title: Decreased extracellular pH inhibits osteogenesis through proton-sensing GPR4-mediated suppression of yes-associated protein.
abstract: The pH of extracellular fluids is a basic property of the tissue microenvironment and is normally maintained at 7.40 ± 0.05 in humans. Many pathological circumstances, such as ischemia, inflammation, and tumorigenesis, result in the reduction of extracellular pH in the affected tissues. In this study, we reported that the osteogenic differentiation of BMSCs was significantly inhibited by decreases in the extracellular pH. Moreover, we demonstrated that proton-sensing GPR4 signaling mediated the proton-induced inhibitory effects on the osteogenesis of BMSCs. Additionally, we found that YAP was the downstream effector of GPR4 signaling. Our findings revealed that the extracellular pH modulates the osteogenic responses of BMSCs by regulating the proton-sensing GPR4-YAP pathway.
authors.affiliation: Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China.
authors.forename: Shi-Cong
authors.initials: SC
authors.lastname: Tao
authors.affiliation: Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China.
authors.forename: You-Shui
authors.initials: YS
authors.lastname: Gao
authors.affiliation: Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China.
authors.forename: Hong-Yi
authors.initials: HY
authors.lastname: Zhu
authors.affiliation: Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China.
authors.forename: Jun-Hui
authors.initials: JH
authors.lastname: Yin
authors.affiliation: Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China.
authors.forename: Yi-Xuan
authors.initials: YX
authors.lastname: Chen
authors.affiliation: Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China.
authors.forename: Yue-Lei
authors.initials: YL
authors.lastname: Zhang
authors.affiliation: Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China.
authors.forename: Shang-Chun
authors.initials: SC
authors.lastname: Guo
authors.affiliation: Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China.|Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China.
authors.forename: Chang-Qing
authors.initials: CQ
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000502:physiology*; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis / Q000235:genetics; D003470:Culture Media / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D045604:Extracellular Fluid / Q000502:physiology*; D020869:Gene Expression Profiling; D006801:Humans; D006863:Hydrogen-Ion Concentration; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000502:physiology; D010006:Osteoblasts / Q000187:drug effects / Q000502:physiology; D010012:Osteogenesis / Q000187:drug effects* / Q000502:physiology; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D011522:Protons; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D015290:Second Messenger Systems; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C526317:CCN2 protein, human; D003470:Culture Media; C091670:GPR4 protein, human; D010750:Phosphoproteins; D011522:Protons; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D055513:Connective Tissue Growth Factor; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases