# REGULATION OF VITAMIN K-DEPENDENT BONE PROTEINS

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 1993 · $227,898

## Abstract

In contribution of our past research interests, we plan to carry out an
integrated series of experiments designed to understand the regulation and
function of Matrix Gla Protein (MGP).  Matrix Gla protein is a 10 kDa
protein which contains 5 residues of the vitamin K-dependent Ca2+-binding
amino acid, gamma-carboxyglutamic acid (Gla).  MGP was originally
discovered in bone but is now known to be synthesized by all vertebrate
tissues tested, with the highest levels of synthesis in ling, heart,
kidney, and cartilage.  We recently sequenced the human MGP gene and
discovered a putative retinoic acid responsive element (RARE) in the MGP
promoter which is virtually identical to the RARE recently identified in
the retinoic acid receptor B (RARB) promoter.  We subsequently found that
retinoic acid (RA) treatment increased the level of MGP mRNA by over 10-
fold in all human cells tested, which include normal and transformed bone
cells, articular cartilage cells, and dermal fibroblasts.  We plan to
assess the MGP mRNA response to RA in a number of additional human cells.
We also plan to investigate the molecular mechanisms of the MGP mRNA
response to RA, including: the use of CAT constructs of defined portions of
the MGP gene promoter to identify the sequence(s) that mediate retinoic
acid responsiveness; the use of mobility shift DNA binding assays,
methylation interference assays, and site directed mutagenesis to
characterize the RARE in the hMGP gene; and the use of cotransfection of
the MGP gene promoter and expression vectors for the different RAR's to
characterize the receptor specificity of the response.  To better
understand the physiological significance of the MGP mRNA response to RA,
we will determine the effect of RA administration and vitamin A deficiency
on MGP synthesis in the rat.  We will also investigate the possible
regulation of MGP synthesis by transcription factors that may act through
the putative AP1 and AP2 sites in the MGP gene promoter, and by growth
factors such as TGFBeta and FGF.  We will further investigate the
proteolytic cleavage at the Arg 80-Arg81 dibasic site which may precede MGP
secretion from the cell and the coagulation-related cleavages in blood at
the Arg18-Arg19 site in order to determine the effect of these cleavages on
biochemical properties of the protein which may be important to its
function, including Ca2+- dependent and Gla-dependent binding to
phospholipid vesicles, and the ability of the protein to strongly self
associate.  We plan to identify the macromolecule(s) which bind MGP in
cartilage and in plasma and to use immunohistology to localize MGP antigen
in the extracellular matrix of tissues and cells.  We will test our
hypothesis that MGP is a locally acting factor that mediates actions of RA
on differentiation and development by investigating the binding of labeled
MGP to target cells and the effects of binding on the cell, as well as the
effect of vitamin K-deficiency on possible functions of MGP, par...

## Key facts

- **NIH application ID:** 3155372
- **Project number:** 5R01AR025921-14
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **SAM.gov UEI:** UYTTZT6G9DT1
- **Principal Investigator:** PAUL ARMS PRICE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $227,898
- **Award type:** 5
- **Project period:** 1979-07-01 → 1995-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3155372

## Citation

> US National Institutes of Health, RePORTER application 3155372, REGULATION OF VITAMIN K-DEPENDENT BONE PROTEINS (5R01AR025921-14). Retrieved via MORVS 2026-10-24 from https://api.morvs.ai/grant/nih/3155372. Licensed CC0.

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