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Crystals in arthritis: new age nonsense or novel therapeutic target?
  1. GERALDINE M MCCARTHY
  1. Department of Clinical Pharmacology, Royal College of Surgeons in Ireland and Mater Misericordiae Hospital, Dublin
    1. PAUL DIEPPE
    1. MRC Health Services Research Collaboration, Univeristy of Bristol, Bristol

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      Apatite crystals are present in up to 70% of fluids from degenerated joints.1 Their presence correlates strongly with radiographic evidence of cartilage degeneration and is associated with larger joint effusions when compared with joints without crystals.2 3 Whether the presence of apatite crystals is a cause of cartilage damage or an effect of cartilage damage is unclear.4 Several lines of evidence suggest that apatite crystals cause joint destruction. For example, apatite crystals induce both mitogenesis and prostaglandin synthesis in synovial fibroblasts and chondrocytes in vitro.5 They also induce matrix metalloprotease (MMP) synthesis and secretion, thus promoting tissue damage.6 7 The cellular mechanisms whereby apatite crystals induce such responses are currently under investigation. Like many other growth promoting agents, apatite crystals induce a variety of transcription factors such as nuclear factor κB (NF-κB) and activator protein 1 (AP-1).8 They also induce mitogen activated protein kineses (MAPK) and protein kinase C (PKC).8 9 Furthermore, such activation is specific as the crystals do not activate protein tyrosine kineses (PTK) or phosphatidylinositol 3-kineses (PI3K).8 If the crystals were present simply as a consequence of joint destruction, we would expect them to be present in other arthropathies characterised by cartilage dissolution and synovial lining proliferation such as rheumatoid arthritis (RA). However, apatite crystals are rarely found in RA joint fluids.1 Thus, current data support the potent biological activity of apatite crystals.

      On the other hand, the clinical significance of apatite crystals in joint degeneration continues to be questioned. Dieppe and Swan doubt that apatite crystals are of pathogenic significance but they fail to refute or to even reference the vast body of literature that supports the biological activity of apatite crystals.10 To add to the confusion, they place apatite in a list of pathogenic crystals in the same article. It seems relevant that the importance of balance in the presentation of scientific papers has recently been emphasised.11

      As noted by Dieppe and Swan, part of the problem is that apatite cannot be readily identified in the same way that monosodium urate (MSU) or calcium pyrophosphate dihydrate (CPPD) can be by polarised light microscopy. Furthermore, the presence of apatite crystals does not change the management of either osteoarthritis (OA) or any other arthropathy in patients at present. Dieppe and Swan conclude therefore that apatite crystals are irrelevant to clinical practice. Historically, the role of cytokines in the pathogenesis of OA was also considered to be speculative.12 As with apatite crystals, levels of cytokines such as interleukin 1 (IL1) or tumour necrosis factor α (TNFα) are not routinely measured in joint fluid from patients with arthritis. After considerable further investigation, however, the roles of IL1 and TNFα in mediating joint degeneration in OA are now considered important.13 As a consequence of such recognition, Pelletier and coworkers have prevented the development of OA in an experimental model by transfer of the IL1 receptor antagonist gene.14 We have shown that apatite crystals induce MMP-1 in human OA (HOA) fibroblasts with a potency equivalent to that of IL1 and TNFα in vitro. Furthermore, apatite crystals, IL1 and TNFα act in synergy to increase MMP-1 production by HOA fibroblasts.15 Efforts continue to discover methods to inhibit the pathogenic effects of IL1 and TNFα. Why not inhibit the effects of apatite crystals also?

      Currently, there is no drug available to retard the progression of OA. A greater understanding of the pathogenesis of OA is essential to the development of rational treatment thus allowing us to target important pathogenic mediators. While it might be tempting to write apatite crystals off as new age nonsense, a considerable body of evidence suggests that, like cytokines, they could serve as a novel therapeutic target as well as a prognostic marker. Without further study, only those with crystal balls can tell.

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      Author’s reply

      We agree with all the points made by Dr McCarthy. Basic calcium phosphates (BCPs) in synovial fluids may be important, and it may be that their identification will be valuable in relation to future treatments. However, she seems to agree with the only two points made about BCPs in our article (which is about the identification of urate and pyrophosphate crystals): that is, that on the basis of current understanding BCPs are of “doubtful significance”, and that their identification should have no influence on contemporary therapeutic decisions.

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