Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
The HCO3/Cl Anion Exchanger SLC4A2 Regulates pH and Actin Organization within Osteoclasts.
Coury1, Fabienne, Stewart3, Andrew K., Stephens2, Sebastien, Neff2, Lynn, Horne2, William C., Alper3, Seth L., Baron2, Roland
Department of Immunology and Infectious Diseases, Harvard School of Public Health, and Department of Medicine, Harvard Medical School, Boston, MA
Department of Oral Medicine Infection and Immunity, Harvard Dental School
Division of Nephrology, Beth Israel Deaconess Medical Center
Overactivation of bone resorption by osteoclasts occurs in numerous rheumatic diseases such as osteoporosis and rheumatoid arthritis. To resorb bone, osteoclasts secrete acid into a resorption lacuna between their apical ruffled membrane and the bone surface. This process is facilitated by reorganization of their actin cytoskeleton to form a sealing zone, which, like a gasket, seals off the resorption lacuna to prevent acid leakage. To prevent cytoplasmic alkalinization during lacunar acid secretion, electroneutral exchange of bicarbonate for chloride occurs through an anion exchanger, Solute carrier family 4, anion exchanger, member 2 (SLC4A2, AE2). We recently showed that in the absence of Slc4a2, mice develop osteopetrosis due to impaired osteoclast function. Accordingly, SLC4A2-deficient osteoclasts are unable to secrete acid and resorb bone. Here, we show that SLC4A2 may serve an additional and previously unrecognized function in the osteoclast: the regulation of actin dynamics and podosome organization. In vitro, SLC4A2 deficient osteoclasts display a delay in actin belt formation. The actin belts ultimately formed by SLC4A2-null osteoclasts are thicker and made up almost completely of punctuate, large podosomes lacking the diffuse actin cloud characteristic of wild-type belts. Furthermore, the average podosome life span is significantly longer in the actin belts of null osteoclasts, while actin polymerization is increased. Interestingly, while SLC4A2 was not required for microtubule assembly, we show it is required to recruit c-Src to the actin belt. c-Src is a major intracellular mediator of osteoclast activation, coordinates organization of the actin belt and is required for osteoclast function in vivo. We also show that SLC4A2 is exclusively expressed at the basolateral membrane of mouse osteoclasts. In addition, in its absence, osteoclasts are unable to exchange Cl- for HCO3- and display intracellular alkalinization. Taken together, our results indicate that SLC4A2 regulates two cell biological processes required for mature osteoclasts to efficiently resorb bone: reorganization of the actin cytoskeleton and acid secretion. Whether the effect of SLC4A2 deficiency on the osteoclast cytoskeleton represents a direct function for this molecule in actin organization or an indirect effect of intracellular alkalinization is currently under investigation. Inhibitors designed to block SLC4A2 as a treatment for diseases characterized by excessive bone remodeling may need to take into account the binary function of this molecule in the osteoclast.
To cite this abstract, please use the following information:
Coury, Fabienne, Stewart, Andrew K., Stephens, Sebastien, Neff, Lynn, Horne, William C., Alper, Seth L., et al; The HCO3/Cl Anion Exchanger SLC4A2 Regulates pH and Actin Organization within Osteoclasts. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1502