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To the Editor:

We read with interest the report by Fuerst et al (1) suggesting that mineralization of articular cartilage by basic calcium (Ca2+) phosphate crystals (BCPs) could be an indissociable process of end-stage osteoarthritis (OA). This is our current understanding of the disease and we do agree with the background the authors presented. Interestingly, Ca2+ pyrophosphate dihydrate crystals (CPPDs) were less frequently identified.

Although the coexistence of Ca2+-containing crystals and OA has been recognized for several decades, their relationship remains controversial. Fuerst and colleagues' report reinforces the hypothesis of a pathologic role of BCPs in OA, as previously suggested by numerous clinical and laboratory studies such as that reported by Nalbant and colleagues, which showed that the presence of BCPs in OA synovial fluid (SF) predicted increased cartilage destruction (2). In vivo, in OA animal models such as guinea pig and STR/ort mouse models, meniscus calcifications preceded cartilage breakdown (3, 4). Additionally, Cheung et al showed that treatment with phosphocitrate, an antimineralizing agent, reduced meniscus calcifications and OA lesions in guinea pigs (5). Finally, in vitro, BCPs display mitogenic, catabolic, apoptotic, and inflammatory properties (6, 7).

Consistent with the findings of Gordon et al (8), Fuerst et al demonstrated the constant presence of BCPs in the medial femoral condyle cartilage in a large sample of 120 patients with knee OA, using digital contact radiography and field-emission scanning electron microscopy (FE-SEM). They also showed that medial femoral condyle cartilage mineralization was associated with symptoms of cartilage breakdown and a promineralizing hypertrophic chondrocyte phenotype (1). This finding is assumed for medial femoral condyle cartilage, but has to be confirmed for other knee joint compartments. We found that cartilage calcifications occurred in all OA knee joint compartments, even in those bearing less weight, such as the lateral femorotibial compartment (9), suggesting that the cartilage mineralization process may reflect a generalized chondrocyte disease. We suggest that an imbalance between inorganic pyrophosphate and inorganic phosphate formation around chondrocytes, associated with abnormalities in the expression and/or activity of related regulatory enzymes (plasma cell membrane glycoprotein 1, tissue-nonspecific alkaline phosphatase, and ANK [the multipass pyrophosphate transporter]), could contribute to the generation of either CPPDs or BCPs within cartilage. This hypothesis is further supported by Fuerst and colleagues' findings that chondrocytes isolated from mineralized OA cartilage could undergo hypertrophic differentiation and might ultimately produce BCPs. However, as recently described by Liu et al (10), and as we have also observed, isolation of chondrocytes from a crystal-containing articular cartilage leads to crystal release in the culture medium, so that the distinction between crystals released from the matrix and newly produced crystals is difficult to ascertain.

In addition, previous studies have suggested that cartilage calcification could be detected in healthy and juvenile cartilage as well (11–13), which makes the absence of calcification in control cartilage samples intriguing. These conflicting results might be explained by the selected narrow exploration area of 1 cm2 designated by Fuerst et al. Strikingly, in their study, age was not the predominant factor driving calcification in articular cartilage, since areas of articular cartilage mineralization were correlated with radiologic and histologic OA grading only, and not with age.

Finally, BCPs were consistently found in articular cartilage and correlated to cartilage breakdown, in contrast with CPPDs, which were detected in only 18% of the samples (1). CPPDs were not correlated with cartilage breakdown, supporting the specific association of BCPs, rather than CPPDs, with OA. However, the exact prevalence of CPPDs during OA is difficult to ascertain. Fuerst and colleagues mentioned that 60% of patients showed mineralization by SF analysis before surgery, but identification of crystals was not indicated. As individual BCPs are not visible under light microscopy, one can assume that crystals visualized in SF were likely CPPDs and/or aggregates of BCPs. The different prevalence of CPPDs between cartilage tissue and SF may also be related to the small size of the samples analyzed by FE-SEM or the possible shedding into the SF of meniscus crystals and/or crystals located at the surface of cartilage. Nonetheless, the correlation between BCPs and chondrocyte differentiation phenotype was a novel and important finding of the study.

In conclusion, Fuerst and colleagues bring a major contribution to the understanding of the association of BCPs and OA. A similar study by the same group showed that BCP deposits also occurred in hip OA cartilage, further emphasizing the generalization of the cartilage mineralization process during OA (14). However, the exact role of BCPs in OA cartilage destruction has yet to be investigated. Further clinical and experimental studies are required to provide definitive evidence that OA is a BCP crystal–associated or even crystal-related arthropathy.

Acknowledgements

Supported by the Fondation pour la Recherche Médicale (FRM) and the Société Française de Rhumatologie (SFR).

  • 1
    Fuerst M, Bertrand J, Lammers L, Dreier R, Echtermeyer F, Nitschke Y, et al. Calcification of articular cartilage in human osteoarthritis. Arthritis Rheum 2009; 60: 2694703.
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Christelle Nguyen MD*, Hang-Korng Ea MD, PhD†, Dominique Bazin PhD‡, Michel Daudon PhD§, Frédéric Lioté MD, PhD¶, * INSERM UMR 606, Hôpital Lariboisière, Université Paris Denis Diderot, † Hôpital Lariboisière, Assistance Publique–Hôpitaux de Paris, Paris, France, ‡ Université Paris Sud, Orsay, France, § Hôpital Necker, Université Paris Sud, ¶ Hôpital Lariboisière, Assistance Publique–Hôpitaux de Paris, Paris, France.