The mechanisms preventing inappropriate calcification of tissues such as the growth plate cartilage or the arteries are poorly understood. The growth plate is a specialized cartilaginous structure responsible for the longitudinal growth of the skeleton. Early calcification of the growth plate leads to an arrest of skeletal growth. one protein that is synthesized by both vascular smooth muscle cells and chondrocytes, is secreted into the extracellular matrix, and is suspected to have mineral- binding properties is matrix gla protein (MGP). To address the possible function of MGP as an inhibitor of calcification we have generated MGP- deficient mice. The MGP-deficient mice have spontaneous calcification of their arteries and of the cartilage in the proliferation zone of the growth plate cartilage, leading to blood vessel ruptures, short stature, osteopenia and fractures. This phenotype indicates that MGP acts as an inhibitor of calcification of the arteries and growth plate cartilage and by that means influence longitudinal growth of the skeleton. We propose: -To rescue the lethal vascular phenotype of the MGP-deficient mice so as to determine the long-term effect of the absence of MGP on bone and cartilage formation and calcification. -To perform a histomorphometric and ultrastructural study of the growth plate in MGP-deficient mice to monitor chondrocyte proliferation and hypertrophy, cartilage calcification and longitudinal bone growth. -To perform a cellular analysis in vitro of the cartilage phenotype of the MGP-deficient mice. -To analyze the effect of MGP overexpression in osteoblasts on bone matrix mineralization in transgenic mice and in tissue culture. -To analyze the effect of MGP overexpression in osteoblasts on bone matrix mineralization in transgenic mice and in tissue culture. -To study human skeletal dysplasias that produce a similar or related phenotype as the one observed in MGP deficient mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR043655-04
Application #
6029980
Study Section
Special Emphasis Panel (ZRG4-ORTH (04))
Program Officer
Sharrock, William J
Project Start
1998-01-01
Project End
2001-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030