# INORGANIC PYROPHOSPHATE METABOLISM IN ARTHRITIS

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 1993 · $188,909

## Abstract

Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease is a
common form of arthritis, particularly in the elderly.  Prevalence
approaches 90% in those over 80.  This disease is associated with acute
attacks of gout-like arthritis termed pseudogout, but more importantly,
with debilitating degenerative arthritis.  These studies are aimed at
determining the mechanism of CPPD crystal formation in cartilage so that
logical therapeutic and prophylactic interventions may be formulated.

This proposal focuses on the role of inorganic pyrophosphate (PPi), the
anionic component of CPPD crystals, in disease pathogenesis.  Disordered
PPi metabolism has been strongly implicated in CPPD crystal deposition
disease.  Specifically emphasized will be experiments to determine the
mechanism(s) by which PPi, a normally intracellular molecule, reaches the
extracellular space where CPPD crystals form; and to devise an in vitro
model of CPPD deposition.  Hypotheses to be tested include: 1. whether PPi
egress from cells is part of a generalized permabilization of cells or is
mediated by an anion transporter (export hypothesis); 2. whether PPi is
cosecreted from chondrocytes with matrix-destined macromolecules
(cosecretion hypothesis); or 3. whether PPi is generated extracellularly by
the ectoenzyme-nucleoside triphosphate pyrophosphohydrolase (ectoenzyme
hypothesis).  The in vitro model will be based on our background knowledge
of NTPPPH, which generates PPi at the site of crystal formation in
cartilage.  Chondrocyte and cartilage explant cultures will be used
extensively for PPi studies; and cartilage explants and vesicles derived
from articular cartilage digests will be used for the CPPD crystal
formation model.  Defining the metabolic abnormality(ies) underlying this
disease and better understanding crystallogenesis offers two levels of
potential therapeutic intervention.

## Key facts

- **NIH application ID:** 3158700
- **Project number:** 5R01AR038656-07
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **SAM.gov UEI:** E8VWJXMMUQ67
- **Principal Investigator:** LAWRENCE M. RYAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $188,909
- **Award type:** 5
- **Project period:** 1987-05-01 → 1996-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3158700

## Citation

> US National Institutes of Health, RePORTER application 3158700, INORGANIC PYROPHOSPHATE METABOLISM IN ARTHRITIS (5R01AR038656-07). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3158700. Licensed CC0.

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