Adenosine A1 receptors (A1Rs) play a critical role in osteoclast formation and function

Firas M. Kara, Violeta Chitu, Jennifer Sloane, Matthew Axelrod, Bertil B. Fredholm, E. Richard Stanley, Bruce N. Cronstein

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

Adenosine regulates a wide variety of physiological processes via interaction with one or more G-protein-coupled receptors (A1R, A 2AR, A2BR, and A3R). Because A1R occupancy promotes fusion of human monocytes to form giant cells in vitro, we determined whether A1R occupancy similarly promotes osteoclast function and formation. Bone marrow cells (BMCs) were harvested from C57Bl/6 female mice or A1R-knockout mice and their wild-type (WT) littermates and differentiated into osteoclasts in the presence of colony stimulating factor-1 and receptor activator of NF-κB ligand in the presence or absence of the A1R antagonist 1,3-dipropyl-8-cyclopentyl xanthine (DPCPX). Osteoclast morphology was analyzed in tartrate-resistant acid phosphatase or F-actin-stained samples, and bone resorption was evaluated by toluidine blue staining of dentin. BMCs from A1R-knockout mice form fewer osteoclasts than BMCs from WT mice, and the A1R antagonist DPCPX inhibits osteoclast formation (IC50=1 nM), with altered morphology and reduced ability to resorb bone. A1R blockade increased ubiquitination and degradation of TRAF6 in RAW264.7 cells induced to differentiate into osteoclasts. These studies suggest a critical role for adenosine in bone homeostasis via interaction with adenosine A1R and further suggest that A1R may be a novel pharmacologic target to prevent the bone loss associated with inflammatory diseases and menopause.

Original languageEnglish (US)
Pages (from-to)2325-2333
Number of pages9
JournalFASEB Journal
Volume24
Issue number7
DOIs
StatePublished - Jul 1 2010

Keywords

  • Osteoporosis
  • P1 receptors

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Kara, F. M., Chitu, V., Sloane, J., Axelrod, M., Fredholm, B. B., Stanley, E. R., & Cronstein, B. N. (2010). Adenosine A1 receptors (A1Rs) play a critical role in osteoclast formation and function. FASEB Journal, 24(7), 2325-2333. https://doi.org/10.1096/fj.09-147447