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 journalArticle

34 Citations (Scopus)

Abstract

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
Volume220
Issue number2
DOIs
StatePublished - Aug 2009

Fingerprint

Osteoclasts
Bicarbonates
Adenylyl Cyclases
Bone
Acid Phosphatase
Skull
Vacuolar Proton-Translocating ATPases
8-Bromo Cyclic Adenosine Monophosphate
Bone and Bones
Proton-Translocating ATPases
Sensors
Bone Resorption
Acidosis
Bone Density
Small Interfering RNA
Tomography
Adenosine Triphosphatases
Chemical activation
Acids
Growth

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

Inhibition of osteoclast formation and function by bicarbonate : Role of soluble adenylyl cyclase. / Geng, Weidong; Hill, Kathy; Zerwekh, Joseph E.; Kohler, Thomas; Müller, Ralph; Moe, Orson W.

In: Journal of Cellular Physiology, Vol. 220, No. 2, 08.2009, p. 332-340.

Research output: Contribution to journalArticle

Geng, Weidong ; Hill, Kathy ; Zerwekh, Joseph E. ; Kohler, Thomas ; Müller, Ralph ; Moe, Orson W. / Inhibition of osteoclast formation and function by bicarbonate : Role of soluble adenylyl cyclase. In: Journal of Cellular Physiology. 2009 ; Vol. 220, No. 2. pp. 332-340.
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