Basic calcium phosphate crystal deposition

Basic calcium phosphate (BCP) crystals deposit within periarticular and articular sites, leading to a variety of clinical presentations. The most well-recognized clinical syndromes associated with BCP crystal deposition are calcific tendinitis and BCP crystal-associated destructive arthritis such as Milwaukee shoulder syndrome. There is emerging evidence that BCP crystals also play a role in osteoarthritis pathogenesis. Within the joint, tissue responses to BCP crystals include induction of pro-catabolic and inflammatory pathways. Clinical management of BCP crystal-associated arthropathies is limited by the lack of reliable and feasible methods to detect crystals, and the current unavailability of systemic therapies that promote BCP crystal dissolution.

Pathophysiology of calcium pyrophosphate deposition

Calcium pyrophosphate (CPP) dihydrate crystals form extracellularly. Their formation requires sufficient extracellular inorganic pyrophosphate (ePPi), calcium, and pro-nucleating factors. As inorganic pyrophosphate (PPi) cannot cross cell membranes passively due to its large size, ePPi results either from hydrolysis of extracellular ATP by the enzyme ectonucleotide pyrophosphatase/phosphodiesterase 1 (also known as plasma cell membrane glycoprotein 1) or from the transcellular transport of PPi by ANKH. ePPi is hydrolyzed to phosphate (Pi) by tissue non-specific alkaline phosphatase. The level of extracellular PPi and Pi is tightly regulated by several interlinked feedback mechanisms and growth factors. The relative concentration of Pi and PPi determines whether CPP or hydroxyapatite crystal is formed, with low Pi/PPi ratio resulting in CPP crystal formation, while a high Pi/PPi ratio promotes basic calcium phosphate crystal formation. CPP crystals are deposited in the cartilage matrix (preferentially in the middle layer) or in areas of chondroid metaplasia. Hypertrophic chondrocytes and specific cartilage matrix changes (e.g. high levels of dermatan sulfate and S-100 protein) are related to CPP crystal deposition and growth. CPP crystals cause inflammation by engaging with the NALP3 inflammasome, and with other components of the innate immune system, and is marked with a prolonged neutrophilic inflitrate. The pathogenesis of resolution of CPP crystal-induced inflammation is not well understood.