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CorrespondenceTransforming Growth Factor-ß Levels in Synovial Fluid of Osteoarthritis With or Without Calcium Pyrophosphate Dihydrate CrystalsTo the Editor: We read with interest the recent article by Derfus, et al and the editorial by Terkeltaub1,2. The article by Derfus clearly demonstrated the high prevalence of calcium pyrophosphate dihydrate (CPPD) and/or basic calcium phosphate (BCP) crystals in knee joints undergoing total arthroplasty for osteoarthritis (OA). This frequency is impressive but not surprising, because it is in agreement with previous reports3. However, the true significance of these crystals in OA joints is still open for discussion. The very instructive editorial by Terkeltaub clearly underlined that the mechanism involved in crystal promotion may be implicated in matrix calcification of OA and subsequently, on disease evolution. In particular, he focused on the role of transforming growth factor-ß (TGF-ß) and interleukin-1ß (IL-1ß), questioning the possibility that the intraarticular measurement of these or other mediators may be useful in the evaluation of severity and prognosis of OA. In this context we think that it may be interesting to report our experience with determination in OA synovial fluid (SF) of IL-1ß and TGF-ß. In our study, we subdivided patients diagnosed for OA according to Altman criteria (Kellgren and Lawrence grade 2 and 3) into 2 groups: the first group (10 patients) characterized by SF presence of CPPD crystals on polarizing microscopy (OA+); the second (16 patients) without these features (OA-). The mean values of TGF-ß, IL-1ß, and matrix metalloproteinases-1 (MMP-1) are reported in Table 1. As shown, the SF TGF-ß levels were significantly higher in OA+ than in OA- (p < 0.0001). Interestingly, MMP-1 levels too were higher in OA+ SF (p = 0.0003), while no difference was observed for IL-1ß between the 2 groups. Our results are in keeping with Terkeltaub's hypothesis1 and seem to confirm the important role of TGF-ß in crystal and calcification promotion. In addition, it is possible that the presence of calcium crystals promote the evolution of OA, as demonstrated by higher levels in OA+ of MMP-1, a substance with well known arthritogenic properties4. Results of a recent study by Das, et al seem in agreement with such an interpretation: addition of colchicine to the usual therapy with nonsteroidal antiinflammatory drugs and/or intraarticular corticosteroid injections improved the symptoms of OA5.
In conclusion, the study by Derfus1 and the editorial by Terkeltaub2 have increased our awareness of the presence of crystals in SF of OA. This information should promote further studies to investigate their possible role in the evolution of OA. LEONARDO PUNZI, MD, PhD; FRANCESCA OLIVIERO, PhD; ROBERTA RAMONDA, MD, PhD, Department of Medical and Surgical Sciences, Division of Rheumatology, University of Padova, Italy. REFERENCES 1. Derfus BA, Kurian JB, Butler JJ, et al. The high prevalence of pathologic crystals in pre-operative knees. J Rheumatol 2002;29:570-4. 2. Terkeltaub RA. What does cartilage calcification tell us about OA? J Rheumatol 2002;29:411-5. 3. Gibilisco PA, Schumacher HR Jr, Hollander JL, Soper KA. Synovial fluid crystals in osteoarthritis. Arthritis Rheum 1985;28:511-5. 4. Martel-Pelletier J. Proinflammatory mediators and osteoarthritis. Osteoarthritis Cart 1999;7:315-6. 5. Das SK, Mishra K, Ramakrishnan S, et al. A randomised controlled trial to evaluate the slow-acting symptom modifying effects of a regimen containing colchicine in a subset of patients with osteoarthritis of the knee. Osteoarthritis Cart 2002;10:247-52. Dr. Rosenthal replies To the Editor: We agree with Drs. Punzi, et al that both the frequency and the significance of calcium crystals in osteoarthritis (OA) are often underestimated. Consequently, the factors permitting crystal formation and the mechanisms of their biologic effects in OA remain poorly characterized. Drs. Punzi, et al provide compelling evidence that levels of the calcium crystal promoting factor, transforming growth factor-ß (TGF-ß), are higher in synovial fluids from OA patients with calcium pyrophosphate dihydrate (CPPD) crystals than those without crystals. TGF-ß promotes elaboration of inorganic pyrophosphate, the anionic component of the CPPD crystal, from cartilage1. TGF-ß also stimulates production of matrix vesicles capable of forming increased quantities of pathologically relevant calcium crystals2. Dr. Punzi, et al's data demonstrating increased levels of metalloproteases in CPPD crystal-containing synovial fluid reinforce the pathologic relevance of similar crystal effects in vitro3. These fluids were not examined for basic calcium phosphate crystals, and these studies do not sort out issues of cause and effects. However, this work reinforces our opinion that these biologically active structures are important. We firmly believe that calcium crystals deserve a place alongside cytokines, growth factors, and proteases in studies of the pathogenesis and treatment of OA. ANN K. ROSENTHAL, MD, Medical College of Wisconsin, Milwaukee, WI, USA. REFERENCES 1. Rosenthal A, Cheung H, Ryan L. Transforming growth factor beta 1 stimulates inorganic pyrophosphate elaboration by porcine cartilage. Arthritis Rheum 1991;34:904-11. 2. Derfus B, Camacho N, Olmez U, et al. Transforming growth factor beta-1 stimulates articular chondrocyte elaboration of matrix vesicles capable of greater calcium pyrophosphate precipitation. Osteoarthritis Cartilage 2001;9:189-94. 3. MCarthy G, Cheung H, Abel S, et al. Basic calcium phosphate crystal-induced collagenase production: Role of intracellular crystal dissolution. Osteoarthritis Cartilage 1998;6:205-13. Dr. Terkeltaub replies To the Editor: The letter by Punzi, et al cites some interesting preliminary data, particularly the distinctions between transforming growth factor-ß (TGF-ß) in osteoarthritis (OA) with and without CPPD crystals grossly detected. The reader should bear in mind that it is possible that crystal trafficking to the synovium might induce increased TGF-ß expression. In addition, the levels of active versus latent TGF-ß at the sites of crystal formation in cartilage may not be accurately reflected by data from joint fluid. Further data on levels of transglutaminase activity (which activates latent TGF-ß) and on matrix metalloproteinases-13 expression would also be informative. I appreciate the positive remarks by the authors about my editorial and the hypotheses advanced therein. Clearly, further studies on a larger scale will be important to definitively address these questions. ROBERT TERKELTAUB, MD, VAMC Rheumatology Section/University of California San Diego, San Diego CA, USA.
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