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Title: Involvement of the G-protein-coupled receptor 4 in RANKL expression by osteoblasts in an acidic environment

Osteoclast activity is enhanced in acidic environments following systemic or local inflammation. However, the regulatory mechanism of receptor activator of NF-κB ligand (RANKL) expression in osteoblasts under acidic conditions is not fully understood. In the present paper, we detected the mRNA expression of the G-protein-coupled receptor (GPR) proton sensors GPR4 and GPR65 (T-cell death-associated gene 8, TDAG8), in osteoblasts. RANKL expression and the cyclic AMP (cAMP) level in osteoblasts were up-regulated under acidic culture conditions. Acidosis-induced up-regulation of RANKL was abolished by the protein kinase A inhibitor H89. To clarify the role of GPR4 in RANKL expression, GPR4 gain and loss of function experiments were performed. Gene knockdown and forced expression of GPR4 caused reduction and induction of RANKL expression, respectively. These results suggested that, at least in part, RANKL expression by osteoblasts in an acidic environment was mediated by cAMP/PKA signaling resulting from GPR4 activation. A comprehensive microarray analysis of gene expression of osteoblasts revealed that, under acidic conditions, the phenotype of osteoblasts was that of an osteoclast supporting cell rather than that of a mineralizing cell. These findings will contribute to a molecular understanding of bone disruption in an acidic environment. - Highlights: • RANKL expression was increasedmore » in osteoblasts under acidosis via cAMP/PKA pathway. • GRP4 knockdown resulted in decrease of RANKL expression. • GRP4 overexpression resulted in increase of RANKL expression. • Osteoblast mineralization was reduced under acidic condition.« less
Authors:
 [1] ;  [2] ;  [1] ;  [1] ;  [3] ;  [1]
  1. Department of Cellular Physiological Chemistry, Tokyo Medical and Dental University, Tokyo (Japan)
  2. (Japan)
  3. Department of Orthodontic Science, Tokyo Medical and Dental University, Tokyo (Japan)
Publication Date:
OSTI Identifier:
22458524
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 458; Journal Issue: 2; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AMP; APOPTOSIS; CONNECTIVE TISSUE CELLS; ENVIRONMENT; GAIN; GENES; GTP-ASES; INDUCTION; INFLAMMATION; LIGANDS; MESSENGER-RNA; MINERALIZATION; PHENOTYPE; PROTONS; RECEPTORS; SENSORS; SIGNALS; SKELETON