Matrix Gla-Protein (MGP) and Twisted Gastrulation (Twsg) are secreted proteins that
reside in the extracellular matrix. MGP is a potent inhibitor of mineralization in both softand
hard- tissues. MGP-/- mice exhibit numerous abnormalities, the most severe being
aortic calcification that leads to death by approximately two months of age. Despite
extensive studies using cartilage and cardiovascular tissues in these mice, little is known
about how MGP deficiency affects bone development, specifically the impact on
osteoblasts and osteoclasts. Twisted Gastrulation is a modulator of BMP signaling in
many tissues. Twsg1 deficient mice exhibit several phenotypes including craniofacial,
salivary gland defects, and skeletal defects. Twsg1 has also been implicated in embryo
patterning and cartilage development but to date, there has been no study of the bone in
these mice. Preliminary analysis using faxitron (x-ray) analysis of MGP and Twsg1 wild
type and homozygous deficient mice revealed reduced bone and an osteopenic bone
phenotype. The goal of my thesis project was to characterize 1) the in vivo (both
dynamic and static) phenotype of Twsg-/- mice and 2) both in vivo and in vitro (static)
skeletal phenotype of MGP-/- mice. Using microcomputer tomography (μCT), both static,
and in the case of Twsg1, dynamic, histomorphometric analysis was performed to
characterize the skeletal phenotype in the animals. In both mouse models there was a
significant decrease in both cortical and trabecular bone present. Primary osteoblasts
and osteoclasts were used to further characterize the in vitro phenotype in the MGP-/-
mouse model. Primary osteoblasts showed premature mineralization and differentiation. Bone sialoprotein (BSP) and osteoclacin (OCN) mRNA levels were both elevated.
Surprisingly, osteoclast differentiation also showed enhancement with increased number
and larger multinuclear TRAP+ osteoclasts. They also showed increases in DC-STAMP
and TRAP mRNA levels compared to the wild type animals. The data collected in this
study was used to evaluate the skeletal phenotype of the MGP and Twsg1-knockout
mouse models to better understand the relationship of osteoporosis, BMP signaling, and mineral metabolism.
University of Minnesota M.S. thesis. August 2010. Major: Oral biology. Advisor: Rajaram Gopalakrishnan B.D.S, PH.D. 1 computer file (PDF); vi, 47 pages.
Emery, Ann Elizabeth.
Analysis of Skeletal Phenotypes of Matrix-Gla Protein (MGP) and Twisted Gastrulation (Twsg1) Deficient Mice..
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