MILWAUKEE, Wisconsin—Osteoarthritis (OA) looks likely to join gout as a disease that requires close attention to crystals in the joints. In a review of calcium deposition diseases published in Current Opinion in Rheumatology, Ann K. Rosenthal, MD, professor of medicine at the Medical College of Wisconsin, in Milwaukee, points to both calcium pyrophosphate dihydrate (CPPD) and basic calcium phosphate (BCP) crystals as likely culprits.¹

"While CPPD crystals are often found in the setting of typical OA, these crystals also define unique clinical subsets of patients with inflammatory arthritis. The presence of articular BCP crystals closely correlates with the severity of articular damage in OA, and BCP crystals are associated with the highly destructive arthritis known as Milwaukee shoulder syndrome," Dr. Rosenthal writes.

CPPD deposition disease, with a prevalence of .42%, approaches the .46% prevalence of gout and thus "is not a rare condition," according to Dr. Rosenthal. For want of a better approach, radiographic chondrocalcinosis is typically used to detect CPPD deposition disease in population-based studies; however, diagnosis remains a problem. "The clinical overlap between CPPD deposition disease and other clinical syndromes remains a challenge for clinicians," Dr. Rosenthal says. She notes that the spine is a particularly under-recognized site of CPPD crystal deposition.

Better diagnostic tools are needed. "There are currently no widely available tests that accurately detect BCP crystals in synovial fluid. CPPD crystals are detectable under polarizing light microscopy, and their presence in synovial fluids remains the gold standard for the diagnosis of CPPD deposition disease. In a typical clinical setting however, synovial fluid examination may have only about a 12% sensitivity for CPPD crystal detection," Dr. Rosenthal writes. Furthermore, cholesterol crystals can be misidentified as CPPD, and magnetic resonance imaging "is particularly poor at distinguishing meniscal tears from CPPD crystal deposits, as both appear as signal voids." She also notes that BCP crystals might be even more common than CPPD in the arthritic joint but "lack even a radiographic correlate."

Understanding underlying mechanisms of action is also a challenge. Chondrocytes near CPPD crystal deposits  are "unusually large" and had other features characteristic of "the hypertrophic chondrocytes responsible for matrix mineralization in growth plate cartilage," and factors driving this change in phenotype probably involve transglutaminase enzymes. Levels of these enzymes are elevated in OA cartilage and with aging, and they mediate pathologic mineralization of articular cartilage.

Treatment is currently only symptomatic, usually involving intra-articular steroids and NSAIDs, but preclinical studies by Herman S. Cheung, PhD, et al, suggest that this might change. Dr. Cheung, the James L. Knight professor of biomedical engineering in the department of medicine at the University of Miami in Coral Gables, Florida, recently reported that blocking the deposition of calcium-containing crystals can reduce cartilage degeneration in an animal model of OA.² Dr. Cheung used a new synthesized formulation of phosophocitrate, CaNaPC, in a guinea pig OA model in which meniscal calcification correlates with aging and with the progression of joint damage. Treatment with the calcium crustal inhibitor reduced meniscal calcification and arrested OA progression.

"Our studies suggest two potential mechanisms by which crystals can cause degeneration," Dr. Cheung told CIAOMed. "The first involves the induction of mitogenesis in synovial fibroblasts and the secretion of matrix metalloproteinases  by cells that phagocytose these crystals. The second potential mechanism may involve changes in joint biomechanics. Articular calcification may lead to altered loading of the joint causing injury to the cartilage matrix, which fails under normal loading and chondrocytes respond by elaborating MMPs and developing inappropriate repair responses."

Dr. Rosenthal comments, "This exciting work not only identifies CaNaPC as a potential therapy for BCP and CPPD crystal-associated arthritis, but supports a role for cartilage calcification in the initiation or perpetuation of osteoarthritis."

References

1. Rosenthal AK. Update in calcium deposition disease. Curr Opin Rheumatol. 2007;19:158-162.
2. Cheung HS, Sallis JD, Demadis KD, et al. Phosphocitrate blocks calcification-induced articular joint degeneration in a guinea pig model. Arthritis Rheum. 2006;54:2452-2461.