Targeted disruption of the Cl super(-)/HCO sub(3) super(-) exchanger Ae2 results in osteopetrosis in mice

Osteoclasts are multinucleated bone-resorbing cells responsible for constant remodeling of bone tissue and for maintaining calcium homeostasis. The osteoclast creates an enclosed space, a lacuna, between their ruffled border membrane and the mineralized bone. They extrude H super(+) and Cl super(-)...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2009-02, Vol.106 (5), p.1638-1641
Hauptverfasser: Josephsen, Kaj, Praetorius, Jeppe, Frische, Sebastian, Gawenis, Lara R, Kwon, Tae-Hwan, Agre, Peter, Nielsen, S¸ren, Fejerskov, Ole
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Sprache:eng
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Zusammenfassung:Osteoclasts are multinucleated bone-resorbing cells responsible for constant remodeling of bone tissue and for maintaining calcium homeostasis. The osteoclast creates an enclosed space, a lacuna, between their ruffled border membrane and the mineralized bone. They extrude H super(+) and Cl super(-) into these lacunae by the combined action of vesicular H super(+)-ATPases and ClC-7 exchangers to dissolve the hydroxyapatite of bone matrix. Along with intracellular production of H super(+) and HCO sub(3) super(-) by carbonic anhydrase II, the H super(+)-ATPases and ClC-7 exchangers seems prerequisite for bone resorption, because genetic disruption of either of these proteins leads to osteopetrosis. We aimed to complete the molecular model for lacunar acidification, hypothesizing that a HCO sub(3) super(-) extruding and Cl super(-) loading anion exchange protein (Ae) would be necessary to sustain bone resorption. The Ae proteins can provide both intracellular pH neutrality and serve as cellular entry mechanism for Cl super(-) during bone resorption. Immunohistochemistry revealed that Ae2 is exclusively expressed at the contra-lacunar plasma membrane domain of mouse osteoclast. Severe osteopetrosis was encountered in Ae2 knockout (Ae2-/-) mice where the skeletal development was impaired with a higher diffuse radio-density on x-ray examination and the bone marrow cavity was occupied by irregular bone speculae. Furthermore, osteoclasts in Ae2-/- mice were dramatically enlarged and fail to form the normal ruffled border facing the lacunae. Thus, Ae2 is likely to be an essential component of the bone resorption mechanism in osteoclasts.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0811682106