# HORMONAL REGULATION OF BONE COLLAGEN METABOLISM

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 1992 · $164,380

## Abstract

The synthesis of type I collagen in osteoblastic cells is under the
complex regulation of systemic and locally-produced hormones and growth
factors and it is likely that other influences such as components of the
extracellular matrix (ECM) are also involved in this regulation.  The
long-term goals of this project are investigate the regulation of
alpha1(l) collagen gene expression in osteoblasts by parathyroid hormone
(PTH) and insulin-like growth factors (IGFs) and to study the role of the
ECM in modulating the activity of alpha1(l) collagen promoter in
osteoblasts.  For many of these studies, transgenic animals which harbor
alpha1(l) collagen promoter DNA constructs will be used.  Transgenic mice
represent a unique model system in which to appreciate the hormonal
regulation of collagen gene expression in a physiologic context.  The
inhibitory effect of PTH on alpha1(l) collagen promoter activity will be
characterized in cultured calvariae from transgenic mice and the role of
cyclic AMP, interleukin-6 and prostaglandins as possible mediators of
this Inhibitory action will be explored.  PTH-responsive loci in the
alpha1(l) collagen gene will be identified by deletion mapping using
stably transfected osteoblastic ROS 17/2.8 cells.  To examine protein-DNA
Interactions, mobility shift assays and DNase footprinting using nuclear
extracts from PTH-treated cells and oligodeoxynucleotides spanning the
alpha1(l) collagen promoter region of interest will be performed.  Once
DNA loci are identified, these regions will be altered using
oligonucleotide-directed mutagenesis.  Selected mutant DNA sequences will
be tested for functional activity in cultured osteoblastic cells and used
to generate new transgenic mouse lines for in vivo validation.  The
effect of IGFs on alpha1(l) collagen promoter activity in cultured
calvariae from transgenic animals will be determined and the possible
autocrine/paracrine role of IGFs in regulating alpha1(I) collagen
promoter activity will be explored using purified inhibitory insulin-like
binding protein-2, IGF neutralizing antibodies and IGF
oligodeoxynucleotides.  A variety experimental systems will be used to
study mechanisms for the downregulation of an alpha1(l) collagen promoter
construct in primary cell cultures derived from transgenic mouse
calvariae and to determine the role of the ECM in regulating promoter
expression.  Primary cell digests from transgenic mouse calvariae will be
plated on ECM substrates and mixed calvarial cells digests will be
cultured in medium which promotes bone nodule formation.  These studies
will help elucidate molecular mechanisms by which PTH, IGF-I and ECM
modulate collagen gene expression thereby providing experimental findings
which will be useful in planning rationale treatment protocols for
metabolic diseases of bone.

## Key facts

- **NIH application ID:** 3155713
- **Project number:** 2R01AR029850-12
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **SAM.gov UEI:** H6D6JMXJXDE6
- **Principal Investigator:** BARBARA E KREAM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1992
- **Award amount:** $164,380
- **Award type:** 2
- **Project period:** 1981-07-01 → 1996-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3155713

## Citation

> US National Institutes of Health, RePORTER application 3155713, HORMONAL REGULATION OF BONE COLLAGEN METABOLISM (2R01AR029850-12). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3155713. Licensed CC0.

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