Targeted disruption of the Cl -/HCO 3 - exchanger Ae2 results in osteopetrosis in mice

Kaj Josephsen, Jeppe Praetorius, Sebastian Frische, Lara R. Gawenis, Tae Hwan Kwon, Peter C Agre, Søren Nielsen, Ole Fejerskov

Research output: Contribution to journalArticle

Abstract

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 + and Cl - into these lacunae by the combined action of vesicular H + -ATPases and ClC-7 exchangers to dissolve the hydroxyapatite of bone matrix. Along with intracellular production of H + and HCO 3 - by carbonic anhydrase II, the H +-ATPasesand 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 3 - extruding and Cl - 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- 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.

Original languageEnglish (US)
Pages (from-to)1638-1641
Number of pages4
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number5
DOIs
StatePublished - Feb 3 2009

Fingerprint

Osteopetrosis
Osteoclasts
Bone Resorption
Antiporters
Bone and Bones
Carbonic Anhydrase II
Bone Marrow Examination
Bone Matrix
Molecular Models
Proton-Translocating ATPases
Durapatite
Radio
Knockout Mice
Proteins
Homeostasis
Immunohistochemistry
Cell Membrane
X-Rays
Calcium
Membranes

Keywords

  • Anion exchanger
  • Bone resorption
  • Osteoclast

ASJC Scopus subject areas

  • General

Cite this

Targeted disruption of the Cl -/HCO 3 - exchanger Ae2 results in osteopetrosis in mice. / Josephsen, Kaj; Praetorius, Jeppe; Frische, Sebastian; Gawenis, Lara R.; Kwon, Tae Hwan; Agre, Peter C; Nielsen, Søren; Fejerskov, Ole.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 5, 03.02.2009, p. 1638-1641.

Research output: Contribution to journalArticle

Josephsen, Kaj ; Praetorius, Jeppe ; Frische, Sebastian ; Gawenis, Lara R. ; Kwon, Tae Hwan ; Agre, Peter C ; Nielsen, Søren ; Fejerskov, Ole. / Targeted disruption of the Cl -/HCO 3 - exchanger Ae2 results in osteopetrosis in mice. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 5. pp. 1638-1641.
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AU - Gawenis, Lara R.

AU - Kwon, Tae Hwan

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AU - Nielsen, Søren

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