Journal Article

A Phe377del mutation in ANK leads to impaired osteoblastogenesis and osteoclastogenesis in a mouse model for craniometaphyseal dysplasia (CMD)

I-Ping Chen, Liping Wang, Xi Jiang, Hector Leonardo Aguila and Ernst J. Reichenberger

in Human Molecular Genetics

Volume 20, issue 5, pages 948-961
Published in print March 2011 | ISSN: 0964-6906
Published online December 2010 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddq541
A Phe377del mutation in ANK leads to impaired osteoblastogenesis and osteoclastogenesis in a mouse model for craniometaphyseal dysplasia (CMD)

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Craniometaphyseal dysplasia (CMD) is a rare genetic disorder with hyperostosis of craniofacial bones and widened metaphyses in long bones. Patients often suffer from neurological symptoms due to obstruction of cranial foramina. No proven treatment is available and the pathophysiology is largely unknown. A Phe377 (TTC1130–1132) deletion in exon 9 of the pyrophosphate (PPi) transporter ANK leads to CMD-like features in an AnkKI/KI mouse model. Here, we investigated the effects of CMD-mutant ANK on mineralization and bone mass at a cellular level. AnkKI/KI osteoblast cultures showed decreased mineral deposition. Expression of bone mineralization regulating genes Mmp13, Ocn, Osx and Phex was reduced in AnkKI/KI osteoblasts, while the Fgf23 mRNA level was highly elevated in AnkKI/KI calvarial and femoral bones. Since ANK is a known PPi transporter, we examined other regulators of Pi/PPi homeostasis Enpp1 and Tnap. Significantly increased ENPP1 activity may compensate for dysfunctional mutant ANK leading to comparable extracellular PPi levels in Ank+/+ osteoblasts. Similar to AnkKI/KI bone marrow-derived macrophage cultures, peripheral blood cultures from CMD patients exhibited reduced osteoclastogenesis. Cell-autonomous effects in AnkKI/KI osteoclasts resulted in disrupted actin ring formation and cell fusion. In addition, AnkKI/KI osteoblasts failed to adequately support osteoclastogenesis. Increased bone mass could partially be rescued by bone marrow transplants supporting our hypothesis that reduced osteoclastogenesis contributes at least in part to hyperostosis. We conclude that the Phe377del mutation in ANK causes impaired osteoblastogenesis and osteoclastogenesis resulting in hypomineralization and a high bone mass phenotype.

Journal Article.  9280 words.  Illustrated.

Subjects: Genetics and Genomics

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