Abstract
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.
Highlights
Basic calcium phosphate (BCP) crystals including carbonatedapatite (CA), hydroxyapatite (HA), octacalcium phosphate (OCP), tricalcium phosphate and whitlockite crystals are associated with osteoarthritis (OA), calcific tendinitis, acute arthritis and atherosclerosis
We stimulated bone marrow derived macrophages from mice with OCP crystals, and analysed by quantitative Real Time PCR (qRT-PCR) the expression of inflammatory cytokine and matrix modifying genes (Figure 4).We found dramatically increased expression (.10x compared to control) of ADAMTS4, syndecan 1 (SDC1), MMP3 and 9, CXCL1 and CXCL2, as well as the cytokines ILA, IL1B, IL6 and TNFA
BCP crystals are highly prevalent in the cartilage of patients presenting for knee and hip surgery in advanced OA [3,26], there has only been one report of BCP crystals in the synovium [27]
Summary
Basic calcium phosphate (BCP) crystals including carbonatedapatite (CA), hydroxyapatite (HA), octacalcium phosphate (OCP), tricalcium phosphate and whitlockite crystals are associated with osteoarthritis (OA), calcific tendinitis, acute arthritis and atherosclerosis (reviewed in [1]) They are identified in the synovial fluid of rapidly destructive OA, as illustrated by the Milwaukee shoulder syndrome [2], and are highly prevalent in cartilage obtained from affected OA joints at the time of knee joint replacement surgery [3]. Fuerst et al demonstrated that chondrocytes isolated from OA cartilage generate BCP crystals in conjunction with chondrocyte hypertrophy [3] This data suggests that both hyaline and fibrous cartilage calcification may be an early and active phenomenon that affects the whole joint and occurs before evidence of cartilage breakdown. In Sprague-Dawley rat, articular cartilage calcification is common and alters cartilage biomechanical properties favouring cartilage destruction [7]
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