The long term goal of this study is to determine mechanisms regulating mineralization in skeletal tissues. Physiological mineralization occurs in growth plate cartilage, bone and teeth, and is restricted to specific sites. Uncontrolled (pathological) mineralization has severe consequences and leads to morbidity and mortality. Therefore, an understanding of the regulatory mechanisms of mineralization is of crucial importance. During our last funding period we made major progress in understanding the role of calcium homeostasis in the regulation of mineralization. Calcium influx mediated through annexin channels regulates the expression of mineralization-related genes, and the release of mineralization-competent matrix vesicles. Interestingly, overexpression of annexin V resulted not only in increased mineralization but also upregulation of ank gene expression. Ank is a newly discovered protein which transports intracellular pyrophosphate (PPi) to the extracellular millieu. Human mutations in Ank are associated with extensive mineralization in articular cartilage and bone. Our preliminary findings reveal that high expression of Ank in mineralizing growth plate cartilage results in increased extracellular PPi. Increased extracellular PPi lead to upregulation of APase expression and activity, and subsequent mineralization. These findings lead to one hypothesis that Ank is a positive physiological regulator of mineralization by regulating PPi homeostasis and APase expression and activities.
In Aims 1 and 2 we propose to determine how Ank regulates the mineralization process and the expression and activities of APase.
In Aim 3 we propose to determine the mechanisms regulating ank gene expression during or just before the initiation of the mineralization process. This study relates directly to mechanisms regulating the mineralization process of skeletal tissues and investigates the role of a protein which has been shown if mutated to lead to pathological or extensive mineralization in cartilage and bone. Therefore, this proposal might provide a novel therapeutic target to prevent pathological mineralization.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR046245-07
Application #
7228523
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Sharrock, William J
Project Start
1999-09-01
Project End
2008-03-31
Budget Start
2007-05-01
Budget End
2008-03-31
Support Year
7
Fiscal Year
2007
Total Cost
$247,817
Indirect Cost
Name
University of Maryland Baltimore
Department
Orthopedics
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Kirsch, Thorsten (2012) Biomineralization--an active or passive process? Connect Tissue Res 53:438-45
Minashima, Takeshi; Small, William; Moss, Stephen E et al. (2012) Intracellular modulation of signaling pathways by annexin A6 regulates terminal differentiation of chondrocytes. J Biol Chem 287:14803-15
Kim, Hyon Jong; Delaney, John D; Kirsch, Thorsten (2010) The role of pyrophosphate/phosphate homeostasis in terminal differentiation and apoptosis of growth plate chondrocytes. Bone 47:657-65
Kim, Hyon Jong; Minashima, Takeshi; McCarthy, Edward F et al. (2010) Progressive ankylosis protein (ANK) in osteoblasts and osteoclasts controls bone formation and bone remodeling. J Bone Miner Res 25:1771-83
Kirsch, Thorsten; Kim, Hyon Jong; Winkles, Jeffrey A (2009) Progressive ankylosis gene (ank) regulates osteoblast differentiation. Cells Tissues Organs 189:158-62
Kirsch, Thorsten (2008) Determinants of pathologic mineralization. Crit Rev Eukaryot Gene Expr 18:1-9
Kim, Hyon Jong; Kirsch, Thorsten (2008) Collagen/annexin V interactions regulate chondrocyte mineralization. J Biol Chem 283:10310-7
Wang, Wei; Kirsch, Thorsten (2006) Annexin V/beta5 integrin interactions regulate apoptosis of growth plate chondrocytes. J Biol Chem 281:30848-56
Wang, Wei; Xu, Jinping; Du, Bin et al. (2005) Role of the progressive ankylosis gene (ank) in cartilage mineralization. Mol Cell Biol 25:312-23
Kirsch, Thorsten (2005) Annexins - their role in cartilage mineralization. Front Biosci 10:576-81

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