2. Academic Validation
  3. The proton-activated G protein-coupled receptor GPR4 regulates the development of osteoarthritis via modulating CXCL12/CXCR7 signaling

The proton-activated G protein-coupled receptor GPR4 regulates the development of osteoarthritis via modulating CXCL12/CXCR7 signaling

  • Cell Death Dis. 2022 Feb 14;13(2):152. doi: 10.1038/s41419-021-04455-4.
Rong Li  # 1,  Zijing Guan  # 1,  Shuyan Bi  # 1,  Fanhua Wang 1 2,  Liang He 1 2,  Xin Niu 1,  Yu You 1,  Yuwei Liu 1,  Yi Ding 1,  Stefan Siwko 3,  Ning Wang 4,  Ziming Zhang 5,  Yunyun Jin 6,  Jian Luo 7 8
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, PR China.
  • 2 Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Tongji University School of Medicine, Shanghai, 201619, PR China.
  • 3 Department of Translational Medical Sciences, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX, 77030, USA.
  • 4 Department of Oncology and Metabolism, The University of Sheffield, Sheffield, UK.
  • 5 Department of Pediatric Orthopedics, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200092, PR China. zhangziming@xinhuamed.com.cn.
  • 6 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, PR China. yyjin@bio.ecnu.edu.cn.
  • 7 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, PR China. jluo@bio.ecnu.edu.cn.
  • 8 Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Tongji University School of Medicine, Shanghai, 201619, PR China. jluo@bio.ecnu.edu.cn.
  • # Contributed equally.
PMID: 35165253 DOI: 10.1038/s41419-021-04455-4
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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