Advances in understanding calcium-containing crystal disease : Current Opinion in Rheumatology (original) (raw)
Introduction
Calcium-containing crystals that encompass calcium pyrophosphate dihydrate (CPPD) and basic calcium phosphate (BCP) crystals are associated with several human diseases such as acute joint inflammation and destructive arthropathies. BCP crystals, including carbonated-substituted hydroxyapatite, tricalcium phosphate and octacalcium phosphate, are heterogeneous in terms of structure, chemical composition and biological properties. Calcium-containing crystal depositions can occur in any tissues, but intraarticular and periarticular locations are the most frequent site. Mechanisms of cartilage crystal deposition involve multiple determinants. Although the coexistence of joint-containing calcium crystals and osteoarthritis has been recognized for several decades, their relationship remains controversial. Whether these crystals contribute to cartilage destruction or rather represent ‘innocent bystanders’ is still unknown. Herein, we will review recent clinical, epidemiological and laboratory findings that highlight new pathogenic mechanisms on calcium crystal-associated arthropathies with the predominant role of the inflammasome in CPPD crystal inflammation and chondrocyte apoptosis in BCP crystal arthropathies.
Cartilage calcification
Mechanisms of cartilage calcification are not completely understood and involve chondrocyte phenotype alterations, including hypertrophic differentiation and apoptosis, extracellular matrix modifications with imbalance between inhibitors and promineralization factors, dysregulated inorganic pyrophosphate (PPi) and inorganic phosphate metabolisms, ageing, altered responses to growth factors and inflammatory cytokines and mediators [1,2,3•,4,5].
Cartilage calcifications are produced, at least partly, in chondrocyte-derived apoptotic bodies [6] and matrix vesicles, the latter being membrane-enclosed particles released from the plasma membrane of mineralization-competent cells [7]. The first mineral phase forms inside the vesicles in a protected environment close to the inner leaflet of vesicle membrane [7]. Channel proteins mediate the influx of Ca2+ and inorganic phosphate into these particles. Kirsch _et al._[8] have identified, by electron microscopy, apatite crystals within matrix vesicles in osteoarthritis cartilage and have nicely shown that annexins 2, 5 and 6 formed channels and mediated the calcium influx into matrix vesicles [9]. Type III sodium/inorganic phosphate cotransporters mediate the influx of inorganic phosphate into matrix vesicles [10]. Proteomic analysis of matrix vesicles identified more than 100 proteins, including annexins, proteins related to ion transport, to metabolism of inorganic phosphate and PPi such as the recently recognized phosphatase, PHOSPHO1, surface receptors such as integrins and regulatory proteins [11,12].
The extracellular inorganic phosphate (ePi), extracellular inorganic pyrophosphate (ePPi) and Ca2+ concentrations are critical determinants of mineralization [13,14]. Production of ePPi results from PPi-generating nucleoside triphosphate pyrophosphohydrolase, PC-1/NPP1, and/or anion transport of intracellular PPi across the cell membrane by ANK protein, a multipass transmembrane PPi transporter. PC-1, the nucleotide triphosphate pyrophosphohydrolase (NTPPPH) isoenzyme plasma cell glycoprotein-1, generates ePPi by cleavage of ATP to AMP. Three proteins regulate ePPi concentration; PC-1 and ANK proteins increase ePPi level, whereas tissue nonspecific alkaline phosphatase decreases ePPi level by hydrolysing PPi to inorganic phosphate (Fig. 1).
Extracellular inorganic pyrophosphate and phosphate regulations
Deficiency of ePPi leads to hydroxyapatite crystal deposition as described in ank/ank, ttw/ttw and PC-1 knockout mice [15–17]. Mutations of the human ortholog of the murine ank gene have been described in craniometaphyseal dysplasia [18,19]. Excess bone formation is observed in affected patients, characterized by progressive thickening and increased mineral density of craniofacial bones and hyperostotic flaring at metaphyses in long bones. Another rare disease is idiopathic infantile arterial calcification due to PC-1 deficiency reported by Rutsch _et al._[20,21]. Affected individuals had low levels of ePPi, diminished PC-1 protein and presented periarticular and arterial hydroxyapatite formation early in life.
Excess ePPi has long been recognized as a likely cause of CPPD crystal deposition disease, and recently ANKH mutations were identified in UK, French and Argentinean families with chondrocalcinosis [22,23]. Pendleton _et al._[22] have shown that intracellular PPi levels significantly diminished in COS cells transfected with mutant ANKH proteins. This suggested that gain of function of ANKH PPi channelling activity, over a long period of time, leads to increased ePPi and CPPD deposition.
Numerous soluble factors modulate ePPi production, as does ageing. The primary stimulus of ePPi production is transforming growth factor (TGF) [24]. TGF-β-induced ePPi rises with ageing [25]. TGF-β enhances the expression of cartilage intermediate layer protein/eNTPPPH [26], PC-1 [27] and ANK [28•,29], all of which increase ePPi levels. Transglutaminase activates latent TGF-β to increase chondrocyte ePPi production. IL-1β as well as TNFα, and donors of nitric oxide, and the potent oxidant peroxinitrite induce increased transglutaminase activity in chondrocytes [30]. Other stimuli for ePPi production include ascorbate, retinoic acid and thyroid hormone. Negative regulators include IL-1β, TNFα, some isoforms of parathyroid hormone-related peptide and insulin-like growth factor 1 [13]. Recently, Yamada _et al._[31] showed that carminerin, a cartilage-specific protein, contributed to chondrocyte calcification during endochondral ossification under physiological and pathological conditions through the transcriptional inhibition of NPP1.
Clinical data and epidemiological studies
Calcium-containing crystal deposition, often asymptomatic, can be associated with a large spectrum of clinical manifestations [32,33]. Intraarticular CPPD crystals can cause attacks of acute pseudogout, mimic a pseudorheumatoid arthritis or a neuropathic arthropathy and can be associated with some cases of secondary osteoarthritis. Extraarticular CPPD and BCP crystals can cause tenosynovitis, peripheral nerve and spinal cord compression and pseudotumoral deposition [32,33]. Both CPPD and BCP crystal deposition around the odontoid process can cause the so-called ‘crowned dens’ syndrome, which is characterized by acute cervical pain and stiffness associated with elevated fever. The diagnosis is made by computerized tomography imaging, which evidenced crystal deposition [34]. Periarticular BCP deposition can cause calcifying tendinitis, acute periarthritis, bursitis and bone pain secondary to bone erosion [35]. Intraarticular BCP crystals can be associated with erosive [36] and severe destructive arthropathies known as the Milwaukee shoulder syndrome [37].
Milwaukee shoulder syndrome is prototypic of BCP crystal-associated joint destruction. It is associated with rotator cuff defects and numerous aggregates of BCP crystals in the synovial fluid of affected joints. Knee joint can be affected similarly. Interestingly, a large skin hematoma is readily visible around the shoulder joint at the time of acute attacks. Characteristically, large joint effusions are present, and synovial fluid is frequently blood tinged and contains low leukocyte count. In some fluids, collagenolytic enzyme activity is detected [38]. Recently, a kindred was described in which several members spanning several generations demonstrated features of Milwaukee shoulder syndrome and osteoarthritis in other joints [39]. This association between Milwaukee shoulder syndrome and osteoarthritis raises the still unresolved role of BCP crystals in osteoarthritis onset.
Relationship between intraarticular calcium-containing crystals and osteoarthritis
The role of intraarticular calcium-containing crystals in osteoarthritis lesion is controversial. Neogi _et al._[40] have evaluated, in two prospective cohorts [Boston Osteoarthritis Knee (BOK) Study and Health, Aging and Body Composition (Health ABC) Study], the relationship between chondrocalcinosis (due to CPPD deposition) and the progression of knee osteoarthritis using longitudinal MRI to assess cartilage loss. In the BOK study, they have identified 23 (9%) chondrocalcinosis among 265 knees and found a protective association between chondrocalcinosis and cartilage loss (adjusted risk ratio, 0.4; 95% confidence interval, 0.2–0.7) (P < 0.002). There was no difference in risk in Health ABC Study. They concluded that there are no harmful effects of the presence of chondrocalcinosis on osteoarthritis progression [40]. In the BOK study, there was, however, a small number of patients with chondrocalcinosis, raising concerns about the robustness of the results. Mitsuyama _et al._[41] showed that knee cartilage calcifications were correlated with ageing and not with osteoarthritis lesions. The authors suggested, however, that cartilage calcification may contribute to the progression of osteoarthritis.
In contrast to these two studies, most epidemiological studies support the hypothesis that calcium crystals cause or worsen osteoarthritis. The coexistence of calcium-containing crystals and osteoarthritis was described a long time ago [42–45]. Sokoloff and Varma [45] showed that CPPD crystals are found six times more frequently in osteoarthritis than in normal joints. Moreover, patients who have familial forms of CPPD crystal deposition disease develop severe and premature osteoarthritis, and CPPD-associated osteoarthritis involves joints that differ from primary osteoarthritis such as the wrist, shoulder, elbow and ankle joints [32,33]. Recently, Muehleman _et al._[46•] showed on 7855 cadaveric samples that CPPD crystal deposition in ankle joints was found in 1.5% of the samples and was correlated with cartilage lesions. Derfus _et al._[42] detected CPPD or BCP crystals or both in 60% of synovial fluids at the time of total knee replacement. BCP crystals were present in 49% of the synovial fluids, whereas CPPD were identified in 30%. Both crystals were found in 19% of synovial fluids, and the presence of calcium crystals in synovial fluids was associated with severe radiographic lesions [42]. In addition, Nalbant _et al._[44], in a prospective and sequential analysis of synovial fluids from 330 patients with knee osteoarthritis, showed that presence of BCP crystals at presentation was associated with radiographic lesion worsening. They also showed that BCP crystals could develop as the disease progressed. Indeed, BCP crystals were identified in only 23% of patients at first aspiration but were present in 58% of patients at the final aspiration after a mean interval of 3.6 ± 1.6 years [44].
However, the prevalence of intraarticular BCP crystals is difficult to establish. These crystals are not visible under light or polarizing light microscopy, and, currently, there are no readily available tests for rapid identification. They are visible under light microscopy with alizarin red staining, which also stains other calcium-containing particulates [47]. It is possible that many osteoarthritis joint fluids contain BCP crystals that are too small to be identified by conventional techniques. Recently, Bertrand _et al._[48] nicely showed that digital contact radiography of cartilage samples revealed calcifications in 100% of 88 osteoarthritis knee cartilage obtained at the time of arthroplasty, whereas calcifications were only detected in 26% by the preoperative conventional knee radiographs. These calcium crystals were characterized as apatite by electron microscopy. Collectively, these clinical data suggest a pathogenic role for calcium-containing crystals in cartilage destruction and osteoarthritis development, which are further evidenced by experimental results.
Experimental data
The pathogenic role of intraarticular calcium-containing crystals in cartilage destruction is largely supported by in-vivo and in-vitro experiments. Cellular effects and mechanisms of cellular activation by calcium crystals were recently reviewed [32,49,50,51•].
Of importance, weekly injection of CPPD crystals into rabbit knee, which were rendered osteoarthritic by partial meniscectomy and section of the collateral ligament, worsened osteoarthritis cartilage destruction [52]. In some spontaneous osteoarthritis animal models, calcifications precede significant cartilage damage. Thus, in the guinea pig model of spontaneous osteoarthritis, calcifications in the meniscus occur before cartilage lesion. The authors suggested that mechanical changes in the calcified meniscus alter the biomechanics of the joint and contribute to osteoarthritis lesion [53].
In-vitro experiments clearly demonstrated the deleterious role of calcium crystals. Calcium-containing crystals may stimulate cells through two mechanisms. These crystals can first activate cells after being endocytosed or phagocytosed, leading to intralysosomal crystal dissolution with subsequent elevation of intracellular Ca2+ levels and release of inflammatory cytokines. Crystal phagocytosis can be enhanced by opsonization by IgG or complement components. The other mechanism of crystal activation involves a direct crystal–cell membrane interaction. This latter can be due either to electrostatic bonds with naked crystal surface or through membrane receptor stimulation by naked or protein-coated crystals [51•]. Crystal–cell interactions induce rapid calcium influx [54] and changes in cytoplasmic membrane permeability, which may facilitate the entry of some molecules [55]; mechanoreceptor or integrin stimulation; and binding to specific membrane receptors related to surface proteins such as Toll-like receptor (TLR)-2 and TLR-4 [56•,57] or, as shown recently, annexin 5 [58••].
In-vitro effects of basic calcium phosphate crystals
BCP crystals may cause joint damage by several mechanisms (Fig. 2), and most studies have not yet focused on their synovial or skin fibroblast effects. BCP crystals induce fibroblast proliferation, protooncogene stimulation, inflammatory cytokine (IL-1β, TNFα) and nitric oxide production, metalloprotease (MMP) production and activation, cyclooxygenase (COX)-1 and COX-2 and prostaglandin E2 (PGE2) production [32,49,50,51•]. We have recently shown that BCP crystals induced chondrocytes to produce nitric oxide and IL-1β [59] and to undergo apoptosis [58••]. BCP crystals activate several intracellular signalling pathways that depend on cellular species and cellular effects (Table 1[58••,60–74,75•,76–79]). Three major signalling pathways are activated by BCP crystals: crystal endocytosis and intracellular crystal dissolution with subsequent intracellular calcium increase, protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) pathways with the preponderant role of p42/44 MAPK.
Mechanisms of basic calcium phosphate crystal-related arthropathies
Signalling pathways activated by basic calcium phosphate crystals according to cellular effects and cell species
Thus, phospholipase C (PLC), PKC, p42/44 MAPK, c-myc and c-fos activation appear to be central regulators of crystal-induced proliferation [49]. Intracellular BCP crystal dissolution is necessary for mitogenesis [61]. Several transcription factors were involved: cyclic adenosine monophosphate response element-binding protein, serum response factor and early growth response 2.
BCP crystal-induced MMP production also requires intracellular crystal dissolution for MMP-13 [75•] but solely crystal endocytosis for MMP-1 and MMP-3 [61]. BCP crystal-induced MMP-1 expression by canine fibroblast-like synoviocytes is secondary to p42/44 MAPK activation and follows the Ras/Raf/MAPK/c-fos/activator protein 1 (AP-1) signalling pathway [69]. p42/44 MAPK activation is PKC dependant [71,72]. Recently, Molloy _et al._[75•] showed that BCP crystal-induced MMP-13 production by human synovial osteoarthritis fibroblasts was secondary to p42/44 MAPK and p38 MAPK activation. They also showed that BCP crystal-induced MMP-13 production was dependent on PGE2 pathway [75•].
BCP crystals induction of PGE2 and TNFα also involves PKC pathway and p42/44 MAPK [78,79]. Recently, Grandjean-Laquerriere _et al._[56•] showed that hydoxyapatite crystal-induced TNFα production was secondary to TLR-4 stimulation. This receptor family is also involved in CPPD and urate monosodium (UMS) crystal inflammation (discussed below).
Although most of these studies focused on fibroblast-like cells, we have recently shown that BCP crystals directly induced bovine articular chondrocytes and bovine cartilage explants inducible nitric oxide synthase expression and nitric oxide production. BCP crystal-induced nitric oxide production involved p38 and C-Jun N-terminal kinase MAPK activation, was independent of IL-1β pathway, but was most likely under the control of AP-1 [59]. Nitric oxide is a catabolic mediator in osteoarthritis pathogenesis. As nitric oxide induces chondrocyte apoptosis, we look at the effect of BCP crystals on chondrocyte apoptosis. We showed that BCP crystals directly induced joint chondrocyte apoptosis. This in-vitro process was independent of IL-1β, TNFα and nitric oxide pathways. It required cell–crystal contact, crystal endocytosis and intralysosomal crystal dissolution responsible for intracellular Ca2+ elevation [58••]. Moreover, we showed that overexpression of annexin 5, which is observed in advanced osteoarthritis cartilage [8], enhanced BCP crystal-induced chondrocyte apoptosis. Finally, annexin 5 was found to interact with BCP crystals and was bound to BCP crystals but not to UMS crystals [58••]. Annexins are ubiquitous proteins that can interact with acid phospholipids, membranes and cytoskeleton constituents in the presence of Ca2+. They are involved in regulating intracellular and extracellular activities such as endocytosis and exocytosis and Ca2+ fluxes [80]. Chondrocytes produce annexins 2, 5 and 6, whose levels are increased in osteoarthritis cartilage. These results suggested that annexin 5 might be involved in calcium influx induced by BCP crystals [58••].
In-vitro effects of calcium pyrophosphate dihydrate crystals
CPPD crystals have several in-vitro properties in common with BCP crystals, such as induction of protooncogenes, mitogenesis and inflammatory cytokine and MMP production. CPPD crystals can induce the expression of TNFα, IL-6 and IL-8 by monocytes and macrophages [81]. IL-8 plays a key role in the generation of the acute inflammation typical of pseudogout by promoting neutrophil recruitment and activation. CPPD crystal induction of the IL-8 promoter is mediated through the p42/44 MAPK pathway and requires nuclear factor-κB complex c-Rel/RelA and AP-1 transcriptional activity [81]. CPPD crystals can directly activate neutrophil oxidative and degranulation responses through several intracellular signalling pathways, including PKC, PLC, phosphatidyl-inositol 3 kinase and p38 MAPK [82,83]. Recent work by Liu-Bryan _et al._[57,84] has demonstrated a link between innate immunity and inflammation in pseudogout. They observed constitutive expression of TLR-2 in normal cartilage. CPPD crystal-induced chondrocyte nitric oxide production was dependant on TLR-2 signalling cascade, including its intracellular adaptor protein, myeloid differentiation primary response protein 88. Finally, Martinon _et al._[85] have shown that CPPD crystals, as well as MSU crystals, induced the inflammasome (namely the NALP-3/ASC/Caspase-1 complex) activation leading to pro-IL-1 processing, IL-1β production and active secretion. IL-1 is able to stimulate cells through its receptor in a paracrine or autocrine fashion, suggesting new therapeutic targets.
Conclusion
Several rheumatologic diseases are associated with calcium-containing crystal deposition. Advances have been made in the understanding of the mechanisms of cartilage calcifications with the identifications of PPi and inorganic phosphate regulation and the mechanisms of calcium crystal-induced cell activation with the implication of the inflammasome complex and chondrocyte apoptosis. The advances may give rise to new treatments such as targeting IL-1β in pseudogout attacks.
Acknowledgements
There is no potential conflict of interest. This work was funded in part by the Société Française de Rhumatologie, the Associations for Research ARPS and ART, the Fond d'étude des Médecins des Hôpitaux de Paris.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 192–193).
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Keywords:
calcium crystals; chondrocyte; inflammasome; matrix vesicle; pyrophosphate
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