# Molecular pathways of calcium pyrophosphate deposition disease

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2024 · $484,743

## Abstract

Calcium pyrophosphate deposition disease (CPDD) is a common type of arthritis defined by the presence of
calcium pyrophosphate (CPP) crystals in articular cartilage. While CPDD typically affects elderly patients in a
sporadic fashion, it also occurs prematurely in familial patterns. Studies of familial forms of this disease present
exciting opportunities to identify novel therapeutic targets for this currently untreatable arthritis. We recently
confirmed that a mutation in the stop codon of TNFRSF11B causes early onset CPDD. TNFRSF11B codes for
osteoprotegerin (OPG). OPG is a decoy receptor for Receptor Activator of Nuclear Factor Kappa B Ligand
(RANKL). RANKL promotes osteoclast formation. Our preliminary data clearly demonstrate that recombinant
mutant OPG (OPGmt) displays inefficient inhibition of RANKL resulting in excess osteoclastogenesis in vitro. Our
genetically engineered mice carrying OPGmt have osteopenia and premature arthritis mirroring the effects of
OPGmt in humans. We have also found that osteoclast conditioned media potently stimulates chondrocyte
pyrophosphate (PPi) production, a necessary process for CPP crystal formation. The purpose of this work is to
investigate the conceptually innovative hypothesis that OPGmt produces CPDD by increasing
osteoclastogenesis in subchondral bone. We propose that excess osteoclasts in subchondral bone stimulate
cartilage PPi production and that high cartilage-derived PPi levels target pre-osteoblasts to exaggerate
subchondral osteoclastogenesis seen in the presence of OPGmt. The scientific premise of this work stems from
careful observations of the phenotype of patients with OPGmt and strong preliminary data. In Aim 1 we will use
Opgmt/+ and Opgmt/mt knock-in mice to comprehensively determine the role of Opgmt in arthritis pathogenesis in
mice and determine if disease can be prevented by blocking RANKL. In Aim 2, we will employ in vitro and in
vivo models to investigate the role of high PPi levels in promoting OPGmt-induced arthritis and elucidate the
underlying mechanisms. This work is the first to identify the OPG/RANKL/RANK pathway in CPDD and to
implicate subchondral bone as a primary target tissue in this disease. This proposal includes a novel mouse
model that will serve as the basis for further mechanistic and pre-clinical studies in CPDD. The shared clinical
features of patients with the OPG mutation and those with age-related CPDD and the existence of available
drugs which target these pathways support rapid translation of this work.

## Key facts

- **NIH application ID:** 10848366
- **Project number:** 5R01AG077732-03
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Gabriel Mbalaviele
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $484,743
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848366

## Citation

> US National Institutes of Health, RePORTER application 10848366, Molecular pathways of calcium pyrophosphate deposition disease (5R01AG077732-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10848366. Licensed CC0.

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