Inhibition of osteoclast formation and function by bicarbonate: Role of soluble adenylyl cyclase

Weidong Geng, Kathy Hill, Joseph E. Zerwekh, Thomas Kohler, Ralph Müller, Orson W. Moe

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


High [HCO-3-] inhibits and low [CO3 - stimulates bone resorption, which mediates part of the effect of chronic acidosis or acid feeding on bone. Soluble adenylyl cyclase (sAC) is a bicarbonate sensor that can potentially mediate the effect of bicarbonate on osteoclasts. Osteoclasts were incubated in 0, 12, and 24mMHCO3 -at pH 7.4 for 7-8 days and assayed for tartrate-resistant acid phosphatase (TRAP) and vacuolar-ATPase expression, and H+ccumulation. Total number and area of TRAP (+)ultinucleated osteoclasts was decreased by HCO3-in a dose-dependent manner. V-ATPase expression and H+accumulation normalized to cell cross-sectional area or protein were not significantly changed. The HCO3--induced inhibition of osteoclast growth and differentiation was blocked by either 2-hydroxyestradiol, an inhibitor of sAC or sAC knockdown by sAC specific siRNA. The model of CO3-inhibiting osteoclast via sAC was further supported by the fact that the HCO3-dose-response on osteoclasts is flat when cells were saturated with 8-bromo-cAMP, a permeant cAMP analog downstream from sAC thus simulating sAC activation. To confirm our in vitro findings in intact bone, we developed a 1-week mouse calvaria culture system where osteoclasts were shown to be viable. Bone volume density (BV/TV) determined by micro-computed tomography (μmCT), was higher in 24 mM HCO 3-compared to 12 mM HCO3-treated calvaria. This HCO3-effect on BV/TV was blocked by 2-hydroxyestradiol. In summary, sAC mediates the inhibition of osteoclast function byHCO3-, by acting as aHCO3 - sensor.

Original languageEnglish (US)
Pages (from-to)332-340
Number of pages9
JournalJournal of cellular physiology
Issue number2
StatePublished - Aug 2009

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology


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