Project 2: Articular Cartilage Calcification in Osteoarthritis

Principal Investigator: Anthony M. Reginato, MD, PhD

Abstract

Articular cartilage calcification is a well-known phenomenon commonly observed in late-stage osteoarthritis (OA). Crystal deposition disease is a rare form of degenerative arthritis that affects the elderly. The prevalence and incidence of crystal induced arthropathies are expected to increase with our aging population. 

The two best recognized forms of calcium-containing crystals are calcium pyrophosphate dihydrate (CPPD) and calcium phosphate (BCP) crystals, which include hydroxyapatite (HA). Recent evidence suggest that calcium crystal deposit occurs in not only mild osteoarthritis lesions, but also in normal articular cartilage. 

We hypothesize that these crystals represent "microcrystal-induced stress" signals to biomechanical stress and clearly play a pathogenic role in development and/or progression of OA. The deposition of cartilage calcification results from an imbalance between inhibitors and pro-mineralization factors. We have excluded mutations in genes known to regulate extracellular PPi/Pi in two large families and our studies suggests that other genes are involved in HA deposition disease (HADD).

Aims

• Specific Aim 1: Perform wide-genome scans in two large families with Milwaukee shoulder and HA deposition disease.
• Specific Aim 2: Evaluate the development of CPP or HA in meniscal surgical mice model (PMM).
• Specific Aim 3: Examine the role of innate immunity and DDR2 on crystal-induced inflammation that leads to the accelerated development of OA using the spontaneous HA deposition disease animal model ank/ank and the Col2-CreERtm;ANKH(fl/fl) mice.

Relevance

The most common calcium-containing crystals are calcium pyrophosphate dihydrate (CPPD) and calcium phosphate (BCP) crystals, which include hydroxyapatite (HA). The mechanisms involved in promoting joint degeneration are still unclear and controversy remains as to whether these crystals simply exacerbate or actually cause osteoarthritis (OA). These studies identify new genes involved in cartilage calcification will lead to a better understanding of the pathophysiology of "microcrystal-induced stress" and development of OA.