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Arthritis und Rheuma 2020; 40(04): 239-245
DOI: 10.1055/a-1193-7607
Schwerpunkt
© Georg Thieme Verlag KG Stuttgart · New York

Kalziumkristalle im Gelenk

Calcium crystals in the joint
Nicole Märtens∗
1   Orthopädische Universitätsklinik, Otto-von-Guericke Universität Magdeburg
,
Jessica Bertrand∗
1   Orthopädische Universitätsklinik, Otto-von-Guericke Universität Magdeburg
› Author Affiliations
Further Information

Publication History

Publication Date:
20 August 2020 (online)

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ZUSAMMENFASSUNG

Es gibt im Wesentlichen 2 Arten von Kalziumkristallen im Gelenk. Zum einen gibt es Kalziumphosphatkristalle (BCP) und zum anderen gibt es Kalziumpyrophosphatkristalle (CPPD). BCP-Kristalle sind mit der Arthrose assoziiert und entstehen durch die hypertrophe Differenzierung von Chondrozyten. CPPD-Kristalle sind mit der Chondrokalzinose assoziiert. Hier ist die Entstehung noch nicht vollständig verstanden. Die Kalziumkristalle lösen eine entzündliche Reaktion im Gelenk aus und induzieren die Sekretion von proinflammatorischen Zytokinen. Unterschiedliche direkte oder indirekte Signalwege sind hierfür bereits beschrieben worden und werden im Text näher erläutert. Die bisherigen Therapien greifen hauptsächlich in das Entzündungsgeschehen ein. Es gibt bisher wenige Ansätze einer gezielten Kristall-abhängigen oder insbesondere Kristall-auflösenden Therapie. Durch besseres Verständnis der zu Grunde liegenden Signalwege wird in Zukunft eventuell eine derartige Therapie zur Verfügung stehen, sodass gezielt die Kalziumkristalle aufgelöst oder die spezifischen Signalwege inhibiert werden können.

ABSTRACT

There are 2 main types of calcium crystals in the joint. On the one hand there are calcium phosphate crystals (BCP) and on the other hand there are calcium pyrophosphate crystals (CPPD). BCP crystals are associated with osteoarthritis and occur due to the hypertrophic differentiation of chondrocytes. CPPD crystals are associated with chondrocalcinosis. The origin of these crystals is not yet fully understood. The calcium crystals trigger an inflammatory reaction in the joint and induce the secretion of pro-inflammatory cytokines. Different direct or indirect signaling pathways have already been established and are explained in more detail in the following paragraphs. Current therapies for calcium crystal induced arthropathies mainly interrupt the inflammatory cascades. So far there have been few approaches to directly target crystal-dependent signaling pathways, or to dissolve the crystal themselves. With a better understanding of the underlying signaling pathways, such a therapy might be available in the future, giving the possibility to dissolve the calcium crystals or specifically inhibit the signaling pathways.

Schlüsselwörter

BCP - CPPD - Chondrozyt - Arthrose - Chondrokalzinose - Entzündung

Keywords

BCP - CPPD - chondrocyte - osteoarthritis - chondrocalcinosis - inflammation
 

  • Literatur

  • 1 Florencio-Silva R. et al Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells. Biomed Res Int 2015; 2015: 421746
    CrossrefPubMedGoogle Scholar
  • 2 Rosenberg N, Rosenberg O, Soudry M. Osteoblasts in bone physiology-mini review. Rambam Maimonides Med J 2012; 3 (02) e0013
    CrossrefPubMedGoogle Scholar
  • 3 Bottini M. et al Matrix vesicles from chondrocytes and osteoblasts: Their biogenesis, properties, functions and biomimetic models. Biochim Biophys Acta Gen Subj 2018; 1862 (03) 532-546
    CrossrefPubMedGoogle Scholar
  • 4 Murshed M, McKee MD. Molecular determinants of extracellular matrix mineralization in bone and blood vessels. Curr Opin Nephrol Hypertens 2010; 19 (04) 359-365
    CrossrefPubMedGoogle Scholar
  • 5 Wiesmann HP. et al Aspects of collagen mineralization in hard tissue formation. Int Rev Cytol 2005; 242: 121-156
    CrossrefPubMedGoogle Scholar
  • 6 McCarty Jr DJ, Gatter RA. Identification of Calcium Hydrogen Phosphate Dihydrate Crystals in Human Fibrocartilage. Nature 1964; 201: 391-392
    CrossrefPubMedGoogle Scholar
  • 7 Aghagolzadeh P. et al Calcification of vascular smooth muscle cells is induced by secondary calciprotein particles and enhanced by tumor necrosis factor-alpha. Atherosclerosis 2016; 251: 404-414
    CrossrefPubMedGoogle Scholar
  • 8 Pasch A. et al Nanoparticle-based test measures overall propensity for calcification in serum. J Am Soc Nephrol 2012; 23 (10) 1744-1752
    CrossrefPubMedGoogle Scholar
  • 9 Garimella R. et al Nature of phosphate substrate as a major determinant of mineral type formed in matrix vesicle-mediated in vitro mineralization: An FTIR imaging study. Bone 2006; 38 (06) 811-817
    CrossrefPubMedGoogle Scholar
  • 10 Russell RG. et al Inorganic pyrophosphate in plasma, urine, and synovial fluid of patients with pyrophosphate arthropathy (chondrocalcinosis or pseudogout). Lancet 1970; 2 7679 899-902
    CrossrefPubMedGoogle Scholar
  • 11 Ryan LM, Kozin F, McCarty DJ. Quantification of human plasma inorganic pyrophosphate. I. Normal values in osteoarthritis and calcium pyrophosphate dihydrate crystal deposition disease. Arthritis Rheum 1979; 22 (08) 886-891
    CrossrefPubMedGoogle Scholar
  • 12 Johnson K. et al Up-regulated expression of the phosphodiesterase nucleotide pyrophosphatase family member PC-1 is a marker and pathogenic factor for knee meniscal cartilage matrix calcification. Arthritis Rheum 2001; 44 (05) 1071-1081
    CrossrefPubMedGoogle Scholar
  • 13 Mebarek S. et al Ankylosing spondylitis, late osteoarthritis, vascular calcification, chondrocalcinosis and pseudo gout: toward a possible drug therapy. Curr Med Chem 2011; 18 (14) 2196-2203
    CrossrefPubMedGoogle Scholar
  • 14 Seifert W. et al The progressive ankylosis protein ANK facilitates clathrin- and adaptor-mediated membrane traffic at the trans-Golgi network-to-endosome interface. Hum Mol Genet 2016; 25 (17) 3836-3848
    CrossrefPubMedGoogle Scholar
  • 15 Rosenthal AK. et al The progressive ankylosis gene product ANK regulates extracellular ATP levels in primary articular chondrocytes. Arthritis Res Ther 2013; 15 (05) R154
    CrossrefPubMedGoogle Scholar
  • 16 McCarty DJ. Crystals and arthritis. Dis Mon 1994; 40 (06) 255-299
    CrossrefPubMedGoogle Scholar
  • 17 Fuerst M. et al Calcification of articular cartilage in human osteoarthritis. Arthritis Rheum 2009; 60 (09) 2694-2703
    CrossrefPubMedGoogle Scholar
  • 18 Dieppe PA. et al Apatite deposition disease. A new arthropathy. Lancet 1976; 1 7954 266-269
    CrossrefPubMedGoogle Scholar
  • 19 Hawellek T. et al Articular cartilage calcification of the hip and knee is highly prevalent, independent of age but associated with histological osteoarthritis: evidence for a systemic disorder. Osteoarthritis Cartilage 2016; 24 (12) 2092-2099
    CrossrefPubMedGoogle Scholar
  • 20 Hawellek T. et al Calcification of the acetabular labrum of the hip: prevalence in the general population and relation to hip articular cartilage and fibrocartilage degeneration. Arthritis Res Ther 2018; 20 (01) 104
    CrossrefPubMedGoogle Scholar
  • 21 Hawellek T. et al Articular cartilage calcification of the humeral head is highly prevalent and associated with osteoarthritis in the general population. J Orthop Res 2016; 34 (11) 1984-1990
    CrossrefPubMedGoogle Scholar
  • 22 Fuerst M, Zustin J, Ruther W. [Crystal arthropathies]. Pathologe 2011; 32 (03) 193-199
    CrossrefPubMedGoogle Scholar
  • 23 Bjelle AO, Sundstrom KG. An ultrastructural study of the articular cartilage in calcium pyrophosphate dihydrate (CPPD) crystal deposition disease (chondrocalcinosis articularis). Calcif Tissue Res 1975; 19 (01) 63-71
    CrossrefPubMedGoogle Scholar
  • 24 Fuerst M. et al [Crystal arthropathies]. Orthopade 2009; 38 (06) 501-510
    CrossrefPubMedGoogle Scholar
  • 25 Neame R. et al Distribution of radiographic osteoarthritis between the right and left hands, hips, and knees. Arthritis Rheum 2004; 50 (05) 1487-1494
    CrossrefPubMedGoogle Scholar
  • 26 Abhishek A. et al Does Chondrocalcinosis Associate With a Distinct Radiographic Phenotype of Osteoarthritis in Knees and Hips? A Case-Control Study. Arthritis Care Res (Hoboken) 2016; 68 (02) 211-216
    CrossrefPubMedGoogle Scholar
  • 27 Karimzadeh H. et al Prevalence of Chondrocalcinosis in Patients above 50 Years and the Relationship with Osteoarthritis. Adv Biomed Res 2017; 6: 98
    CrossrefPubMedGoogle Scholar
  • 28 Misra D. et al CT imaging for evaluation of calcium crystal deposition in the knee: initial experience from the Multicenter Osteoarthritis (MOST) study. Osteoarthritis Cartilage 2015; 23 (02) 244-248
    CrossrefPubMedGoogle Scholar
  • 29 Baldwin CT. et al Linkage of early-onset osteoarthritis and chondrocalcinosis to human chromosome 8q. Am J Hum Genet 1995; 56 (03) 692-697
    PubMedGoogle Scholar
  • 30 Rojas K. et al Physical map and characterization of transcripts in the candidate interval for familial chondrocalcinosis at chromosome 5p15.1. Genomics 1999; 62 (02) 177-183
    CrossrefPubMedGoogle Scholar
  • 31 Abhishek A, Doherty M. Pathophysiology of articular chondrocalcinosis – role of ANKH. Nat Rev Rheumatol 2011; 7 (02) 96-104
    CrossrefPubMedGoogle Scholar
  • 32 Abhishek A. et al The association between ANKH promoter polymorphism and chondrocalcinosis is independent of age and osteoarthritis: results of a case-control study. Arthritis Res Ther 2014; 16 (01) R25
    CrossrefPubMedGoogle Scholar
  • 33 Zaka R, Williams CJ. Genetics of chondrocalcinosis. Osteoarthritis Cartilage 2005; 13 (09) 745-750
    CrossrefPubMedGoogle Scholar
  • 34 Cheng PT, Pritzker KP. Ferrous [Fe + + ] but not ferric [Fe] ions inhibit de novo formation of calcium pyrophosphate dihydrate crystals: possible relationships to chondrocalcinosis and hemochromatosis. J Rheumatol 1988; 15 (02) 321-324
    Google Scholar
  • 35 Cimbek EA. et al Chondrocalcinosis related to familial hypomagnesemia with hypercalciuria and nephrocalcinosis. J Pediatr Endocrinol Metab 2015; 28 5–6 713-716
    CrossrefPubMedGoogle Scholar
  • 36 Richette P. et al Hypomagnesemia and chondrocalcinosis in short bowel syndrome. J Rheumatol 2005; 32 (12) 2434-2436
    Google Scholar
  • 37 Pappu R. et al Musculoskeletal manifestations of primary hyperparathyroidism. Clin Rheumatol 2016; 35 (12) 3081-3087
    CrossrefPubMedGoogle Scholar
  • 38 Beck C. et al How can calcium pyrophosphate crystals induce inflammation in hypophosphatasia or chronic inflammatory joint diseases?. Rheumatol Int 2009; 29 (03) 229-238
    CrossrefPubMedGoogle Scholar
  • 39 Hachicha M, Naccache PH, McColl SR. Inflammatory microcrystals differentially regulate the secretion of macrophage inflammatory protein 1 and interleukin 8 by human neutrophils: a possible mechanism of neutrophil recruitment to sites of inflammation in synovitis. J Exp Med 1995; 182 (06) 2019-2025
    CrossrefPubMedGoogle Scholar
  • 40 Roberge CJ. et al Crystal-induced neutrophil activation. V. Differential production of biologically active IL-1 and IL-1 receptor antagonist. J Immunol 1994; 152 (11) 5485-5494
    CrossrefPubMedGoogle Scholar
  • 41 Tramontini N. et al Central role of complement membrane attack complex in monosodium urate crystal-induced neutrophilic rabbit knee synovitis. Arthritis Rheum 2004; 50 (08) 2633-2639
    CrossrefPubMedGoogle Scholar
  • 42 Ea HK. et al Octacalcium phosphate crystals directly stimulate expression of inducible nitric oxide synthase through p38 and JNK mitogen-activated protein kinases in articular chondrocytes. Arthritis Res Ther 2005; 7 (05) R915-R926
    CrossrefPubMedGoogle Scholar
  • 43 Liu-Bryan R. et al TLR2 signaling in chondrocytes drives calcium pyrophosphate dihydrate and monosodium urate crystal-induced nitric oxide generation. J Immunol 2005; 174 (08) 5016-5023
    CrossrefPubMedGoogle Scholar
  • 44 Hari A. et al Activation of NLRP3 inflammasome by crystalline structures via cell surface contact. Sci Rep 2014; 4: 7281
    CrossrefPubMedGoogle Scholar
  • 45 Ng G. et al Receptor-independent, direct membrane binding leads to cell-surface lipid sorting and Syk kinase activation in dendritic cells. Immunity 2008; 29 (05) 807-818
    CrossrefPubMedGoogle Scholar
  • 46 Barabe F. et al Crystal-induced neutrophil activation VI. Involvment of FcgammaRIIIB (CD16) and CD11b in response to inflammatory microcrystals. FASEB J 1998; 12 (02) 209-220
    CrossrefPubMedGoogle Scholar
  • 47 Grandjean-Laquerriere A. et al Involvement of toll-like receptor 4 in the inflammatory reaction induced by hydroxyapatite particles. Biomaterials 2007; 28 (03) 400-404
    CrossrefPubMedGoogle Scholar
  • 48 Macmullan P, McCarthy G. Treatment and management of pseudogout: insights for the clinician. Ther Adv Musculoskelet Dis 2012; 4 (02) 121-131
    CrossrefPubMedGoogle Scholar
  • 49 Mitroulis I, Skendros P, Ritis K. Targeting IL-1beta in disease; the expanding role of NLRP3 inflammasome. Eur J Intern Med 2010; 21 (03) 157-163
    CrossrefPubMedGoogle Scholar
  • 50 Theofilopoulos AN. et al Sensors of the innate immune system: their link to rheumatic diseases. Nat Rev Rheumatol 2010; 6 (03) 146-156
    CrossrefPubMedGoogle Scholar
  • 51 Meng ZH. et al Monosodium urate, hydroxyapatite, and calcium pyrophosphate crystals induce tumor necrosis factor-alpha expression in a mononuclear cell line. J Rheumatol 1997; 24 (12) 2385-2388
    Google Scholar
  • 52 Nguyen C. et al Intracellular calcium oscillations in articular chondrocytes induced by basic calcium phosphate crystals lead to cartilage degradation. Osteoarthritis Cartilage 2012; 20 (11) 1399-1408
    CrossrefPubMedGoogle Scholar
  • 53 Pazar B. et al Basic calcium phosphate crystals induce monocyte/macrophage IL-1beta secretion through the NLRP3 inflammasome in vitro. J Immunol 2011; 186 (04) 2495-2502
    CrossrefPubMedGoogle Scholar
  • 54 Roch-Arveiller M. et al Inflammatory reactions induced by various calcium pyrophosphate crystals. Biomed Pharmacother 1990; 44 (09) 467-474
    CrossrefPubMedGoogle Scholar
  • 55 Watanabe W, Baker DG, Schumacher Jr HR. Comparison of the acute inflammation induced by calcium pyrophosphate dihydrate, apatite and mixed crystals in the rat air pouch model of a synovial space. J Rheumatol 1992; 19 (09) 1453-1457
    Google Scholar
  • 56 Gratton SE. et al The effect of particle design on cellular internalization pathways. Proc Natl Acad Sci U S A 2008; 105 (33) 11613-11618
    CrossrefPubMedGoogle Scholar
  • 57 Nakayama M. Macrophage Recognition of Crystals and Nanoparticles. Front Immunol 2018; 9: 103
    CrossrefPubMedGoogle Scholar
  • 58 Kozin F, McCarty DJ. Protein adsorption to monosodium urate, calcium pyrophosphate dihydrate, and silica crystals: relationship to the pathogenesis of crystal-induced inflammation. Arthritis Rheum 1976; 19 (Suppl. 03) 433-438
    CrossrefPubMedGoogle Scholar
  • 59 Ortiz-Bravo E, Sieck MS, Schumacher Jr HR. Changes in the proteins coating monosodium urate crystals during active and subsiding inflammation. Immunogold studies of synovial fluid from patients with gout and of fluid obtained using the rat subcutaneous air pouch model. Arthritis Rheum 1993; 36 (09) 1274-1285
    CrossrefPubMedGoogle Scholar
  • 60 Winternitz CI, Jackson JK, Burt HM. The interaction of monoclinic calcium pyrophosphate dihydrate crystals with neutrophils. Rheumatol Int 1996; 16 (03) 101-107
    CrossrefPubMedGoogle Scholar
  • 61 Dalal P. et al Molecular dynamics simulation studies of the effect of phosphocitrate on crystal-induced membranolysis. Biophys J 2005; 89 (04) 2251-2257
    CrossrefPubMedGoogle Scholar
  • 62 Gras P. et al Crystal structure of monoclinic calcium pyrophosphate dihydrate (m-CPPD) involved in inflammatory reactions and osteoarthritis. Acta Crystallogr B Struct Sci Cryst Eng Mater 2016; 72 Pt 1 96-101
    CrossrefPubMedGoogle Scholar
  • 63 Roane DW. et al Prospective use of intramuscular triamcinolone acetonide in pseudogout. J Rheumatol 1997; 24 (06) 1168-1170
    Google Scholar
  • 64 Nuki G. Colchicine: its mechanism of action and efficacy in crystal-induced inflammation. Curr Rheumatol Rep 2008; 10 (03) 218-227
    CrossrefPubMedGoogle Scholar
  • 65 Rosales-Alexander JL, Balsalobre Aznar J, Magro-Checa C. Calcium pyrophosphate crystal deposition disease: diagnosis and treatment. Open Access Rheumatol 2014; 6: 39-47
    CrossrefPubMedGoogle Scholar
  • 66 Andres M, Sivera F, Pascual E. Methotrexate is an option for patients with refractory calcium pyrophosphate crystal arthritis. J Clin Rheumatol 2012; 18 (05) 234-236
    CrossrefPubMedGoogle Scholar
  • 67 Chollet-Janin A. et al Methotrexate as an alternative therapy for chronic calcium pyrophosphate deposition disease: an exploratory analysis. Arthritis Rheum 2007; 56 (02) 688-692
    CrossrefPubMedGoogle Scholar
  • 68 Rothschild B, Yakubov LE. Prospective 6-month, double-blind trial of hydroxychloroquine treatment of CPDD. Compr Ther 1997; 23 (05) 327-331
    PubMedGoogle Scholar
  • 69 Announ N. et al Anakinra is a possible alternative in the treatment and prevention of acute attacks of pseudogout in end-stage renal failure. Joint Bone Spine 2009; 76 (04) 424-426
    CrossrefPubMedGoogle Scholar
  • 70 Ottaviani S. et al Efficacy of anakinra in calcium pyrophosphate crystal-induced arthritis: a report of 16 cases and review of the literature. Joint Bone Spine 2013; 80 (02) 178-182
    CrossrefPubMedGoogle Scholar
  • 71 Vincent TL. IL-1 in osteoarthritis: time for a critical review of the literature. F1000Res 2019: 8
    PubMedGoogle Scholar
  • 72 Cheung HS. et al Inhibition of calcium pyrophosphate dihydrate crystal formation in articular cartilage vesicles and cartilage by phosphocitrate. J Biol Chem 1996; 271 (45) 28082-28085
    CrossrefPubMedGoogle Scholar
  • 73 Cheung HS. et al Phosphocitrate blocks calcification-induced articular joint degeneration in a guinea pig model. Arthritis Rheum 2006; 54 (08) 2452-2461
    CrossrefPubMedGoogle Scholar