# REGULATION OF METALLOPROTEINASE GENE EXPRESSION

> **NIH NIH R01** · DARTMOUTH COLLEGE · 1989 · $204,356

## Abstract

Metalloproteinases are enzymes that are active at neutral pH, that
contain Zn++, and that are generally not stored within the cells.  The
enzymes are secreted in latent form and upon activation, are capable of
degrading the extracellular matrix.  Metalloproteinases comprise a multi-
gene family and two members are collagenase and stromelysin.  Collagenase
has the singular ability to initiate the degradation of collagen, the
body's most abundant structural protein while stromelysin degrades non-
collagenous matrix, such as proteoglycans, laminin and fibronectin.  Of
interest is the fact that stromelysin shares considerable homology with
transin, a rat oncogene-induced proteinase, thus supporting the
hypothesis that metalloproteinases may play a role in tumor/tissue
invasion.  Indeed, the combination of collagenase and stromelysin permits
a concerted attack on most matrix components.  No where is this
degradative/invasive ability more apparent than in rheumatoid arthritis.
In this disease, excessive production of collagenase and stromelysin by
the fibroblasts that line the joint mediates the degradation of articular
cartilage and subchondral bone, resulting in severe crippling and
deformity.

Previously, these studies have used monolayer cultures of rabbit synovial
fibroblasts as a model system to study mechanisms controlling
metalloproteinase gene expression as they pertained to joint disease.
Most recently, however, they have been extended to human fibroblasts and
results indicate that common mechanisms controlling the expression of
these enzymes may be operative throughout the body.

Plans for the next grant period will extend our knowledge of collagenase
and stromelysin to include a more detailed understanding of the
relationship between them.  Thus, the specific aims of the proposal are
(1) to study mechanisms regulating transcription of the rabbit
collagenase gene by characterizing the sequences responsible for the
induction (by agents such as Interleukin-1, phorbol esters, heat shock)
and suppression (by glucocorticoids and retinoids) of collagenase
synthesis; (2) to understand the comparative roles of rabbit and human
stromelysin I and II in connective tissue degradation and the mechanisms
regulating their expression; (3) to understand the relationship of rat
collagenase to rabbit and human collagenase; and, (4) to investigate the
importance of metalloproteinase expression in normal development and in
tumor invasion by developing transgenic mice which carry the rabbit
collagenase gene.  These studies should increase our understanding of he
role of metalloproteinases in the connective tissue modeling and
remodeling that occurs in both normal and disease states.

## Key facts

- **NIH application ID:** 3155435
- **Project number:** 2R01AR026599-10
- **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:** 1989
- **Award amount:** $204,356
- **Award type:** 2
- **Project period:** 1980-03-01 → 1994-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3155435

## Citation

> US National Institutes of Health, RePORTER application 3155435, REGULATION OF METALLOPROTEINASE GENE EXPRESSION (2R01AR026599-10). Retrieved via MORVS 2026-10-24 from https://api.morvs.ai/grant/nih/3155435. Licensed CC0.

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