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Ae2_a,b-Deficient mice exhibit osteopetrosis of long bones but not of calvaria

Ineke D. C. Jansen^*,,1, Pablo Mardones, Fernando Lecanda^#, Teun J. de Vries^*,, Sergio Recalde^#, Kees A. Hoeben^||, Ton Schoenmaker^*,, Jan-Hindrik Ravesloot^¶, Marcel M. G. J. van Borren^¶, Theo M. van Eijden^,2, Antonius L. J. J. Bronckers, Sakari Kellokumpu^**, Juan F. Medina^#,, Vincent Everts^*, and Ronald P. J. Oude Elferink

^* Department of Periodontology,

Department of Oral Cell Biology, and

Department of Functional Anatomy, Academic Centre for Dentistry Amsterdam, University of Amsterdam and VU University Amsterdam, Research Institute MOVE, Amsterdam, The Netherlands;

AMC Liver Center,

^|| Department of Cell Biology and Histology, and

^¶ Department of Physiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;

^# School of Medicine and Centro de Investigación Médica Aplicada (CIMA), University of Navarra, Pamplona, Spain;

^** Department of Biochemistry, University of Oulu, Oulu, Finland; and

Division of Gene Therapy and Hepatology, CIMA and Clinic, University of Navarra and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Pamplona, Spain

¹ Correspondence: Department of Periodontology, Academic Centre for Dentistry Amsterdam (ACTA), VU University Amsterdam, van der Boechorststraat 7, Amsterdam, Netherlands 1081 BT. E-mail: ineke.jansen{at}vumc.nl

Extracellular acidification by osteoclasts is essential to bone resorption. During proton pumping, intracellular pH (pH_i) is thought to be kept at a near-neutral level by chloride/bicarbonate exchange. Here we show that the Na⁺-independent chloride/bicarbonate anion exchanger 2 (Ae2) is relevant for this process in the osteoclasts from the long bones of Ae2_a,b^–/–mice (deficient in the main isoforms Ae2a, Ae2b₁, and Ae2b₂). Although the long bones of these mice had normal numbers of multinucleated osteoclasts, these cells lacked a ruffled border and displayed impaired bone resorption activity, resulting in an osteopetrotic phenotype of long bones. Moreover, in vitro osteoclastogenesis assays using long-bone marrow cells from Ae2_a,b^–/–mice suggested a role for Ae2 in osteoclast formation, as fusion of preosteoclasts for the generation of active multinucleated osteoclasts was found to be slightly delayed. In contrast to the abnormalities observed in the long bones, the skull of Ae2_a,b^–/–mice showed no alterations, indicating that calvaria osteoclasts may display normal resorptive activity. Microfluorimetric analysis of osteoclasts from normal mice showed that, in addition to Ae2 activity, calvaria osteoclasts—but not long-bone osteoclasts—possess a sodium-dependent bicarbonate transporting activity. Possibly, this might compensate for the absence of Ae2 in calvaria osteoclasts of Ae2_a,b^–/–mice.—Jansen, I. D. C., Mardones, P., Lecanda, F., de Vries, T. J., Recalde, S., Hoeben, K. A., Schoenmaker, T., Ravesloot, J.-H., van Borren, M. M. G. J., van Eijden, T. M., Bronckers, A. L. J. J., Kellokumpu, S., Medina, J. F., Everts, V., Oude Elferink, R. P. J. Ae2_a,b-deficient mice exhibit osteopetrosis of long bones but not of calvaria.

Key Words: osteoclast • osteoclastogenesis • skull • solute carriers • tibia