# CONTROL OF COLLAGEN DESTRUCTION IN ARTHRITIS

> **NIH NIH R01** · UNIV OF MED/DENT NJ-R W JOHNSON MED SCH · 1989 · $267,574

## Abstract

Much evidence implicates collagenolysis by specific enzymes in joint
destruction in rheumatoid arthritis and other chronic states of synovial
inflammation.  Monolayer culture of synovial cells has facilitated
determination of mechanisms involved during induction, biosynthesis,
secretion and activation of collagenase.  In the rabbit system (and
preliminary data indicate that the same is true for human rheumatoid
synovial cells), procollagenase (proC) is secreted along with a latent
procollagenase activator (proA).  ProA is essential for activation of
proC.  Like proC, proA is a metalloproteinase.  ProA must itself be
activated before it can activate proC.  In order to study in more detail
the induction, activation and inhibition of collagenolysis in disease
states, pure probes that can measure the synthetic machinery for proC and
proA must be constructed.

Rabbit and human cDNA for proC and proA will be generated in expressing
plasmid vectors introduced into E.coli.  The probes for proC and proA will
be isolated, purified, and characterized by several techniques (i.e.,
direct immunologic screening, use of immunoprecipitated polysomes,
differential hybridization, and/or hybridization with synthetic
oligonucleotides).  The cDNA probes will be used to:  (1) characterize
genomic DNA for proC and proA; (2) determine amino acid sequences for proC
and proA in the rabbit and human; (3) help determine how proC is activated
by proA so that the value of generating an inhibitor of this process may be
assessed; (4) study the kinetics of induction of mRNA for proC and proA and
the kinetics of inhibition of synthesis of proC and proA by glucocorticoids
and retinoids; (5) examine by in situ hybridization the localization of
mRNA for proC and proA (compared with mRNA for procollagen) in
cartilage/pannus junction and surrounding tissue in joints removed at
arthroplasty in RA; (6) sort out the apparent abnormalities in the sequence
of biosynthesis and/or activation of proC in "Milwaukee Shoulder" and (7)
examine the hypothesis that complexes of alpha 2 macroglobulin collagenase
phagocytosed by synovial cells results in alterations of gene expression by
these cells.  It is hoped with precise knowledge about the intricacies of
biosynthesis and activation of proC, useful and specific ways of
intervening to retard the collagenolytic cascade might be suggested.

## Key facts

- **NIH application ID:** 3156639
- **Project number:** 5R01AR033714-07
- **Recipient organization:** UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
- **Principal Investigator:** MARKKU T KURKINEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1989
- **Award amount:** $267,574
- **Award type:** 5
- **Project period:** 1983-09-01 → 1990-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3156639

## Citation

> US National Institutes of Health, RePORTER application 3156639, CONTROL OF COLLAGEN DESTRUCTION IN ARTHRITIS (5R01AR033714-07). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3156639. Licensed CC0.

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