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Departments of Cellular and Molecular Physiology (P.B., C.M.F., W.F.B.) and Internal Medicine (H.S., T.I., T.K., K.L.I.), Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut 06520
Address all correspondence and requests for reprints to: Patrice Bouyer, Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, POB 208026, New Haven, Connecticut 06520-8026. E-mail: Patrice.Bouyer{at}Yale.edu.
Colony-stimulating factor-1 (CSF-1) promotes the survival of osteoclasts, short-lived cells that resorb bone. Although a rise in intracellular pH (pHi) has been linked to inhibition of apoptosis, the effect of CSF-1 on pHi in osteoclasts has not been reported. The present study shows that, in the absence of CO2/HCO3–, CSF-1 causes little change in osteoclast pHi. In contrast, exposing these cells to CSF-1 in the presence of CO2/HCO3– causes a rapid and sustained cellular alkalinization. The CSF-1-induced rise in pHi is not blocked by 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, an inhibitor of HCO3– transporters but is abolished by removing extracellular sodium. This inhibition profile is similar to that of the electroneutral Na/HCO3 cotransporter NBCn1. By RT-PCR, NBCn1 transcripts are present in both osteoclasts and osteoclast-like cells (OCLs), and by immunoblotting, the protein is present in OCLs. Moreover, CSF-1 promotes osteoclast survival in the presence of CO2/HCO3– buffer but not in its absence. Preventing the activation of NBCn1 markedly attenuates the ability of CSF-1 to 1) block activation of caspase-8 and 2) prolong osteoclast survival. Inhibiting caspase-3 or caspase-8 in OCLs prolongs osteoclast survival to the same extent as does CSF-1. This study provides the first evidence that osteoclasts express a CSF-1-regulated Na/HCO3 cotransporter, which may play a role in cell survival.
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