Craniometaphyseal dysplasia (CMD) is a rare genetic bone disorder, which results in hyperostosis of craniofacial bones and flaring of metaphyses in long bones. We have created an animal model for this orphan disease by introducing one of the most common CMD mutations, a Phe377 deletion, into the mouse Ank gene by homologous recombination. ANK is a transmembrane protein known to transport intracellular pyrophosphate (PPi) into the extracellular environment. PPi is an important regulator of mineralization in bone. Ank Phe377del knock-in mice develop hyperostotic cranial and facial bone, reduced diameters of cranial foramina and undertrabeculated widened metaphyses, thus expressing the skeletal hallmarks of CMD. In this application, we propose 1) to study the role of phosphate and pyrophosphate in the hypomineralization phenotype of the AnkKI/KI mouse model and 2) to investigate direct effects of the ANK Phe377del mutation on gene regulation of specific differentiation stages during osteoblastogenesis. 3) We will investigate the contribution of osteoclasts to the bone mass phenotype of AnkKI/KI mice. Our long-term goal is to study molecular control mechanisms that regulate bone formation and bone remodeling in patients with CMD or similar craniotubular conditions. This Ank Phe377del knock-in model is the first to fully replicate the CMD phenotype enabling us to study the pathophysiology of CMD in an in vivo model. These studies will have broad impact on our understanding of bone homeostasis and are expected to impact future treatment of CMD and related disorders. A better understanding of mechanisms for bone mineralization and control of bone mass is important for large segments of the population who suffer from imbalance of bone formation and resorption, including patients with osteoporosis and osteopetrosis.

Public Health Relevance

The questions we ask in this application seek to understand the consequences of the CMD mutation on bone remodeling and to investigate mechanisms that lead to the CMD-like phenotype in our Ank knock-in mouse model. We expect that understanding mechanisms that lead to CMD will help to develop strategies for therapeutic intervention for this debilitating disorder. We also expect a broad impact on the field of bone remodeling as the mutation in this animal model affects some key mechanisms for bone mineralization and regulation of bone cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE019458-03
Application #
8446917
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Wan, Jason
Project Start
2011-04-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$351,120
Indirect Cost
$123,120
Name
University of Connecticut
Department
Dentistry
Type
Schools of Dentistry
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Chen, I-P; Tadinada, A; Dutra, E H et al. (2014) Dental Anomalies Associated with Craniometaphyseal Dysplasia. J Dent Res 93:553-558
Dutra, E H; Chen, I-P; Reichenberger, E J (2013) Dental abnormalities in a mouse model for craniometaphyseal dysplasia. J Dent Res 92:173-9