Blood-induced joint disease: The pathophysiology of hemophilic arthropathy

Journal of Thrombosis and Haemostasis

Volumn 8, Issue 9, 2010, Pages 1895-1902

  Valentino, L A ^a  

^a Rush Children's Hospital and Rush University Medical Center   (United States)

Author keywords

Arthropathy; Hemarthrosis; Hemophilia; Joint bleeding; Joint damage

Indexed keywords

ALBUMIN; CATHEPSIN; CHYMASE; COLLAGENASE 3; ELASTASE; GAMMA INTERFERON; HYALURONIC ACID; INTERLEUKIN 1; INTERLEUKIN 1BETA; INTERLEUKIN 6; INTERSTITIAL COLLAGENASE; PLATELET DERIVED GROWTH FACTOR; STROMELYSIN; THROMBIN; TISSUE INHIBITOR OF METALLOPROTEINASE 1; TRYPTASE; TUMOR NECROSIS FACTOR ALPHA; VASCULOTROPIN;

ANGIOGENESIS; ANKYLOSIS; ARTHROPATHY; ARTICULAR CARTILAGE; BONE CELL; CARTILAGE CELL; CARTILAGE DEGENERATION; CD3+ T LYMPHOCYTE; ENDOTHELIUM CELL; FIBROBLAST; HEMARTHROSIS; HEMOPHILIA; HUMAN; JOINT DESTRUCTION; LEUKOCYTE; MACROPHAGE; OSTEOBLAST; OSTEOCLAST; OSTEOPOROSIS; PATELLA; PATHOPHYSIOLOGY; PERICYTE; PHAGOCYTE; PRIORITY JOURNAL; PROTEOGLYCAN SYNTHESIS; RANGE OF MOTION; REVIEW; RHEUMATOID ARTHRITIS; SMOOTH MUSCLE FIBER; SYNOVIAL FLUID; SYNOVIUM;

ARTHRITIS, RHEUMATOID; ARTHROPATHY, NEUROGENIC; BONE AND BONES; CARTILAGE, ARTICULAR; HEMOPHILIA A; HUMANS; INFLAMMATION; JOINT DISEASES; JOINTS; OSTEOARTHRITIS; SYNOVIAL MEMBRANE;

EID: 77956489886     PISSN: 15387933     EISSN: 15387836     Source Type: Journal    
DOI: 10.1111/j.1538-7836.2010.03962.x     Document Type: Review

References (129)

1. Wessel LM, Scholz S, Rusch M. Characteristic pattern and management of intra-articular knee lesions in different pediatric age groups. J Pediatr Orthop 2001, 21:14-9.
2. Pergantou H, Matsinos G, Papadopoulos A, Platokouki H, Aronis S. Comparative study of validity of clinical, X-ray and magnetic resonance imaging scores in evaluation and management of haemophilic arthropathy in children. Haemophilia 2006, 12:241-7.
3. Stein H, Duthie RB. The pathogenesis of chronic haemophilic arthropathy. J Bone Joint Surg Br 1981, 63B:601-9.
4. Roosendaal G, Lafeber FP. Pathogenesis of haemophilic arthropathy. Haemophilia 2006, 12(Suppl. 3):117-21.
5. Jansen NW, Roosendaal G, Wenting MJ, Bijlsma JW, Theobald M, Hazewinkel HA, Lafeber FP. Very rapid clearance after a joint bleed in the canine knee cannot prevent adverse effects on cartilage and synovial tissue. Osteoarthritis Cartilage 2009, 17:433-40.
6. Saxne T, Heinegard D. Cartilage oligomeric matrix protein: a novel marker of cartilage turnover detectable in synovial fluid and blood. Br J Rheumatol 1992, 31:583-91.
7. Garnero P, Christgau S, Delmas PD. The bisphosphonate zoledronate decreases type II collagen breakdown in patients with Paget's disease of bone. Bone 2001, 28:461-4.
8. Sowers MF, Karvonen-Gutierrez CA, Yosef M, Jannausch M, Jiang Y, Garnero P, Jacobson J. Longitudinal changes of serum COMP and urinary CTX-II predict X-ray defined knee osteoarthritis severity and stiffness in women. Osteoarthritis Cartilage 2009, 17:1609-14.
9. Ishiguro N, Kojima T, Poole AR. Mechanism of cartilage destruction in osteoarthritis. Nagoya J Med Sci 2002, 65:73-84.
10. Muller-Ladner U, Gay RE, Gay S. Molecular biology of cartilage and bone destruction. Curr Opin Rheumatol 1998, 10:212-19.
11. Evans CH. The role of proteinases in cartilage destruction. Agents Actions Suppl 1991, 32:135-52.
12. Cohen NP, Foster RJ, Mow VC. Composition and dynamics of articular cartilage: structure, function, and maintaining healthy state. J Orthop Sports Phys Ther 1998, 28:203-15.
13. Bjelle A. Content and composition of glycosaminoglycans in human knee joint cartilage. Variation with site and age in adults. Connect Tissue Res 1975, 3:141-7.
14. Slowman SD, Brandt KD. Composition and glycosaminoglycan metabolism of articular cartilage from habitually loaded and habitually unloaded sites. Arthritis Rheum 1986, 29:88-94.
15. Parsons JR, Zingler BM, McKeon JJ. Mechanical and histological studies of acute joint hemorrhage. Orthopedics 1987, 10:1019-26.
16. Hooiveld MJ, Roosendaal G, van den Berg HM, Bijlsma JW, Lafeber FP. Haemoglobin-derived iron-dependent hydroxyl radical formation in blood-induced joint damage: an in vitro study. Rheumatology (Oxford) 2003, 42:784-90.
17. Pettipher ER, Higgs GA, Henderson B. Interleukin 1 induces leukocyte infiltration and cartilage proteoglycan degradation in the synovial joint. Proc Natl Acad Sci USA 1986, 83:8749-53.
18. Nishiya K. Stimulation of human synovial cell DNA synthesis by iron. J Rheumatol 1994, 21:1802-7.
19. Hashizume M, Hayakawa N, Mihara M. IL-6 trans-signalling directly induces RANKL on fibroblast-like synovial cells and is involved in RANKL induction by TNF-alpha and IL-17. Rheumatology (Oxford) 2008, 47:1635-40.
20. Wen FQ, Jabbar AA, Chen YX, Kazarian T, Patel DA, Valentino LA. c-myc proto-oncogene expression in hemophilic synovitis: in vitro studies of the effects of iron and ceramide. Blood 2002, 100:912-16.
21. Hakobyan N, Kazarian T, Jabbar AA, Jabbar KJ, Valentino LA. Pathobiology of hemophilic synovitis I: overexpression of mdm2 oncogene. Blood 2004, 104:2060-4.
22. Yanni G, Whelan A, Feighery C, Bresnihan B. Synovial tissue macrophages and joint erosion in rheumatoid arthritis. Ann Rheum Dis 1994, 53:39-44.
23. Ghadially FN, Ailsby RL, Yong NK. Ultrastructure of the haemophilic synovial membrane and electron-probe X-ray analysis of haemosiderin. J Pathol 1976, 120:201-8.
24. Semenza GL. Therapeutic angiogenesis: another passing phase? Circ Res 2006, 98:1115-16.
25. Sosman JA, Puzanov I. Molecular targets in melanoma from angiogenesis to apoptosis. Clin Cancer Res 2006, 12:2376s-83s.
26. Paleolog EM, Miotla JM. Angiogenesis in arthritis: role in disease pathogenesis and as a potential therapeutic target. Angiogenesis 1998, 2:295-307.
27. Nicosia RF, Villaschi S. Rat aortic smooth muscle cells become pericytes during angiogenesis in vitro. Lab Invest 1995, 73:658-66.
28. Israely T, Dafni H, Granot D, Nevo N, Tsafriri A, Neeman M. Vascular remodeling and angiogenesis in ectopic ovarian transplants: a crucial role of pericytes and vascular smooth muscle cells in maintenance of ovarian grafts. Biol Reprod 2003, 68:2055-64.
29. Nehls V, Schuchardt E, Drenckhahn D. The effect of fibroblasts, vascular smooth muscle cells, and pericytes on sprout formation of endothelial cells in a fibrin gel angiogenesis system. Microvasc Res 1994, 48:349-63.
30. Nasonova VA, Musaev SK, Iakovleva GI, Abasov E, Rustamov R. The clinico-morphological characteristics of synovial membrane involvement in beta-thalassemia. Revmatologiia (Mosk) 1991, 3-5.
31. de Sousa M, Dynesius-Trentham R, Mota-Garcia F, da Silva MT, Trentham DE. Activation of rat synovium by iron. Arthritis Rheum 1988, 31:653-61.
32. Bignold LP. Importance of platelets in increased vascular permeability evoked by experimental haemarthrosis in synovium of the rat. Pathology 1980, 12:169-79.
33. Wallny TA, Scholz DT, Oldenburg J, Nicolay C, Ezziddin S, Pennekamp PH, Stoffel-Wagner B, Kraft CN. Osteoporosis in haemophilia - an underestimated comorbidity? Haemophilia 2007, 13:79-84.
34. Gerstner G, Damiano ML, Tom A, Worman C, Schultz W, Recht M, Stopeck AT. Prevalence and risk factors associated with decreased bone mineral density in patients with haemophilia. Haemophilia 2009, 15:559-65.
35. Cayla J. Articular manifestations of hemophilia. Cah Coll Med Hop Paris 1967, 8:731-46.
36. Arnold WD, Hilgartner MW. Hemophilic arthropathy. current concepts of pathogenesis and management. J Bone Joint Surg Am 1977, 59:287-305.
37. Katsarou O, Terpos E, Chatzismalis P, Provelengios S, Adraktas T, Hadjidakis D, Kouramba A, Karafoulidou A. Increased bone resorption is implicated in the pathogenesis of bone loss in hemophiliacs: correlations with hemophilic arthropathy and HIV infection. Ann Hematol 2009, http://dx.doi.org/10.1007/s00277-009-0759-x, DOI:
38. Tlacuilo-Parra A, Morales-Zambrano R, Tostado-Rabago N, Esparza-Flores MA, Lopez-Guido B, Orozco-Alcala J. Inactivity is a risk factor for low bone mineral density among haemophilic children. Br J Haematol 2008, 140:562-7.
39. Kovacs CS. Hemophilia, low bone mass, and osteopenia/osteoporosis. Transfus Apher Sci 2008, 38:33-40.
40. Nair AP, Jijina F, Ghosh K, Madkaikar M, Shrikhande M, Nema M. Osteoporosis in young haemophiliacs from western India. Am J Hematol 2007, 82:453-7.
41. Pollmann H, Richter H, Ringkamp H, Jurgens H. When are children diagnosed as having severe haemophilia and when do they start to bleed? A 10-year single-centre PUP study. Eur J Pediatr 1999, 158(Suppl. 3):S166-70.
42. Fischer K, van der Bom JG, Mauser-Bunschoten EP, Roosendaal G, Prejs R, de Kleijn P, Grobbee DE, van den Berg M. The effects of postponing prophylactic treatment on long-term outcome in patients with severe hemophilia. Blood 2002, 99:2337-41.
43. Fischer K, van Hout BA, van der Bom JG, Grobbee DE, van den Berg HM. Association between joint bleeds and Pettersson scores in severe haemophilia. Acta Radiol 2002, 43:528-32.
44. Pain in haemophilia. Lancet 1973, 1:931-2.
45. Ahlberg A. Haemophilia in Sweden. VII. Incidence, treatment and prophylaxis of arthropathy and other musculo-skeletal manifestations of haemophilia A and B. Acta Orthop Scand 1965, 77:3-132.
46. Gonzalez LM, Querol F, Gallach JE, Gomis M, Aznar VA. Force fluctuations during the maximum isometric voluntary contraction of the quadriceps femoris in haemophilic patients. Haemophilia 2007, 13:65-70.
47. Battistella LR. Maintenance of musculoskeletal function in people with haemophilia. Haemophilia 1998, 4(Suppl. 2):26-32.
48. Defaria CR, De Melo-Souza SE, Pinheiro ED. Haemophilic neuromyopathy. J Neurol Neurosurg Psychiatry 1979, 42:600-5.
49. Jones EW. Musculoskeletal complications of hemophilia. Calif Med 1958, 88:316-19.
50. Hilgartner MW. Recent advances in hemophilia. Part V. Discussion paper: Degenerative joint disease. Ann N Y Acad Sci 1975, 240:340-1.
51. Rippey JJ, Hill RR, Lurie A, Sweet MB, Thonar EJ, Handelsman JE. Articular cartilage degradation and the pathology of haemophilic arthropathy. S Afr Med J 1978, 54:345-51.
52. DePalma AF. Hemophilic arthropathy. Clin Orthop Relat Res 1967, 52:145-65.
53. Handelsman JE, Lurie A. Pathological changes in the juvenile haemophilic knee. S Afr J Surg 1975, 13:243-9.
54. Horky D, Bozdech Z, Horn V. Ultrastructure of the synovial membrane and articular cartilage in transmission and scanning electron microscopy. Cas Lek Cesk 1974, 113:777-81.
55. Handelsman JE, Lurie A. Orthopaedic aspects of haemophilia. S Afr Med J 1973, 47:1897-903.
56. Rodriguez-Merchan EC. Effects of hemophilia on articulations of children and adults. Clin Orthop 1996, 7-13.
57. Speer DP. Early pathogenesis of hemophilic arthropathy. Evolution of the subchondral cyst. Clin Orthop Relat Res 1984, 185:250-65.
58. Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, Ingram JD, Manco-Johnson ML, Funk S, Jacobson L, Valentino LA, Hoots WK, Buchanan GR, DiMichele D, Recht M, Brown D, Leissinger C, Bleak S, Cohen A, Mathew P. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007, 357:535-44.
59. Hlavacek WS, Faeder JR, Blinov ML, Perelson AS, Goldstein B. The complexity of complexes in signal transduction. Biotechnol Bioeng 2003, 84:783-94.
60. Safran MR, Johnston-Jones K, Kabo JM, Meals RA. The effect of experimental hemarthrosis on joint stiffness and synovial histology in a rabbit model. Clin Orthop Relat Res 1994, 303:280-8.
61. Dryll A, Lansaman J, Bardin T, Ryckewaert A. Hemopigmented villonodular synovitis: ultrastructural study and a comparison with hemophiliac synovitis. Rev Rhum Mal Osteoartic 1983, 50:87-93.
62. Roosendaal G, Vianen ME, Wenting MJ, van Rinsum AC, van den Berg HM, Lafeber FP, Bijlsma JW. Iron deposits and catabolic properties of synovial tissue from patients with haemophilia. J Bone Joint Surg Br 1998, 80:540-5.
63. Valentino LA, Hakobyan N, Rodriguez N, Hoots WK. Pathogenesis of haemophilic synovitis: experimental studies on blood-induced joint damage. Haemophilia 2007, 13(Suppl. 3):10-13.
64. Roosendaal G, Lafeber FP. Blood-induced joint damage in hemophilia. Semin Thromb Hemost 2003, 29:37-42.
65. Roosendaal G, Vianen ME, Marx JJ, van den Berg HM, Lafeber FP, Bijlsma JW. Blood-induced joint damage: a human in vitro study. Arthritis Rheum 1999, 42:1025-32.
66. Gordon EA, Fenton JW, Carney DH. Thrombin-receptor occupancy initiates a transient increase in cAMP levels in mitogenically responsive hamster (NIL) fibroblasts. Ann N Y Acad Sci 1986, 485:249-63.
67. Ohba T, Takase Y, Ohhara M, Kasukawa R. Thrombin in the synovial fluid of patients with rheumatoid arthritis mediates proliferation of synovial fibroblast-like cells by induction of platelet derived growth factor. J Rheumatol 1996, 23:1505-11.
68. Flick MJ, LaJeunesse CM, Talmage KE, Witte DP, Palumbo JS, Pinkerton MD, Thornton S, Degen JL. Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin alphaMbeta2 binding motif. J Clin Invest 2007, 117:3224-35.
69. Mainardi CL, Levine PH, Werb Z, Harris ED. Proliferative synovitis in hemophilia: biochemical and morphologic observations. Arthritis Rheum 1978, 21:137-44.
70. Furmaniak-Kazmierczak E, Cooke TD, Manuel R, Scudamore A, Hoogendorn H, Giles AR, Nesheim M. Studies of thrombin-induced proteoglycan release in the degradation of human and bovine cartilage. J Clin Invest 1994, 94:472-80.
71. Saklatvala J, Barrett AJ. Identification of proteinases in rheumatoid synovium. Detection of leukocyte elastase cathepsin G and another serine proteinase. Biochim Biophys Acta 1980, 615:167-77.
72. Roosendaal G, Mauser-Bunschoten EP, De Kleijn P, Heijnen L, van den Berg HM, van Rinsum AC, Lafeber FP, Bijlsma JW. Synovium in haemophilic arthropathy. Haemophilia 1998, 4:502-5.
73. Smeets TJ, Barg EC, Kraan MC, Smith MD, Breedveld FC, Tak PP. Analysis of the cell infiltrate and expression of proinflammatory cytokines and matrix metalloproteinases in arthroscopic synovial biopsies: comparison with synovial samples from patients with end stage, destructive rheumatoid arthritis. Ann Rheum Dis 2003, 62:635-8.
74. Kraan MC, Haringman JJ, Ahern MJ, Breedveld FC, Smith MD, Tak PP. Quantification of the cell infiltrate in synovial tissue by digital image analysis. Rheumatology (Oxford) 2000, 39:43-9.
75. Fernandes JC, Martel-Pelletier J, Pelletier JP. The role of cytokines in osteoarthritis pathophysiology. Biorheology 2002, 39:237-46.
76. Ovlisen K, Kristensen AT, Jensen AL, Tranholm M. IL-1 beta, IL-6, KC and MCP-1 are elevated in synovial fluid from haemophilic mice with experimentally induced haemarthrosis. Haemophilia 2009, 15:802-10.
77. Ovlisen K, Kristensen AT, Tranholm M. In vivo models of haemophilia - status on current knowledge of clinical phenotypes and therapeutic interventions. Haemophilia 2008, 14:248-59.
78. Telfer JF, Brock JH. Proinflammatory cytokines increase iron uptake into human monocytes and synovial fibroblasts from patients with rheumatoid arthritis. Med Sci Monit 2004, 10:BR91-5.
79. Murata M, Yudoh K, Masuko K. The potential role of vascular endothelial growth factor (VEGF) in cartilage: how the angiogenic factor could be involved in the pathogenesis of osteoarthritis? Osteoarthritis Cartilage 2008, 16:279-86.
80. Moskowitz RW, Boja B, Denko CW. The role of growth factors in degenerative joint disorders. J Rheumatol Suppl 1991, 27:147-8.
81. Clavel G, Bessis N, Lemeiter D, Fardellone P, Mejjad O, Menard JF, Pouplin S, Boumier P, Vittecoq O, Le Loet X, Boissier MC. Angiogenesis markers (VEGF, soluble receptor of VEGF and angiopoietin-1) in very early arthritis and their association with inflammation and joint destruction. Clin Immunol 2007, 124:158-64.
82. Whitnall M, Howard J, Ponka P, Richardson DR. A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics. Proc Natl Acad Sci USA 2006, 103:14901-6.
83. Richardson DR, Kalinowski DS, Lau S, Jansson PJ, Lovejoy DB. Cancer cell iron metabolism and the development of potent iron chelators as anti-tumour agents. Biochim Biophys Acta 2009, 1790:702-17.
84. Xu X, Sutak R, Richardson DR. Iron chelation by clinically relevant anthracyclines: alteration in expression of iron-regulated genes and atypical changes in intracellular iron distribution and trafficking. Mol Pharmacol 2008, 73:833-44.
85. Wang L, Johnson EE, Shi HN, Walker WA, Wessling-Resnick M, Cherayil BJ. Attenuated inflammatory responses in hemochromatosis reveal a role for iron in the regulation of macrophage cytokine translation. J Immunol 2008, 181:2723-31.
86. Walter PB, Macklin EA, Porter J, Evans P, Kwiatkowski JL, Neufeld EJ, Coates T, Giardina PJ, Vichinsky E, Olivieri N, Alberti D, Holland J, Harmatz P. Inflammation and oxidant-stress in beta-thalassemia patients treated with iron chelators deferasirox (ICL670) or deferoxamine: an ancillary study of the Novartis CICL670A0107 trial. Haematologica 2008, 93:817-25.
87. Tacchini L, Gammella E, De Ponti C, Recalcati S, Cairo G. Role of HIF-1 and NF-kappaB transcription factors in the modulation of transferrin receptor by inflammatory and anti-inflammatory signals. J Biol Chem 2008, 283:20674-86.
88. Tripathi L, Kumar P, Singhai AK. Role of chelates in treatment of cancer. Indian J Cancer 2007, 44:62-71.
89. De Ponti C, Carini R, Alchera E, Nitti MP, Locati M, Albano E, Cairo G, Tacchini L. Adenosine A2a receptor-mediated, normoxic induction of HIF-1 through PKC and PI-3K-dependent pathways in macrophages. J Leukoc Biol 2007, 82:392-402.
90. Denhardt DT, Noda M, O'Regan AW, Pavlin D, Berman JS. Osteopontin as a means to cope with environmental insults: regulation of inflammation, tissue remodeling, and cell survival. J Clin Invest 2001, 107:1055-61.
91. Taylor PC, Sivakumar B. Hypoxia and angiogenesis in rheumatoid arthritis. Curr Opin Rheumatol 2005, 17:293-8.
92. Gazitt Y, Reddy SV, Alcantara O, Yang J, Boldt DH. A new molecular role for iron in regulation of cell cycling and differentiation of HL-60 human leukemia cells: iron is required for transcription of p21(WAF1/CIP1) in cells induced by phorbol myristate acetate. J Cell Physiol 2001, 187:124-35.
93. Mapp PI, Grootveld MC, Blake DR. Hypoxia, oxidative stress and rheumatoid arthritis. Br Med Bull 1995, 51:419-36.
94. Allen RE, Blake DR, Nazhat NB, Jones P. Superoxide radical generation by inflamed human synovium after hypoxia. Lancet 1989, 2:282-3.
95. Schneider N, Mouithys-Mickalad AL, Lejeune JP, Deby-Dupont GP, Hoebeke M, Serteyn DA. Synoviocytes, not chondrocytes, release free radicals after cycles of anoxia/re-oxygenation. Biochem Biophys Res Commun 2005, 334:669-73.
96. Fassl S, Leisser C, Huettenbrenner S, Maier S, Rosenberger G, Strasser S, Grusch M, Fuhrmann G, Leuhuber K, Polgar D, Stani J, Tichy B, Nowotny C, Krupitza G. Transferrin ensures survival of ovarian carcinoma cells when apoptosis is induced by TNFalpha, FasL, TRAIL, or Myc. Oncogene 2003, 22:8343-55.
97. Kofoed H. Synovitis causes hypoxia and acidity in synovial fluid and subchondral bone. Injury 1986, 17:391-4.
98. Rempel D, Abrahamsson SO. The effects of reduced oxygen tension on cell proliferation and matrix synthesis in synovium and tendon explants from the rabbit carpal tunnel: an experimental study in vitro. J Orthop Res 2001, 19:143-8.
99. Safronova O, Nakahama K, Onodera M, Muneta T, Morita I. Effect of hypoxia on monocyte chemotactic protein-1 (MCP-1) gene expression induced by Interleukin-1beta in human synovial fibroblasts. Inflamm Res 2003, 52:480-6.
100. Charbonneau M, Harper K, Grondin F, Pelmus M, McDonald PP, Dubois CM. Hypoxia-inducible factor mediates hypoxic and tumor necrosis factor alpha-induced increases in tumor necrosis factor-alpha converting enzyme/ADAM17 expression by synovial cells. J Biol Chem 2007, 282:33714-24.
101. Bosco MC, Delfino S, Ferlito F, Puppo M, Gregorio A, Gambini C, Gattorno M, Martini A, Varesio L. The hypoxic synovial environment regulates expression of vascular endothelial growth factor and osteopontin in juvenile idiopathic arthritis. J Rheumatol 2009, 36:1318-29.
102. Muz B, Khan MN, Kiriakidis S, Paleolog EM. Hypoxia. The role of hypoxia and HIF-dependent signalling events in rheumatoid arthritis. Arthritis Res Ther 2009, 11:201.
103. Bosco MC, Delfino S, Ferlito F, Battaglia F, Puppo M, Gregorio A, Gambini C, Gattorno M, Martini A, Varesio L. Hypoxic synovial environment and expression of macrophage inflammatory protein 3gamma/CCL20 in juvenile idiopathic arthritis. Arthritis Rheum 2008, 58:1833-8.
104. Ahn JK, Koh EM, Cha HS, Lee YS, Kim J, Bae EK, Ahn KS. Role of hypoxia-inducible factor-1alpha in hypoxia-induced expressions of IL-8, MMP-1 and MMP-3 in rheumatoid fibroblast-like synoviocytes. Rheumatology (Oxford) 2008, 47:834-9.
105. Pfander D, Gelse K. Hypoxia and osteoarthritis: how chondrocytes survive hypoxic environments. Curr Opin Rheumatol 2007, 19:457-62.
106. Hashimoto A, Tarner IH, Bohle RM, Gaumann A, Manetti M, Distler O, Steinmeyer J, Ulfgren AK, Schulz A, Gay S, Muller-Ladner U, Neumann E. Analysis of vascular gene expression in arthritic synovium by laser-mediated microdissection. Arthritis Rheum 2007, 56:1094-105.
107. Peters CL, Morris CJ, Mapp PI, Blake DR, Lewis CE, Winrow VR. The transcription factors hypoxia-inducible factor 1alpha and Ets-1 colocalize in the hypoxic synovium of inflamed joints in adjuvant-induced arthritis. Arthritis Rheum 2004, 50:291-6.
108. Makino Y, Nakamura H, Ikeda E, Ohnuma K, Yamauchi K, Yabe Y, Poellinger L, Okada Y, Morimoto C, Tanaka H. Hypoxia-inducible factor regulates survival of antigen receptor-driven T cells. J Immunol 2003, 171:6534-40.
109. Giatromanolaki A, Sivridis E, Maltezos E, Athanassou N, Papazoglou D, Gatter KC, Harris AL, Koukourakis MI. Upregulated hypoxia inducible factor-1alpha and -2alpha pathway in rheumatoid arthritis and osteoarthritis. Arthritis Res Ther 2003, 5:R193-201.
110. Thornton RD, Lane P, Borghaei RC, Pease EA, Caro J, Mochan E. Interleukin 1 induces hypoxia-inducible factor 1 in human gingival and synovial fibroblasts. Biochem J 2000, 1:307-12.
111. Akhavani MA, Madden L, Buysschaert I, Sivakumar B, Kang N, Paleolog EM. Hypoxia upregulates angiogenesis and synovial cell migration in rheumatoid arthritis. Arthritis Res Ther 2009, 11:R64.
112. Hollander AP, Corke KP, Freemont AJ, Lewis CE. Expression of hypoxia-inducible factor 1alpha by macrophages in the rheumatoid synovium: implications for targeting of therapeutic genes to the inflamed joint. Arthritis Rheum 2001, 44:1540-4.
113. Boyce BF, Xing L. Biology of RANK, RANKL, and osteoprotegerin. Arthritis Res Ther 2007, 9(Suppl. 1):S1.
114. Anandarajah AP. Role of RANKL in bone diseases. Trends Endocrinol Metab 2009, 20:88-94.
115. Zannettino AC, Holding CA, Diamond P, Atkins GJ, Kostakis P, Farrugia A, Gamble J, To LB, Findlay DM, Haynes DR. Osteoprotegerin (OPG) is localized to the Weibel-Palade bodies of human vascular endothelial cells and is physically associated with von Willebrand factor. J Cell Physiol 2005, 204:714-23.
116. Shahbazi S, Lenting PJ, Fribourg C, Terraube V, Denis CV, Christophe OD. Characterization of the interaction between von Willebrand factor and osteoprotegerin. J Thromb Haemost 2007, 5:1956-62.
117. Hakobyan N, Kazarian T, Valentino LA. Synovitis in a murine model of human factor VIII deficiency. Haemophilia 2005, 11:227-32.
118. Dhaouadi T, Sfar I, Abelmoula L, Jendoubi-Ayed S, Aouadi H, Ben Abdellah T, Ayed K, Zouari R, Gorgi Y. Role of immune system, apoptosis and angiogenesis in pathogenesis of rheumatoid arthritis and joint destruction, a systematic review. Tunis Med 2007, 85:991-8.
119. Gravallese EM. Bone destruction in arthritis. Ann Rheum Dis 2002, 61(Suppl. 2):ii84-6.
120. Vega D, Maalouf NM, Sakhaee K. CLINICAL Review #: the role of receptor activator of nuclear factor-kappaB (RANK)/RANK ligand/osteoprotegerin: clinical implications. J Clin Endocrinol Metab 2007, 92:4514-21.
121. Manolagas SC. Cell number versus cell vigor - what really matters to a regenerating skeleton? Endocrinology 1999, 140:4377-81.
122. Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 2000, 21:115-37.
123. Katagiri T, Takahashi N. Regulatory mechanisms of osteoblast and osteoclast differentiation. Oral Dis 2002, 8:147-59.
124. Xu G, Sun W, He D, Wang L, Zheng W, Nie H, Ni L, Zhang D, Li N, Zhang J. Overexpression of osteopontin in rheumatoid synovial mononuclear cells is associated with joint inflammation, not with genetic polymorphism. J Rheumatol 2005, 32:410-16.
125. Poubelle PE, Chakravarti A, Fernandes MJ, Doiron K, Marceau AA. Differential expression of RANK, RANK-L, and osteoprotegerin by synovial fluid neutrophils from patients with rheumatoid arthritis and by healthy human blood neutrophils. Arthritis Res Ther 2007, 9:R25.
126. Kawanaka N, Yamamura M, Aita T, Morita Y, Okamoto A, Kawashima M, Iwahashi M, Ueno A, Ohmoto Y, Makino H. CD14+,CD16+ blood monocytes and joint inflammation in rheumatoid arthritis. Arthritis Rheum 2002, 46:2578-86.
127. Lorenzo J, Horowitz M, Choi Y. Osteoimmunology: interactions of the bone and immune system. Endocr Rev 2008, 29:403-40.
128. Yao Z, Li P, Zhang Q, Schwarz EM, Keng P, Arbini A, Boyce BF, Xing L. Tumor necrosis factor-alpha increases circulating osteoclast precursor numbers by promoting their proliferation and differentiation in the bone marrow through up-regulation of c-Fms expression. J Biol Chem 2006, 281:11846-55.
129. Zhang Q, Guo R, Schwarz EM, Boyce BF, Xing L. TNF inhibits production of stromal cell-derived factor 1 by bone stromal cells and increases osteoclast precursor mobilization from bone marrow to peripheral blood. Arthritis Res Ther 2008, 10:R37.