# REGULATION OF COLLAGENASE GENE EXPRESSION

> **NIH NIH R01** · DARTMOUTH COLLEGE · 1988 · $163,545

## Abstract

The neutral proteinase collagenase is the only enzyme initiating breakdown
of the interstitial collagens, Tupes I, II, and III, the body's most
abundant structural proteins.  Collagen remodeling occurs in normal
processes, such as uterine resorption and wound healing, and in
pathophysiological conditions, such as tumor invasion and rheumatoid
arthritis.  Nowhere is the impact of collagenase more apparent than in this
latter disease where there is gross destruction of cartilage, tendon and
bone, with subsequent deformity and loss of joint function.  Our work
focuses on mechanisms operating at the level of the gene to control
collagenase production in rheumatoid arthritis.

For these studies, we use a model system of monolayer cultures of rabbit
synovial fibroblasts.  These cells are readily available, grow well in
culture, and importantly, can be induced to synthesize and secrete large
quantities of collagenase, Mr. 57K and 61K.  Equally attractive is the fact
that collagenase synthesis can be suppressed by glucocorticoids or the
synthetic Vitamin A analogues, the retinoids.  Along with collagenase,
another protein, Mr 52K and 54K, that functions to activate latent
collagenase is also induced and repressed.  Both inducers and repressors
appear to affect collagenase and its activator by acting
transcriptionally.  Confirmation of this hypothesis is one aim of this
proposal.

Our studies to date have resulted in the isolation and characterization of
both cDNA and genomic clones for synovial cell collagenase and these are
appropriate tools for extending our work.  Specifically, we will (1)
determine whether steroids and retinoids affect collagenase mRNA 1/2 life;
(2) isolate the 5' end of the collagenase gene and characterize its
promoter regions; (3) study the coordinate regulation of collagenase and
its activator protein by isolating and characterizing cDNA and genomic
clones for this activator; (4) determine the chromosomal location(s) for
the rabbit synovial cell collagenase gene(s) so as to investigate the
genetic basis for multiple forms of collagenase protein (e.g., macrophage,
neutrophil, synovial cell collagenase); and (5) sequence the cDNA and
genomic clones for collagenase and its activator.

Results of these studies are important to our understanding not only of how
the destructive potential of synovial cells is regulated in rheumatoid
arthritis but also to the control of collagenolysis by various other cell
types throughout the body.

## Key facts

- **NIH application ID:** 3155437
- **Project number:** 5R01AR026599-09
- **Recipient organization:** DARTMOUTH COLLEGE
- **SAM.gov UEI:** EB8ASJBCFER9
- **Principal Investigator:** CONSTANCE E BRINCKERHOFF
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1988
- **Award amount:** $163,545
- **Award type:** 5
- **Project period:** 1980-03-01 → 1989-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3155437

## Citation

> US National Institutes of Health, RePORTER application 3155437, REGULATION OF COLLAGENASE GENE EXPRESSION (5R01AR026599-09). Retrieved via MORVS 2026-10-24 from https://api.morvs.ai/grant/nih/3155437. Licensed CC0.

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