Backgroundbasic calcium phosphate (BCP) crystals are commonly found in osteoarthritis (OA) and are associated with cartilage destruction. BCP crystals induce in vitro catabolic responses with the production of metalloproteases and inflammatory cytokines such as interleukin-1 (IL-1). In vivo, IL-1 production induced by BCP crystals is both dependant and independent of NLRP3 inflammasome. We aimed to clarify 1/ the role of BCP crystals in cartilage destruction and 2/ the role of IL-1 and NLRP3 inflammasome in cartilage degradation related to BCP crystals.Methodology/ Principal Findingssynovial membranes isolated from OA knees were analysed by alizarin Red and FTIR. Pyrogen free BCP crystals were injected into right knees of WT, NLRP3 -/-, ASC -/-, IL-1α -/- and IL-1β-/- mice and PBS was injected into left knees. To assess the role of IL-1, WT mice were treated by intra-peritoneal injections of anakinra, the IL-1Ra recombinant protein, or PBS. Articular destruction was studied at d4, d17 and d30 assessing synovial inflammation, proteoglycan loss and chondrocyte apoptosis. BCP crystals were frequently found in OA synovial membranes including low grade OA. BCP crystals injected into murine knee joints provoked synovial inflammation characterized by synovial macrophage infiltration that persisted at day 30, cartilage degradation as evidenced by loss of proteoglycan staining by Safranin-O and concomitant expression of VDIPEN epitopes, and increased chondrocyte apoptosis. BCP crystal-induced synovitis was totally independent of IL-1α and IL-1β signalling and no alterations of inflammation were observed in mice deficient for components of the NLRP3-inflammasome, IL-1α or IL-1β. Similarly, treatment with anakinra did not prevent BCP crystal effects. In vitro, BCP crystals elicited enhanced transcription of matrix degrading and pro-inflammatory genes in macrophages.Conclusions/ Significanceintra-articular BCP crystals can elicit synovial inflammation and cartilage degradation suggesting that BCP crystals have a direct pathogenic role in OA. The effects are independent of IL-1 and NLRP3 inflammasome.

IntroductionCalcium pyrophosphate deposition (CPPD) may cause severe arthropathy, major joint destruction and treatment options are limited. The aim of this study was to test the therapeutic efficacy of methotrexate (MTX) in chronic or recurrent CPPD arthropathy.MethodsPatients with CPPD arthropathy were randomized to receive either weekly subcutaneous injections of 15 mg/week of MTX or placebo (PBO) for three months, in a double-blind, crossover randomized controlled trial. Inclusion criteria comprised definite CPPD disease, recurrent arthritis or persistent polyarthritis, and an insufficient response to NSAIDs, glucocorticoids or colchicine. The primary outcome was an improvement in the disease activity scores based on 44 joints (DAS44). The analysis was performed on an intent-to-treat basis.ResultsWe randomized 26 patients, and compared 25 treatment periods on MTX with 21 treatment periods on PBO. Baseline characteristics were balanced between the groups. The evolution of the DAS44 was not statistically significantly different between groups (median DAS44 decreased by −0.08 on MTX versus −0.13 on PBO, after three months, P = 0.44). Furthermore, pain levels remained stable in both groups (median change in VAS Pain −1 unit on MTX and 0 on PBO, P = 0.43), and none of the secondary outcomes was significantly different between the two groups. Minor adverse events (AE) did not differ in frequency between the groups, but the only serious AE occurred on MTX (bicytopenia).ConclusionsThe results of this trial with MTX in this older population with chronic or recurrent CPPD arthropathy suggest no strong effect of MTX on disease activity.Trial registrationEudraCT No: 2007-003479-37. Registered 26 April 2008

A radiological and anatomico-pathological study of 17 cases of calcaneal cysts in young patients without other known affections is documented.There are two essential histological characteristics of the fibrous wall lining the cysts: (1) hemosiderin deposits together with cholesterol and an associated giant cell reaction, which can be attributed to previous hemorrhages; (2) newly formed bone -similar to that observed in solitary cysts of the humerus and femur -applied to preexisting trabeculae which forms a bony wall explaining the typical radiological picture.These uncommon cysts may be the evolution of purely local hemorrhages in the trigonum calcis.

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The aim of the study was to investigate the frequency of development of local calcium pyrophosphate (CPPD) crystal deposition in patients with knee OA initially found negative for these crystals, as well as to discover whether prognostic indicators for this subset of patients can be found. A clinical follow-up of records of outpatients with idiopathic knee OA was established. An anteroposterior plain radiography of the knee joints was made initially and at the end of the observation period. The follow-up period needed to be more than 1 year. Patients were divided into two groups. The first included patients with knee OA who did not develop intra-articular CPPD crystal deposition during the observation period (OA group). The second included those patients whose X-rays or synovial fluid (SF) analysis in the follow-up showed these crystal deposits to be present (OA + CPPD group). There were 59 patients (42 women, 17 men) who met the selection criteria. During the observation period (8.1 + 7.4 years in the OA group, 10.4 +/- 6 years in the OA + CPPD group), intra-articular CPPD deposits were observed in 15 patients (25%): 10 on the X-rays, eight in the SF and three in both examinations. Age at diagnosis of OA and incidence of obesity were similar in both groups. There was a trend (P = 0.21) towards men developing intra-articular CPPD crystal deposits more frequently than women. OA in only one knee joint was significantly more frequent in the group with CPPD (P<0.01). Of those with CPPD deposits 40% required surgery at the end of the observation period, compared to 27.2% of those without deposits (P = 0.27). The waiting period before knee surgery was shorter in the OA + CPPD group but the difference was not statistically significant. In conclusion, local CPPD crystal deposition was observed in 25% of cases during the evolution of knee OA. No predictive factors were found. OA of the knee could, per se, favour the development of CPPD deposits. The occurrence of intra-articular CPPD deposits seemed to be related to a more rapid and severe evolution of OA of the knee.