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Bone Abstracts (2013) 1 PP474 | DOI: 10.1530/boneabs.1.PP474

1Bambino Gesù Children’s Hospital, Rome, Italy; 2IUPUI, Indianapolis, Indiana, USA; 3University of L’Aquila, L’Aquila, Italy.

Autosomal dominant osteopetrosis type II (ADO2) is a rare osteosclerotic disease due heterozygous missense mutations of the CLC7 gene encoding the type seven chloride channel. Our two labs independently generated the first C57 black 6 (B6) mouse model of ADO2 by inserting the pG213R-clc7 mutation. Homozygous mice showed lack of tooth eruption and died within 30 days of age with severe osteopetrosis and central nervous system degeneration. Compared to WT, heterozygous B6 ADO2 mice showed increase of whole body aBMD (4%, P<0.05) and much greater change at distal femur for BV/TV and Trab.N (75 and 65%, P<0.01). Histomorphometric analysis revealed twofold increase of osteoclast number in the proximal tibia compared to WT mice. Bone marrow monocytes from B6 ADO2 mice showed twofold increase of osteoclast formation, and 80% reduction of resorption pits, confirming cell autonomous impairment of bone resorption. Since the penetrance of the disorder in humans is ~66% and severity varies considerably, we cross-bred B6 ADO2 with mice of different genetic backgrounds (129, D2, Balb/c and CD1). Compared to WT, the whole body aBMD and BMC at 12 weeks of age were very high in ADO2 mice on 129 background (8 and 12%, P<0.01). ADO2 mice on D2 background also had significantly higher whole body aBMD (4%, P<0.02). The BV/TV was significantly higher at distal femur in ADO2 mice on 129, D2 and Balb/c backgrounds. CTX/TRAcP ratio was significantly lower in all ADO2 backgrounds, except the D2. Our results demonstrate that we have generated the first animal model of ADO2 that will help us to study the mechanisms of incomplete penetrance and test innovative therapies to treat this incurable disease.

Volume 1

European Calcified Tissue Society Congress 2013

Lisbon, Portugal
18 May 2013 - 22 May 2013

European Calcified Tissue Society 

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