Articular cartilage calcification in osteoarthritis: Insights into crystal‐induced stress

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Osteoarthritis (OA) is the most common form of rheumatic disease, leading ultimately to chronic pain, restriction of joint mobility, and disability. OA affects millions of people worldwide, and its prevalence is expected to increase with the concomitant prevalence of obesity and aging (1). OA is a disease affecting the whole joint and is characterized by articular cartilage destruction along with changes occurring in other joint components including bone, menisci, synovium, ligaments, capsule, and muscles (2). Multiple parameters contribute to the pathogenesis and progression of OA, including hereditary factors, mechanical overload, intraarticular calcium-containing microcrystal (Ca crystals) deposition, and aging. Ca crystals, which encompass calcium pyrophosphate dihydrate (CPPD) and basic calcium phosphate (BCP) crystals, have been associated with severe OA for many years. However, the role of CPPD and BCP crystals in OA remains controversial (3,4). BCP crystals, a heterogeneous group of apatite crystals including carbonated apatite, octacalcium phosphate, immature amorphous apatite, tricalcium phosphate (5), and magnesium-substituted apatite (whitlockite) crystals (6), are considered by some investigators to be “innocent bystanders” and/or markers of end-stage disease, because they can be released from bone as apatite mineral (4). Similarly, CPPD crystal deposition is considered to be a common aging-related process (4,7). However, numerous clinical and experimental data provide strong evidence that cartilage calcification occurs as an active process, and that calcification clearly plays a pathogenic role in OA, a phenomenon referred to as “microcrystal-induced stress.” This is different from the previously described and well-known mechanical, oxidative, or cytokine stresses in OA. The aim of this review is to highlight this old but forgotten and neglected concept. Ultimately, cartilage calcification could be considered as a potential therapeutic target in OA. As such, several therapeutic strategies will be discussed.