodular synovitis uncover the regulation of monocyte differentiation by the ADGRE5-NF-κB pathway.BMC medicine · 2025Article
- Molecular mechanism of pH sensing and activation in GPR4 reveals proton-mediated GPCR signaling.Cell discovery · 2025Article
- Structural basis of stepwise proton sensing-mediated GPCR activation.Cell research · 2025Article
- The Role of G Protein-Coupled Receptors in the Regulation of Orthopaedic Diseases by Gut Microbiota.Nutrients · 2025Review
- Biased agonism of G protein-coupled receptors as a novel strategy for osteoarthritis therapy.Bone research · 2025Review
- Identification and experimental verification of biomarkers related to butyrate metabolism in osteoarthritis.Scientific reports · 2025Article
- Molecular roles in membrane receptor signaling pathways and cascade reactions in chondrocytes: a review.Journal of molecular histology · 2025Review
- Correlation Analysis of Serum G-Protein-Coupled Receptor 4 and Biglycan Levels with the Severity of Intervertebral Disc Degeneration.Orthopedic research and reviews · 2025Article
- The function of GPCRs in different bone cells.International journal of biological sciences · 2025Review
- Inhibition of acid-sensing receptor GPR4 attenuates neuronal ferroptosis via RhoA/YAP signaling in a rat model of subarachnoid hemorrhage.Free radical biology & medicine · 2024Article
- Review
- GITR exacerbates lysophosphatidylcholine-induced macrophage pyroptosis in sepsis via posttranslational regulation of NLRP3.Cellular & molecular immunology · 2024Article
Corrections and comments
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Authors and funding
14 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Inflammatory diseases decrease the extracellular environmental pH. However, whether proton-activated G protein-coupled receptors (GPCRs) can regulate the development of osteoarthritis (OA) is largely unknown. In this study, we report that proton-activated GPR4 is essential for OA development. We found a marked increase in expression of the proton-activated GPR4 in human and mouse OA cartilage. Lentivirus-mediated overexpression of GPR4 in mouse joints accelerated the development of OA, including promotion of articular cartilage damage, synovial hyperplasia, and osteophyte formation, while Gpr4 knockout effectively attenuated the development of posttraumatic and aging-associated OA in mice. We also found that inhibition of GPR4 with the antagonist NE52-QQ57 ameliorated OA progression in mice, promoted extracellular matrix (ECM) production, and protected cartilage from degradation in human articular cartilage explants. Moreover, GPR4 overexpression upregulated matrix-degrading enzymes' expression and inflammation factors under pro-inflammatory and slightly acidic conditions. Mechanistically, GPR4 suppressed chondrocyte differentiation and upregulated cartilage homeostasis through NF-κB/MAPK signaling activation by regulating CXCR7/CXCL12 expression. Together, our results take the lead to illustrate that proton-activated GPCR acts as a key regulator for OA pathogenesis in vivo, and support that GPR4 could be a promising therapeutic target for OA treatment.
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