Pathogenesis of CPPD crystal formation
A high level of inorganic pyrophosphate (PPi) in cartilage is an important contributor to CPP crystal formation and is caused by:
- • ANKH mutations: transport of more pyrophosphate from chondrocytes into cartilage.
- • Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) and ENPP3 overactivity: generates more intracellular and extracellular pyrophosphate via hydrolysis of ATP.
- • Tissue-nonspecific lack of alkaline phosphatase (ALP) or underactivity (hypophosphatasia): the normal function of ALP is to break down PPi. When ALP function is abnormal, PPi levels increase. Magnesium is a cofactor for ALP, so hypomagnesemia lessens its activity. In addition, calcium (hyperparathyroidism), iron (hemochromatosis), and copper (Wilson disease) inhibit ALP.
Enhanced nucleation of CPP crystals in cartilage is also an important contributor to CPP crystal formation:
- • Increased calcium concentrations (hyperparathyroidism) enhance crystal formation.
- • Enhanced nucleation of CPP crystals due to increased iron (hemochromatosis) and copper (Wilson disease).
- • Lack of inhibitors of nucleation: magnesium inhibits nucleation so low levels contribute to crystal formation.
- • Multiple changes in osteoarthritic cartilage composition (CILP, osteopontin) facilitate CPP crystal formation/deposition.
