Evaluación de los niveles de la proteína Dickkopf- 1 (Dkk-1) y su asociación con índices de actividad clínica reumática en pacientes con Artritis Reumatoide temprana
La artritis reumatoide (AR) es una enfermedad de naturaleza autoinmune sistémica, se caracteriza por un estado de inflamación crónico, discapacidad progresiva, daño osteoarticular y consecuencias socioeconómicas de gran impacto en la calidad de vida del paciente. La determinación de la AR en etapas...
- Autores:
-
Arias Arias, Angela Miyared
- Tipo de recurso:
- Trabajo de grado de pregrado
- Fecha de publicación:
- 2018
- Institución:
- Colegio Mayor de Cundinamarca
- Repositorio:
- Repositorio Colegio Mayor de Cundinamarca
- Idioma:
- spa
- OAI Identifier:
- oai:repositorio.unicolmayor.edu.co:unicolmayor/3762
- Acceso en línea:
- https://repositorio.unicolmayor.edu.co/handle/unicolmayor/3762
- Palabra clave:
- Enfermedad
Naturaleza autoinmune
EULAR/ACR
Artritis reumatoide
Proteína DKK-1
- Rights
- closedAccess
- License
- Universidad Colegio Mayor de Cundinamarca, 2018
id |
UCOLMAYOR2_7f3f733157c8b0346f166c2171394b8f |
---|---|
oai_identifier_str |
oai:repositorio.unicolmayor.edu.co:unicolmayor/3762 |
network_acronym_str |
UCOLMAYOR2 |
network_name_str |
Repositorio Colegio Mayor de Cundinamarca |
repository_id_str |
|
dc.title.spa.fl_str_mv |
Evaluación de los niveles de la proteína Dickkopf- 1 (Dkk-1) y su asociación con índices de actividad clínica reumática en pacientes con Artritis Reumatoide temprana |
title |
Evaluación de los niveles de la proteína Dickkopf- 1 (Dkk-1) y su asociación con índices de actividad clínica reumática en pacientes con Artritis Reumatoide temprana |
spellingShingle |
Evaluación de los niveles de la proteína Dickkopf- 1 (Dkk-1) y su asociación con índices de actividad clínica reumática en pacientes con Artritis Reumatoide temprana Enfermedad Naturaleza autoinmune EULAR/ACR Artritis reumatoide Proteína DKK-1 |
title_short |
Evaluación de los niveles de la proteína Dickkopf- 1 (Dkk-1) y su asociación con índices de actividad clínica reumática en pacientes con Artritis Reumatoide temprana |
title_full |
Evaluación de los niveles de la proteína Dickkopf- 1 (Dkk-1) y su asociación con índices de actividad clínica reumática en pacientes con Artritis Reumatoide temprana |
title_fullStr |
Evaluación de los niveles de la proteína Dickkopf- 1 (Dkk-1) y su asociación con índices de actividad clínica reumática en pacientes con Artritis Reumatoide temprana |
title_full_unstemmed |
Evaluación de los niveles de la proteína Dickkopf- 1 (Dkk-1) y su asociación con índices de actividad clínica reumática en pacientes con Artritis Reumatoide temprana |
title_sort |
Evaluación de los niveles de la proteína Dickkopf- 1 (Dkk-1) y su asociación con índices de actividad clínica reumática en pacientes con Artritis Reumatoide temprana |
dc.creator.fl_str_mv |
Arias Arias, Angela Miyared |
dc.contributor.advisor.none.fl_str_mv |
Romero Sánchez, María Consuelo Chila Moreno, Leidy Lorena Navarrete, Janeth |
dc.contributor.author.none.fl_str_mv |
Arias Arias, Angela Miyared |
dc.contributor.corporatename.spa.fl_str_mv |
Universidad Colegio Mayor de Cundinamarca |
dc.subject.lemb.none.fl_str_mv |
Enfermedad Naturaleza autoinmune EULAR/ACR |
topic |
Enfermedad Naturaleza autoinmune EULAR/ACR Artritis reumatoide Proteína DKK-1 |
dc.subject.proposal.spa.fl_str_mv |
Artritis reumatoide Proteína DKK-1 |
description |
La artritis reumatoide (AR) es una enfermedad de naturaleza autoinmune sistémica, se caracteriza por un estado de inflamación crónico, discapacidad progresiva, daño osteoarticular y consecuencias socioeconómicas de gran impacto en la calidad de vida del paciente. La determinación de la AR en etapas tempranas de la enfermedad puede predecir desenlaces del trastorno y así disminuir daños irreversibles. La EULAR/ACR establecieron en el año 2010 una serie de criterios clínicos clasificatorios y pruebas de laboratorio que incluyen el Factor Reumatoide (FR) y los anticuerpos anti-proteínas citrulinadas (anti-CCP), los cuales están asociados a la actividad de la enfermedad y al pronóstico de la misma. La identificación de nuevos biomarcadores que puedan asociarse a manifestaciones en estadios tempranos de le enfermedad ha cobrado gran interés, ya que hay pacientes que presentan niveles muy bajos o indetectables de FR y anti-CCP aun así presentando un elevado daño articular, dificultando el diagnóstico y las posibles opciones terapéuticas. La proteína Dickkopf-1 (DKK-1) es un regulador de la masa ósea y remodelación articular, se ha evidenciado su aumento a nivel sérico en presencia de resorción ósea, asociándose a un elevado valor predictivo en el desarrollo y severidad de la enfermedad. En el presente estudio se pretende establecer los niveles de la proteína DKK-1 en pacientes con diagnóstico de AR temprana y su asociación con índices de actividad clínica reumática, con el fin de determinar las condiciones que asocian la presencia de la DKK-1 y sus posibles capacidades de pronóstico durante el curso de la enfermedad. |
publishDate |
2018 |
dc.date.issued.none.fl_str_mv |
2018-05-31 |
dc.date.accessioned.none.fl_str_mv |
2021-12-02T21:11:52Z |
dc.date.available.none.fl_str_mv |
2021-12-02T21:11:52Z |
dc.type.spa.fl_str_mv |
Trabajo de grado - Pregrado |
dc.type.coar.spa.fl_str_mv |
http://purl.org/coar/resource_type/c_7a1f |
dc.type.coarversion.spa.fl_str_mv |
http://purl.org/coar/version/c_970fb48d4fbd8a85 |
dc.type.content.spa.fl_str_mv |
Text |
dc.type.driver.spa.fl_str_mv |
info:eu-repo/semantics/bachelorThesis |
dc.type.redcol.spa.fl_str_mv |
https://purl.org/redcol/resource_type/TP |
dc.type.version.spa.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
format |
http://purl.org/coar/resource_type/c_7a1f |
status_str |
publishedVersion |
dc.identifier.uri.none.fl_str_mv |
https://repositorio.unicolmayor.edu.co/handle/unicolmayor/3762 |
dc.identifier.barcode.none.fl_str_mv |
58425 |
url |
https://repositorio.unicolmayor.edu.co/handle/unicolmayor/3762 |
identifier_str_mv |
58425 |
dc.language.iso.spa.fl_str_mv |
spa |
language |
spa |
dc.relation.references.spa.fl_str_mv |
McInnes I. The Pathogenesis of Rheumatoid Arthritis. N Engl J Med. 2011;365:2205–19. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/ European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569-2581. Helmick CG, Felson DT, Lawrence RC, et al; National Arthritis Data Workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58(1):15-25 Schellekens GA, De Jong BAW, Van Den Hoogen FHJ, Van De Putte LBA, Van Venrooij WJ. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest. 1998;101(1):273–81 Mc Ardle A, Flatley B, Pennington SR, FitzGerald O. Early biomarkers of joint damage in rheumatoid and psoriatic arthritis. Arthritis Res Ther. 2015;17:141. Chou C, Liao H, Chen C, Chen W, Wang H, Su K. The Clinical Application of Anti-CCP in Rheumatoid Arthritis and Other Rheumatic Diseases. Biomark Insights. 2007;2(201):165–71 Brink M, Verheul MK, Rönnelid J, Berglin E, Holmdahl R, Toes REM, et al. Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage. Arthritis Res Ther. 2015;17:25 Seror R, Boudaoud S, Pavy S, Nocturne G, Schaeverbeke T, Saraux A, et al. Increased Dickkopf-1 in Recent-onset Rheumatoid Arthritis is a New Biomarker of Structural Severity. Data from the ESPOIR Cohort. Sci Rep. 2016;6(November 2015):18421. Burska A, Boissinot M, Ponchel F. Cytokines as biomarkers in rheumatoid arthritis. Mediators Inflamm. 2014;2014. Chang K, Yang SM, Kim SH, Han KH, Park SJ, Shin J Il. Smoking and rheumatoid arthritis. Int J Mol Sci. 2014;15(12):22279–95. García-Arias M, Pascual-Salcedo D, Ramiro S, Ueberschlag M-E, Jermann TM, Cara C, et al. Calprotectin in rheumatoid arthritis : association with disease activity in a cross-sectional and a longitudinal cohort. Mol Diagn Ther [Internet]. 2013;17(1):49–56 Aho K, Palosuo T, Raunio V, Puska P, Aromaa A, Salonen JT. When does rheumatoid disease start? Arthritis Rheum. 1985;28(5):485–9. Berglin E, Padyukov L, Sundin U, Hallmans G, Stenlund H, Van Venrooij WJ, et al. A combination of autoantibodies to cyclic citrullinated peptide (CCP) and. Arthritis Res Ther. 2004;6(4):R303-308 Fuggle NR, Smith TO, Kaul A, Sofat N. Hand to mouth: A systematic review and meta-analysis of the association between rheumatoid arthritis and periodontitis. Front Immunol. 2016;7(MAR) Pecani A, Alessandri C, Spinelli FR, Colasanti T, Pendolino M, Barbati C, et al. Prevalence, sensitivity and specificity of antibodies against carbamylated proteins in a large cohort of Italian rheumatoid arthritis patients. Ann Rheum Dis. 2016;75:675. Shi J, van Steenbergen HW, van Nies JAB, Levarht EWN, Huizinga TWJ, van der Helm-van Mil AHM, et al. The specificity of anti-carbamylated protein antibodies for rheumatoid arthritis in a setting of early arthritis. Arthritis Res Ther. 2015;17(1):339. Daoussis D, Andonopoulos AP. The Emerging Role of Dickkopf-1 in Bone Biology: Is It the Main Switch Controlling Bone and Joint Remodeling? Semin Arthritis Rheum. 2011;41(2):170–7. Diarra D, Stolina M, Polzer K, Zwerina J, Ominsky MS, Dwyer D, et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med. 2007;13(2):156–63 Wang SY, Liu YY, Ye H, Guo JP, Li RU, Liu X, et al. Circulating dickkopf-1 is correlated with bone erosion and inflammation in rheumatoid arthritis. J Rheumatol. 2011;38(5):821–7. de Rooy DPC, Yeremenko NG, Wilson AG, Knevel R, Lindqvist E, Saxne T, et al. Genetic studies on components of the Wnt signalling pathway and the severity of joint destruction in rheumatoid arthritis. Ann Rheum Dis. 2013;72(5):769–75. Kahlenberg JM, Fox DA. Advances in the medical treatment of rheumatoid arthritis. Vol. 27, Hand Clinics. 2011. p. 11–20 .Silman AJ, Pearson JE. Epidemiology and genetics of rheumatoid arthritis. Arthritis Res. 2002;4(suppl 3):S265-S272.) Anaya JM.Genes y artritis reumatoidea. Rev ColombReumatol 1999;6:24050 Verheijden GFM, Rijnders AWM, Bos E, Coenen-deRoo CJJ, van Staveren CJ, Miltenburg AMM, et al.Human cartilage glycoprotein-39 as a candidateautoantigen in rheumatoid arthritis. Arthritis Rheum 1999; 40:1115- 25. Shi J, Knevel R, Suwannalai P, van der Linden MP, Janssen GMC, van Veelen P a., et al. Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage. Proc Natl Acad Sci. 2011;108(42):17372–7 Gerlag DM, Raza K, van Baarsen LGM, Brouwer E, Buckley CD, Burmester GR, et al. EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the Study Group for Risk Factors for Rheumatoid Arthritis. Ann Rheum Dis. 2012;71(5):638–41 Francesca Ingegnoli, Roberto Castelli, Roberta Gualtierotti. Rheumatoid Factors: Clinical Applications. Dis Markers. 2013; 35(6): 727–734 Y.W. Song E.H. Kang. Autoantibodies in rheumatoid arthritis: rheumatoid factors and anticitrullinated protein antibodies. QJM: An International Journal of Medicine, Volume 103, Issue 3, 1 March 2010, Pages 139–146 O. M. R. Westwood P. N. Nelson F. C. Hay. Rheumatoid factors: what's new? Rheumatology, Volume 45, Issue 4, 1 April 2006, Pages 379–385 Haberman AM, William J, Euler C, Shlomchik MJ. Rheumatoid factors in health and disease: structure, function, induction and regulation. Current Directions in Autoimmunity. 2003;6:169–195 Annette HM van der Helm-van Mil, Kirsten N Verpoort, Ferdinand C Breedveld, René EM Toes, Tom WJ Huizinga. Antibodies to citrullinated proteins and differences in clinical progression of rheumatoid arthritis. Arthritis Res Ther. 2005; 7(5): R949–R958. Kroot EJ et al. The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis. Arthritis Rheum. 2000 Aug;43(8):1831-5 D M Lee, P H Schur. Clinical utility of the anti-CCP assay in patients with rheumatic diseases. Ann Rheum Dis 2003;62:870–874 Masson-Bessière C, Sebbag M, Girbal-Neuhauser E, Nogueira L, Vincent C. Vossenaar ER1, Zendman AJ, van Venrooij WJ, Pruijn GJ. PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease. Valesini G, Gerardi MC, Iannuccelli C, Pacucci VA, Pendolino M, Shoenfeld Y. Citrullination and autoimmunity. Autoimmun Rev [Internet]. 2015 Jun;14(6):490–7 .Linn-Rasker SP. Smoking is a risk factor for anti-CCP antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles. Ann Rheum Dis [Internet]. 2006 Mar 1;65(3):366–71. .Pedersen M, Jacobsen S, Garred P, Madsen HO, Klarlund M, Svejgaard A, et al. Strong combined gene–environment effects in anti–cyclic citrullinated peptide–positive rheumatoid arthritis: A nationwide case–control study in Denmark. Arthritis Rheum [Internet]. 2007 May;56(5):1446–53. Senshu T, et al. The major synovial targets of the rheumatoid arthritisspecific antifilaggrin autoantibodies are deiminated forms of the alpha- and beta-chains of fibrin. J Immunol. 2001;166:4177–84 Koivula MK, Aman S, Karjalainen A, Hakala M, Risteli J. Are there autoantibodies reacting against citrullinated peptides derived from type I and type II collagens in patients with rheumatoid arthritis? Ann Rheum Dis. 2005;64:1443–50. Vossenaar ER, Despres N, Lapointe E, van der Heijden A, Lora M, Senshu T, et al. Rheumatoid arthritis specific anti-Sa antibodies target citrullinated vimentin. Arthritis Res Ther. 2004;6:R142–50 Zeneng Wang et al. Protein carbamylation links inflammation, smoking, uremia and atherogenesis. Nature Medicine 13, 1176 - 1184 (2007) Jing Shi et al. Carbamylation and antibodies against carbamylated proteins in autoimmunity and other pathologies. Autoimmunity Reviews 13 (2014) 225–230 . Arbi Pecani et al. Prevalence, sensitivity and specificity of antibodies against carbamylated proteins in a monocentric cohort of patients with rheumatoid arthritis and other autoimmune rheumatic diseases. Arthritis Res Ther. 2016; 18: 276 Trouw LA, Mahler M. Closing the serological gap: promising novel biomarkers for the early diagnosis of rheumatoid arthritis. Autoimmun Rev. 2012 Dec; 12(2):318-22 M. Holzer, K. Zangger, D. El-Gamal, V. Binder, S. Curcic, V. Konya, et al.Myeloperoxidase-derived chlorinating species induce protein carbamylation through decomposition of thiocyanate and urea: novel pathways generating dysfunctional high-density lipoprotein Antioxid Redox Signal, 17 (2012), pp. 1043-1052 Nzeusseu Toukap A et al. Myeloperoxidase and its products in synovial fluid of patients with treated or untreated rheumatoid arthritis. Free Radic Res. 2014 Apr; 48(4):461-5. Z. Prokopowicz, J. Marcinkiewicz, D.R. Katz, B.M. Chain. Neutrophil myeloperoxidase: soldier and statesman. Arch Immunol Ther Exp (Warsz), 60 (2012), pp. 43-54 Pepys MB, Baltz ML. Acute phase proteins with special reference to Creactive protein and related proteins (pentaxins) and serum amyloid A protein. Adv Immunol. 1983; 34():141-212 Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003 Jun; 111(12):1805-12 Harnett W, Harnett MM. Phosphorylcholine: friend or foe of the immune system? Immunol Today. 1999 Mar; 20(3):125-9. Volanakis JE, Wirtz KW. Interaction of C-reactive protein with artificial phosphatidylcholine bilayers. Nature. 1979 Sep 13; 281(5727):155-7 Gershov D, Kim S, Brot N, Elkon KB. C-Reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinflammatory innate immune response: implications for systemic autoimmunity. J Exp Med. 2000 Nov 6; 192(9):1353-64. Pepys MB, Rowe IF, Baltz ML. C-reactive protein: binding to lipids and lipoproteins. Int Rev Exp Pathol. 1985; 27:83-111. CarolynMold, HenryGewurz, Terry W Du Closbd. Regulation of complement activation by C-reactive protein. Immunopharmacology. 1999 May;42(13):23-30. Katherine B Bodman-Smith et al. C-reactive protein-mediated phagocytosis and phospholipase D signalling through the high-affinity receptor for immunoglobulin G (FcγRI). Immunology. 2002 Oct; 107(2): 252–260. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999 Feb 11; 340(6):448-54 Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999 Jan 14; 340(2):115-26 Renuka Devi Ramamoorthy, Vijaykumar Nallasamy, Raghavendra Reddy, Nalini Esther, Yuvaraja Maruthappan. A review of C-reactive protein: A diagnostic indicator in periodontal medicine. J Pharm Bioallied Sci. 2012 Aug; 4(Suppl 2): S422–S426 Nancy A. Shadick et al. C-Reactive Protein in the Prediction of Rheumatoid Arthritis in Women. Arch Intern Med. 2006;166(22):2490-2494 Tishler MCaspi DYaron M C-reactive protein levels in patients with rheumatoid arthritis: the impact of therapy. Clin Rheumatol 1985;4321- 324 Kyoung-Woon Kim, Bo-Mi Kim, Hee-Won Moon, Sang-Heon Lee and HaeRim Kim. Role of C-reactive protein in osteoclastogenesis in rheumatoid arthritis. Arthritis Research & Therapy201517:41. Masi ATAldag JCSipes J Do elevated levels of serum C-reactive protein predict rheumatoid arthritis in men: correlations with pre-RA status and baseline positive rheumatoid factors. J Rheumatol 2001;282359- 2361 Schett, G, & Gravallese, E. Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev. Rheum 2012;8(11): 656– 664 Karsenty G, Kronenberg HM, Settembre C. Genetic control of bone formation. Annu. Rev. Cell. Dev. Biol. 2009; 25:629–648 Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003; 423:337–342 Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function. Nat. Rev. Genet. 2003;4:638–649 Firestein GS, et al. Cytokines in chronic inflammatory arthritis. I. Failure to detect T cell lymphokines (interleukin 2 and interleukin 3) and presence of macrophage colony-stimulating factor (CSF-1) and a novel mast cell growth factor in rheumatoid synovitis. J. Exp. Med. 1988;168:1573–1586 Gravallese EM, et al. Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum. 2000;43:250–258. Shigeyama Y, et al. Expression of osteoclast differentiation factor in rheumatoid arthritis. Arthritis Rheum. 2000;43:2523–2530. Visser H, le Cessie S, Vos K, Breedveld FC, Hazes JM. How to diagnose rheumatoid arthritis early: a prediction model for persistent (erosive) arthritis. Arthritis Rheum. 2002;46:357–365. Kastbom A, Strandberg G, Lindroos A, Skogh T. Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project) Ann. Rheum. Dis. 2004;63:1085– 1089. Meyer O, et al. Anticitrullinated protein/peptide antibody assays in early rheumatoid arthritis for predicting five year radiographic damage. Ann. Rheum. Dis. 2003;62:120–126. Schett G, Saag KG, Bijlsma JW. From bone biology to clinical outcome: state of the art and future perspectives. Ann. Rheum. Dis. 2010;69:1415– 1419. Harre U, et al. Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J. Clin. Invest. 2012;122:1791– 1802. Walsh NC1, Gravallese EM. Bone remodeling in rheumatic disease: a question of balance. Immunol Rev. 2010 Jan;233(1):301-12 Machold, K., Stamm, T., Nell, V., Pflugbeil, S., Aletaha, D., Steiner, G., Uffmann, M. and Smolen, J. (2006). Very recent onset rheumatoid arthritis: clinical and serological patient characteristics associated with radiographic progression over the first years of disease. Rheumatology, 46(2), pp.342349. habet MM, Huizinga TW, van der Heijde DM, van der Helm-van Mil AH. The prognostic value of baseline erosions in undifferentiated arthritis. Arthritis Res Ther 2009; 11:R155 Miao CG et al. Wnt signaling pathway in rheumatoid arthritis, with special emphasis on the different roles in synovial inflammation and bone remodeling. Cell Signal. 2013 Oct;25(10):2069-78. Li J, Sarosi I, Cattley RC, Pretorius J, Asuncion F, Grisanti M et al. Dkk1mediated inhibition of Wnt signaling in bone results in osteopenia. Bone. 2006;39(4):754-66. M. Sen. Wnt signalling in rheumatoid arthritis. Rheumatology, 44 (2005), pp–713 Daoussis Dimitrios, et al. Evidence That Dkk-1 Is Dysfunctional in Ankylosing Spondylitis. Arthritis & Rheumatism. 2010; 62 (1): 150–158 de Rooy DP, Yeremenko NG, Wilson AG, et al. Genetic studies on components of the Wnt signalling pathway and the severity of joint destruction in rheumatoid arthritis. Ann Rheum Dis 2013;72:769–75. Nusse R., Varmus H.E. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell (1982) 31:99–109 Van Ooyen A., Nusse R. Structure and nucleotide sequence of the putative mammary oncogene int-1; proviral insertions leave the protein-encoding domain intact. Cell (1984) 39:233–240. Cabrera C.V., Alonso M.C., Johnston P., Phillips R.G., Lawrence P.A. (1987) Phenocopies induced with antisense RNA identify the wingless gene. Cell 50:659–663. Miller JR. The Wnts. Genome Biol, 3 (2002), pp. reviews3001 Wodarz A,Nusse R. Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol, 14 (1998), pp. 59-88 Ken M. Cadigan, Roel Nusse. Wnt signaling: a common theme in animal development. Genes & Dev. 1997. 11:3286-3305 M. Sen. Wnt signalling in rheumatoid arthritis. Rheumatology, 44 (2005), pp–713 Cheng-gui Miao et al, Wnt signaling pathway in rheumatoid arthritis, with special emphasis on the different roles in synovial inflammation and bone remodeling. Cell Signal 2013;25:2069-2078 Michael D. Gordon, Roel Nusse. Wnt signaling: multiple phathways, multiple receptors, and multiple transcription factors. The Journal of Biological Chemistry 2006 281, 22429-22433. Velasco J, Riancho J. La vía Wnt y el hueso. Rev Esp Enferm metab oseas 2008;117:5-9 Niehrs C. Function and biological roles of the Dickkopf family of Wnt modulators. Oncogene, 25 (2006), pp. 7469-81 Danielle Diarra et al. Dickkopf-1 is a master regulator of joint remodeling. Nature medicine 2007 Glinka A, Wu W, Dellus H, Monaghan P, Blumenstock C, Niehrs C. Dickkopf1 is a member of a new family of secreted proteins and functions in head induction. Nature 1998;391:357-362 Bafico A1, Liu G, Yaniv A, Gazit A, Aaronson SA. Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow. Nat Cell Biol. 2001 Jul;3(7):683-6. Prevoo ML et al. Modified disease activity scores that include twentyeightjoint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995 Jan;38(1):44-8. Karsenty G, Kronenberg HM, Settembre C. Genetic control of bone formation. Annu. Rev. Cell. Dev. Biol. 2009; 25:629–648 Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003; 423:337–342 Dias E, Lukas C, Landewe R, Fatenejad S, van der Heijde D. Reliability and sensitivity to change of the Simple Erosion Narrowing Score compared with the Sharp-van der Heijde method for scoring radiographs in rheumatoid arthritis. 2018 Chaparro del Moral R, Rillo O, Casalla L, Morón C, Citera G, Cocco J et al. Work Productivity in Rheumatoid Arthritis: Relationship with Clinical and Radiological Features. Arthritis. 2012;2012:1-7. Garnero P, Tabassi N, Voorzanger-Rousselot N. Circulating Dickkopf1 and Radiological Progression in Patients with Early Rheumatoid Arthritis Treated with Etanercept. The Journal of Rheumatology. 2008;35(12):2313. Gómez-Vaquero C, Martín I, Loza E, Carmona L, Ivorra J, Narváez JA et al. Effect of Osteoprotegerin and Dickkopf-Related Protein 1 on Radiological Progression in Tightly Controlled Rheumatoid Arthritis. PLoS One. 2016;11(12):e0166691 Harris ED Jr. Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med 1990;322:1277–89. Baratelle AM, van der Heijde D. Radiographic imaging end points in rheumatoid arthritis trials. In: Reid DM, Miller CG, editors. Clinical trials in rheumatoid arthritis and osteoarthritis. London: Springer-Verlag, 2008:201– 21. Kahlenberg J. Michelle , M.D., Ph.D.a and David A. Fox M. Advances in the Medical Treatment of Rheumatoid Arthritis. NIH Public Access. 2011;27(1):11–20. Wilder RL, Sternberg EM. Neuroendocrine hormonal factors in rheumatoid arthritis and related conditions. Curr Opin Rheumatol [Internet]. 1990 Jun;2(3):436–40 Ahmed SA, Hissong BD, Verthelyi D, Donner K, Becker K, KarpuzogluSahin E. Gender and risk of autoimmune diseases: Possible role of estrogenic compounds. Environ Health Perspect. 1999;107(SUPPL. 5):681–6. THU0070 RANKL, OPG and OSCAR but Not Dkk-1 Predict Radiographic Progression in An Inception Cohort of Seropositive Rheumatoid Arthritis (RA) Treated-To-Target with Combination Conventional DMARD Therapy. 2018. Rossini M, Viapiana O, Adami S, Fracassi E, Idolazzi L, Dartizio C et al. In patients with rheumatoid arthritis, Dickkopf-1 serum levels are correlated with parathyroid hormone, bone erosions and bone mineral density. Clin Exp Rheumatol. 2015;33(1):77-83 Leech MT, Bartold PM. The association between rheumatoid arthritis and periodontitis. Best Pract Res Clin Rheumatol. 2015;29(2):189– 201. Pischon N, Pischon T, Kröger J, Gülmez E, Kleber B-M, Bernimoulin J-P, et al. Association among rheumatoid arthritis, oral hygiene, and periodontitis. J Periodontol. 2008;79(6):979–86. Äyräväinen L, Leirisalo-Repo M, Kuuliala A, Ahola K, Koivuniemi R, Meurman JH, et al. Periodontitis in early and chronic rheumatoid arthritis: a prospective follow-up study in Finnish population. BMJ Open [Internet]. 2017;7(1):e011916 Pons-Fuster A et al. Clinical evaluation of periodontal disease in patients with rheumatoid arthritis: A cross-sectional study. Quintessence Int. 2015;46:817-22 Scher J et al. Periodontal disease and the oral microbiota in newonset rheumatoid arthritis. Arthritis Rheumatol 2012;64:3083-309 Napimoga M, Nametala C, Silva F et al. Involvement of the Wntβcatenin signalling antagonists, sclerostin and dickkopf-related protein 1, in chronic periodontitis. J Clin Periodontol; 2014;41:550–7 Bello-Gualtero J, etal. Periodontal disease in subjects with genetic risk to develop arthritis and early rheumatoid arthritis: a cross sectional study. J periodontol 2016;87:346-456. |
dc.rights.spa.fl_str_mv |
Universidad Colegio Mayor de Cundinamarca, 2018 |
dc.rights.uri.spa.fl_str_mv |
https://creativecommons.org/licenses/by-nc-sa/4.0/ |
dc.rights.accessrights.spa.fl_str_mv |
info:eu-repo/semantics/closedAccess |
dc.rights.creativecommons.spa.fl_str_mv |
Atribución-NoComercial-CompartirIgual 4.0 Internacional (CC BY-NC-SA 4.0) |
dc.rights.coar.spa.fl_str_mv |
http://purl.org/coar/access_right/c_14cb |
rights_invalid_str_mv |
Universidad Colegio Mayor de Cundinamarca, 2018 https://creativecommons.org/licenses/by-nc-sa/4.0/ Atribución-NoComercial-CompartirIgual 4.0 Internacional (CC BY-NC-SA 4.0) http://purl.org/coar/access_right/c_14cb |
eu_rights_str_mv |
closedAccess |
dc.format.extent.spa.fl_str_mv |
73p. |
dc.format.mimetype.spa.fl_str_mv |
application/pdf |
dc.publisher.spa.fl_str_mv |
Universidad Colegio Mayor de Cundinamarca |
dc.publisher.faculty.spa.fl_str_mv |
Facultad de Ciencias de la Salud |
dc.publisher.place.spa.fl_str_mv |
Bogotá D.C |
dc.publisher.program.spa.fl_str_mv |
Bacteriología y Laboratorio Clínico |
institution |
Colegio Mayor de Cundinamarca |
bitstream.url.fl_str_mv |
https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3762/1/presentaci%c3%b3n-sustentaci%c3%b3n-angelaarias.%20artrits.pdf https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3762/2/PROYECTO%20ArtritisDKK-1%20Angela-Arias%20Cartas%20Derechos%20de%20Autor.pdf https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3762/3/PROYECTO%20ArtritisDKK-1%20Angela-Arias..pdf https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3762/4/license.txt https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3762/5/presentaci%c3%b3n-sustentaci%c3%b3n-angelaarias.%20artrits.pdf.txt https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3762/7/PROYECTO%20ArtritisDKK-1%20Angela-Arias%20Cartas%20Derechos%20de%20Autor.pdf.txt https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3762/9/PROYECTO%20ArtritisDKK-1%20Angela-Arias..pdf.txt https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3762/6/presentaci%c3%b3n-sustentaci%c3%b3n-angelaarias.%20artrits.pdf.jpg https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3762/8/PROYECTO%20ArtritisDKK-1%20Angela-Arias%20Cartas%20Derechos%20de%20Autor.pdf.jpg https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3762/10/PROYECTO%20ArtritisDKK-1%20Angela-Arias..pdf.jpg |
bitstream.checksum.fl_str_mv |
0ade6161367f13862e80edba8415b460 4319bcc1d98a124144e1905dcd8ecc0f 4366de7171eb44077e9248b745d362ff 2f9959eaf5b71fae44bbf9ec84150c7a 5392cb208dc04be25aaef3012f6dc54f f9a8e002ebec227d74399f9906f369c3 a1e0587ff7cd57a076dde4040eeab2ce 69b763e29c478617c351993a8e254cf6 222a742d0efebae6fb2e9283f7756ba2 4482ac8d595cf0362aaa55b676c13917 |
bitstream.checksumAlgorithm.fl_str_mv |
MD5 MD5 MD5 MD5 MD5 MD5 MD5 MD5 MD5 MD5 |
repository.name.fl_str_mv |
Biblioteca Digital Unicolmayor |
repository.mail.fl_str_mv |
repositorio@unicolmayor.edu.co |
_version_ |
1812210059607801856 |
spelling |
Romero Sánchez, María Consueloadef63ccda8465428682bb4b85aab02bChila Moreno, Leidy Lorena4cf9279b88e653b3ab1a8b78e5bf2628Navarrete, Janeth4db39dabcf90619f3d41a1c08ebe945eArias Arias, Angela Miyaredd0fea736c2f4721a15b58d7cb1ea1f34Universidad Colegio Mayor de Cundinamarca2021-12-02T21:11:52Z2021-12-02T21:11:52Z2018-05-31https://repositorio.unicolmayor.edu.co/handle/unicolmayor/376258425La artritis reumatoide (AR) es una enfermedad de naturaleza autoinmune sistémica, se caracteriza por un estado de inflamación crónico, discapacidad progresiva, daño osteoarticular y consecuencias socioeconómicas de gran impacto en la calidad de vida del paciente. La determinación de la AR en etapas tempranas de la enfermedad puede predecir desenlaces del trastorno y así disminuir daños irreversibles. La EULAR/ACR establecieron en el año 2010 una serie de criterios clínicos clasificatorios y pruebas de laboratorio que incluyen el Factor Reumatoide (FR) y los anticuerpos anti-proteínas citrulinadas (anti-CCP), los cuales están asociados a la actividad de la enfermedad y al pronóstico de la misma. La identificación de nuevos biomarcadores que puedan asociarse a manifestaciones en estadios tempranos de le enfermedad ha cobrado gran interés, ya que hay pacientes que presentan niveles muy bajos o indetectables de FR y anti-CCP aun así presentando un elevado daño articular, dificultando el diagnóstico y las posibles opciones terapéuticas. La proteína Dickkopf-1 (DKK-1) es un regulador de la masa ósea y remodelación articular, se ha evidenciado su aumento a nivel sérico en presencia de resorción ósea, asociándose a un elevado valor predictivo en el desarrollo y severidad de la enfermedad. En el presente estudio se pretende establecer los niveles de la proteína DKK-1 en pacientes con diagnóstico de AR temprana y su asociación con índices de actividad clínica reumática, con el fin de determinar las condiciones que asocian la presencia de la DKK-1 y sus posibles capacidades de pronóstico durante el curso de la enfermedad.RESUMEN 8 INTRODUCCIÓN 10 1. OBJETIVOS 12 5.1 OBJETIVO GENERAL 12 5.2 OBJETIVOS ESPECÍFICOS 12 ANTECEDENTES 13 2. MARCO TEÓRICO 19 6.1 ARTRITIS REUMATOIDE 19 6.2 BIOMARCADORES ASOCIADOS A ENFERMEDAD 20 6.3 MANIFESTACIONES CLÍNICAS 25 6.3.1 EROSIONES OSEAS EN ARTRITIS REUMATOIDE 25 6.4 VÍA Wnt 28 6.4.1 LA VÍA CANÓNICA 29 6.4.2 VÍA NO CANÓNICA 30 6.5 PROTEÍNA DICKKOPF-1 (DKK-1 31 6.6 RELACIÓN ENTRE NIVELES DE DKK1 Y DESENLACES EN AR 32 3. METODOLOGÍA 34 7.1 . TIPO DE INVESTIGACIÓN 34 7.2 POBLACIÓN 34 7.3 MUESTRA 34 7.4 SELECCIÓN DE LA MUESTRA 34 7.5 CRITERIOS DE INCLUSIÓN 35 7.6 CRITERIOS DE EXCLUSIÓN 35 7.7 TÉCNICAS Y PROCEDIMIENTOS 35 7.8 ASPECTOS ÉTICOS 37 4. RESULTADOS 38 5. DISCUSIÓN 57 6. CONCLUSIONES 59 7. REFERENCIAS 65 ÍNDICE DE FIGURASPregradoBacteriólogo(a) y Laboratorista Clínico73p.application/pdfspaUniversidad Colegio Mayor de CundinamarcaFacultad de Ciencias de la SaludBogotá D.CBacteriología y Laboratorio ClínicoUniversidad Colegio Mayor de Cundinamarca, 2018https://creativecommons.org/licenses/by-nc-sa/4.0/info:eu-repo/semantics/closedAccessAtribución-NoComercial-CompartirIgual 4.0 Internacional (CC BY-NC-SA 4.0)http://purl.org/coar/access_right/c_14cbEvaluación de los niveles de la proteína Dickkopf- 1 (Dkk-1) y su asociación con índices de actividad clínica reumática en pacientes con Artritis Reumatoide tempranaTrabajo de grado - Pregradohttp://purl.org/coar/resource_type/c_7a1fhttp://purl.org/coar/version/c_970fb48d4fbd8a85Textinfo:eu-repo/semantics/bachelorThesishttps://purl.org/redcol/resource_type/TPinfo:eu-repo/semantics/publishedVersionMcInnes I. The Pathogenesis of Rheumatoid Arthritis. N Engl J Med. 2011;365:2205–19.Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/ European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569-2581.Helmick CG, Felson DT, Lawrence RC, et al; National Arthritis Data Workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58(1):15-25Schellekens GA, De Jong BAW, Van Den Hoogen FHJ, Van De Putte LBA, Van Venrooij WJ. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest. 1998;101(1):273–81Mc Ardle A, Flatley B, Pennington SR, FitzGerald O. Early biomarkers of joint damage in rheumatoid and psoriatic arthritis. Arthritis Res Ther. 2015;17:141.Chou C, Liao H, Chen C, Chen W, Wang H, Su K. The Clinical Application of Anti-CCP in Rheumatoid Arthritis and Other Rheumatic Diseases. Biomark Insights. 2007;2(201):165–71Brink M, Verheul MK, Rönnelid J, Berglin E, Holmdahl R, Toes REM, et al. Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage. Arthritis Res Ther. 2015;17:25Seror R, Boudaoud S, Pavy S, Nocturne G, Schaeverbeke T, Saraux A, et al. Increased Dickkopf-1 in Recent-onset Rheumatoid Arthritis is a New Biomarker of Structural Severity. Data from the ESPOIR Cohort. Sci Rep. 2016;6(November 2015):18421.Burska A, Boissinot M, Ponchel F. Cytokines as biomarkers in rheumatoid arthritis. Mediators Inflamm. 2014;2014.Chang K, Yang SM, Kim SH, Han KH, Park SJ, Shin J Il. Smoking and rheumatoid arthritis. Int J Mol Sci. 2014;15(12):22279–95.García-Arias M, Pascual-Salcedo D, Ramiro S, Ueberschlag M-E, Jermann TM, Cara C, et al. Calprotectin in rheumatoid arthritis : association with disease activity in a cross-sectional and a longitudinal cohort. Mol Diagn Ther [Internet]. 2013;17(1):49–56Aho K, Palosuo T, Raunio V, Puska P, Aromaa A, Salonen JT. When does rheumatoid disease start? Arthritis Rheum. 1985;28(5):485–9.Berglin E, Padyukov L, Sundin U, Hallmans G, Stenlund H, Van Venrooij WJ, et al. A combination of autoantibodies to cyclic citrullinated peptide (CCP) and. Arthritis Res Ther. 2004;6(4):R303-308Fuggle NR, Smith TO, Kaul A, Sofat N. Hand to mouth: A systematic review and meta-analysis of the association between rheumatoid arthritis and periodontitis. Front Immunol. 2016;7(MAR)Pecani A, Alessandri C, Spinelli FR, Colasanti T, Pendolino M, Barbati C, et al. Prevalence, sensitivity and specificity of antibodies against carbamylated proteins in a large cohort of Italian rheumatoid arthritis patients. Ann Rheum Dis. 2016;75:675.Shi J, van Steenbergen HW, van Nies JAB, Levarht EWN, Huizinga TWJ, van der Helm-van Mil AHM, et al. The specificity of anti-carbamylated protein antibodies for rheumatoid arthritis in a setting of early arthritis. Arthritis Res Ther. 2015;17(1):339.Daoussis D, Andonopoulos AP. The Emerging Role of Dickkopf-1 in Bone Biology: Is It the Main Switch Controlling Bone and Joint Remodeling? Semin Arthritis Rheum. 2011;41(2):170–7.Diarra D, Stolina M, Polzer K, Zwerina J, Ominsky MS, Dwyer D, et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med. 2007;13(2):156–63Wang SY, Liu YY, Ye H, Guo JP, Li RU, Liu X, et al. Circulating dickkopf-1 is correlated with bone erosion and inflammation in rheumatoid arthritis. J Rheumatol. 2011;38(5):821–7.de Rooy DPC, Yeremenko NG, Wilson AG, Knevel R, Lindqvist E, Saxne T, et al. Genetic studies on components of the Wnt signalling pathway and the severity of joint destruction in rheumatoid arthritis. Ann Rheum Dis. 2013;72(5):769–75.Kahlenberg JM, Fox DA. Advances in the medical treatment of rheumatoid arthritis. Vol. 27, Hand Clinics. 2011. p. 11–20.Silman AJ, Pearson JE. Epidemiology and genetics of rheumatoid arthritis. Arthritis Res. 2002;4(suppl 3):S265-S272.)Anaya JM.Genes y artritis reumatoidea. Rev ColombReumatol 1999;6:24050Verheijden GFM, Rijnders AWM, Bos E, Coenen-deRoo CJJ, van Staveren CJ, Miltenburg AMM, et al.Human cartilage glycoprotein-39 as a candidateautoantigen in rheumatoid arthritis. Arthritis Rheum 1999; 40:1115- 25.Shi J, Knevel R, Suwannalai P, van der Linden MP, Janssen GMC, van Veelen P a., et al. Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage. Proc Natl Acad Sci. 2011;108(42):17372–7Gerlag DM, Raza K, van Baarsen LGM, Brouwer E, Buckley CD, Burmester GR, et al. EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the Study Group for Risk Factors for Rheumatoid Arthritis. Ann Rheum Dis. 2012;71(5):638–41Francesca Ingegnoli, Roberto Castelli, Roberta Gualtierotti. Rheumatoid Factors: Clinical Applications. Dis Markers. 2013; 35(6): 727–734Y.W. Song E.H. Kang. Autoantibodies in rheumatoid arthritis: rheumatoid factors and anticitrullinated protein antibodies. QJM: An International Journal of Medicine, Volume 103, Issue 3, 1 March 2010, Pages 139–146O. M. R. Westwood P. N. Nelson F. C. Hay. Rheumatoid factors: what's new? Rheumatology, Volume 45, Issue 4, 1 April 2006, Pages 379–385Haberman AM, William J, Euler C, Shlomchik MJ. Rheumatoid factors in health and disease: structure, function, induction and regulation. Current Directions in Autoimmunity. 2003;6:169–195Annette HM van der Helm-van Mil, Kirsten N Verpoort, Ferdinand C Breedveld, René EM Toes, Tom WJ Huizinga. Antibodies to citrullinated proteins and differences in clinical progression of rheumatoid arthritis. Arthritis Res Ther. 2005; 7(5): R949–R958.Kroot EJ et al. The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis. Arthritis Rheum. 2000 Aug;43(8):1831-5D M Lee, P H Schur. Clinical utility of the anti-CCP assay in patients with rheumatic diseases. Ann Rheum Dis 2003;62:870–874Masson-Bessière C, Sebbag M, Girbal-Neuhauser E, Nogueira L, Vincent C. Vossenaar ER1, Zendman AJ, van Venrooij WJ, Pruijn GJ. PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease.Valesini G, Gerardi MC, Iannuccelli C, Pacucci VA, Pendolino M, Shoenfeld Y. Citrullination and autoimmunity. Autoimmun Rev [Internet]. 2015 Jun;14(6):490–7.Linn-Rasker SP. Smoking is a risk factor for anti-CCP antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles. Ann Rheum Dis [Internet]. 2006 Mar 1;65(3):366–71..Pedersen M, Jacobsen S, Garred P, Madsen HO, Klarlund M, Svejgaard A, et al. Strong combined gene–environment effects in anti–cyclic citrullinated peptide–positive rheumatoid arthritis: A nationwide case–control study in Denmark. Arthritis Rheum [Internet]. 2007 May;56(5):1446–53.Senshu T, et al. The major synovial targets of the rheumatoid arthritisspecific antifilaggrin autoantibodies are deiminated forms of the alpha- and beta-chains of fibrin. J Immunol. 2001;166:4177–84Koivula MK, Aman S, Karjalainen A, Hakala M, Risteli J. Are there autoantibodies reacting against citrullinated peptides derived from type I and type II collagens in patients with rheumatoid arthritis? Ann Rheum Dis. 2005;64:1443–50.Vossenaar ER, Despres N, Lapointe E, van der Heijden A, Lora M, Senshu T, et al. Rheumatoid arthritis specific anti-Sa antibodies target citrullinated vimentin. Arthritis Res Ther. 2004;6:R142–50Zeneng Wang et al. Protein carbamylation links inflammation, smoking, uremia and atherogenesis. Nature Medicine 13, 1176 - 1184 (2007)Jing Shi et al. Carbamylation and antibodies against carbamylated proteins in autoimmunity and other pathologies. Autoimmunity Reviews 13 (2014) 225–230. Arbi Pecani et al. Prevalence, sensitivity and specificity of antibodies against carbamylated proteins in a monocentric cohort of patients with rheumatoid arthritis and other autoimmune rheumatic diseases. Arthritis Res Ther. 2016; 18: 276Trouw LA, Mahler M. Closing the serological gap: promising novel biomarkers for the early diagnosis of rheumatoid arthritis. Autoimmun Rev. 2012 Dec; 12(2):318-22M. Holzer, K. Zangger, D. El-Gamal, V. Binder, S. Curcic, V. Konya, et al.Myeloperoxidase-derived chlorinating species induce protein carbamylation through decomposition of thiocyanate and urea: novel pathways generating dysfunctional high-density lipoprotein Antioxid Redox Signal, 17 (2012), pp. 1043-1052Nzeusseu Toukap A et al. Myeloperoxidase and its products in synovial fluid of patients with treated or untreated rheumatoid arthritis. Free Radic Res. 2014 Apr; 48(4):461-5.Z. Prokopowicz, J. Marcinkiewicz, D.R. Katz, B.M. Chain. Neutrophil myeloperoxidase: soldier and statesman. Arch Immunol Ther Exp (Warsz), 60 (2012), pp. 43-54Pepys MB, Baltz ML. Acute phase proteins with special reference to Creactive protein and related proteins (pentaxins) and serum amyloid A protein. Adv Immunol. 1983; 34():141-212Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003 Jun; 111(12):1805-12Harnett W, Harnett MM. Phosphorylcholine: friend or foe of the immune system? Immunol Today. 1999 Mar; 20(3):125-9.Volanakis JE, Wirtz KW. Interaction of C-reactive protein with artificial phosphatidylcholine bilayers. Nature. 1979 Sep 13; 281(5727):155-7Gershov D, Kim S, Brot N, Elkon KB. C-Reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinflammatory innate immune response: implications for systemic autoimmunity. J Exp Med. 2000 Nov 6; 192(9):1353-64.Pepys MB, Rowe IF, Baltz ML. C-reactive protein: binding to lipids and lipoproteins. Int Rev Exp Pathol. 1985; 27:83-111.CarolynMold, HenryGewurz, Terry W Du Closbd. Regulation of complement activation by C-reactive protein. Immunopharmacology. 1999 May;42(13):23-30.Katherine B Bodman-Smith et al. C-reactive protein-mediated phagocytosis and phospholipase D signalling through the high-affinity receptor for immunoglobulin G (FcγRI). Immunology. 2002 Oct; 107(2): 252–260.Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999 Feb 11; 340(6):448-54Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999 Jan 14; 340(2):115-26Renuka Devi Ramamoorthy, Vijaykumar Nallasamy, Raghavendra Reddy, Nalini Esther, Yuvaraja Maruthappan. A review of C-reactive protein: A diagnostic indicator in periodontal medicine. J Pharm Bioallied Sci. 2012 Aug; 4(Suppl 2): S422–S426Nancy A. Shadick et al. C-Reactive Protein in the Prediction of Rheumatoid Arthritis in Women. Arch Intern Med. 2006;166(22):2490-2494Tishler MCaspi DYaron M C-reactive protein levels in patients with rheumatoid arthritis: the impact of therapy. Clin Rheumatol 1985;4321- 324Kyoung-Woon Kim, Bo-Mi Kim, Hee-Won Moon, Sang-Heon Lee and HaeRim Kim. Role of C-reactive protein in osteoclastogenesis in rheumatoid arthritis. Arthritis Research & Therapy201517:41.Masi ATAldag JCSipes J Do elevated levels of serum C-reactive protein predict rheumatoid arthritis in men: correlations with pre-RA status and baseline positive rheumatoid factors. J Rheumatol 2001;282359- 2361Schett, G, & Gravallese, E. Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev. Rheum 2012;8(11): 656– 664Karsenty G, Kronenberg HM, Settembre C. Genetic control of bone formation. Annu. Rev. Cell. Dev. Biol. 2009; 25:629–648Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003; 423:337–342Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function. Nat. Rev. Genet. 2003;4:638–649Firestein GS, et al. Cytokines in chronic inflammatory arthritis. I. Failure to detect T cell lymphokines (interleukin 2 and interleukin 3) and presence of macrophage colony-stimulating factor (CSF-1) and a novel mast cell growth factor in rheumatoid synovitis. J. Exp. Med. 1988;168:1573–1586Gravallese EM, et al. Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum. 2000;43:250–258.Shigeyama Y, et al. Expression of osteoclast differentiation factor in rheumatoid arthritis. Arthritis Rheum. 2000;43:2523–2530.Visser H, le Cessie S, Vos K, Breedveld FC, Hazes JM. How to diagnose rheumatoid arthritis early: a prediction model for persistent (erosive) arthritis. Arthritis Rheum. 2002;46:357–365.Kastbom A, Strandberg G, Lindroos A, Skogh T. Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project) Ann. Rheum. Dis. 2004;63:1085– 1089.Meyer O, et al. Anticitrullinated protein/peptide antibody assays in early rheumatoid arthritis for predicting five year radiographic damage. Ann. Rheum. Dis. 2003;62:120–126.Schett G, Saag KG, Bijlsma JW. From bone biology to clinical outcome: state of the art and future perspectives. Ann. Rheum. Dis. 2010;69:1415– 1419.Harre U, et al. Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J. Clin. Invest. 2012;122:1791– 1802.Walsh NC1, Gravallese EM. Bone remodeling in rheumatic disease: a question of balance. Immunol Rev. 2010 Jan;233(1):301-12Machold, K., Stamm, T., Nell, V., Pflugbeil, S., Aletaha, D., Steiner, G., Uffmann, M. and Smolen, J. (2006). Very recent onset rheumatoid arthritis: clinical and serological patient characteristics associated with radiographic progression over the first years of disease. Rheumatology, 46(2), pp.342349.habet MM, Huizinga TW, van der Heijde DM, van der Helm-van Mil AH. The prognostic value of baseline erosions in undifferentiated arthritis. Arthritis Res Ther 2009; 11:R155Miao CG et al. Wnt signaling pathway in rheumatoid arthritis, with special emphasis on the different roles in synovial inflammation and bone remodeling. Cell Signal. 2013 Oct;25(10):2069-78.Li J, Sarosi I, Cattley RC, Pretorius J, Asuncion F, Grisanti M et al. Dkk1mediated inhibition of Wnt signaling in bone results in osteopenia. Bone. 2006;39(4):754-66.M. Sen. Wnt signalling in rheumatoid arthritis. Rheumatology, 44 (2005), pp–713Daoussis Dimitrios, et al. Evidence That Dkk-1 Is Dysfunctional in Ankylosing Spondylitis. Arthritis & Rheumatism. 2010; 62 (1): 150–158de Rooy DP, Yeremenko NG, Wilson AG, et al. Genetic studies on components of the Wnt signalling pathway and the severity of joint destruction in rheumatoid arthritis. Ann Rheum Dis 2013;72:769–75.Nusse R., Varmus H.E. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell (1982) 31:99–109Van Ooyen A., Nusse R. Structure and nucleotide sequence of the putative mammary oncogene int-1; proviral insertions leave the protein-encoding domain intact. Cell (1984) 39:233–240.Cabrera C.V., Alonso M.C., Johnston P., Phillips R.G., Lawrence P.A. (1987) Phenocopies induced with antisense RNA identify the wingless gene. Cell 50:659–663.Miller JR. The Wnts. Genome Biol, 3 (2002), pp. reviews3001Wodarz A,Nusse R. Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol, 14 (1998), pp. 59-88Ken M. Cadigan, Roel Nusse. Wnt signaling: a common theme in animal development. Genes & Dev. 1997. 11:3286-3305M. Sen. Wnt signalling in rheumatoid arthritis. Rheumatology, 44 (2005), pp–713Cheng-gui Miao et al, Wnt signaling pathway in rheumatoid arthritis, with special emphasis on the different roles in synovial inflammation and bone remodeling. Cell Signal 2013;25:2069-2078Michael D. Gordon, Roel Nusse. Wnt signaling: multiple phathways, multiple receptors, and multiple transcription factors. The Journal of Biological Chemistry 2006 281, 22429-22433.Velasco J, Riancho J. La vía Wnt y el hueso. Rev Esp Enferm metab oseas 2008;117:5-9Niehrs C. Function and biological roles of the Dickkopf family of Wnt modulators. Oncogene, 25 (2006), pp. 7469-81Danielle Diarra et al. Dickkopf-1 is a master regulator of joint remodeling. Nature medicine 2007Glinka A, Wu W, Dellus H, Monaghan P, Blumenstock C, Niehrs C. Dickkopf1 is a member of a new family of secreted proteins and functions in head induction. Nature 1998;391:357-362Bafico A1, Liu G, Yaniv A, Gazit A, Aaronson SA. Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow. Nat Cell Biol. 2001 Jul;3(7):683-6.Prevoo ML et al. Modified disease activity scores that include twentyeightjoint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995 Jan;38(1):44-8.Karsenty G, Kronenberg HM, Settembre C. Genetic control of bone formation. Annu. Rev. Cell. Dev. Biol. 2009; 25:629–648Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003; 423:337–342Dias E, Lukas C, Landewe R, Fatenejad S, van der Heijde D. Reliability and sensitivity to change of the Simple Erosion Narrowing Score compared with the Sharp-van der Heijde method for scoring radiographs in rheumatoid arthritis. 2018Chaparro del Moral R, Rillo O, Casalla L, Morón C, Citera G, Cocco J et al. Work Productivity in Rheumatoid Arthritis: Relationship with Clinical and Radiological Features. Arthritis. 2012;2012:1-7.Garnero P, Tabassi N, Voorzanger-Rousselot N. Circulating Dickkopf1 and Radiological Progression in Patients with Early Rheumatoid Arthritis Treated with Etanercept. The Journal of Rheumatology. 2008;35(12):2313.Gómez-Vaquero C, Martín I, Loza E, Carmona L, Ivorra J, Narváez JA et al. Effect of Osteoprotegerin and Dickkopf-Related Protein 1 on Radiological Progression in Tightly Controlled Rheumatoid Arthritis. PLoS One. 2016;11(12):e0166691Harris ED Jr. Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med 1990;322:1277–89.Baratelle AM, van der Heijde D. Radiographic imaging end points in rheumatoid arthritis trials. In: Reid DM, Miller CG, editors. Clinical trials in rheumatoid arthritis and osteoarthritis. London: Springer-Verlag, 2008:201– 21.Kahlenberg J. Michelle , M.D., Ph.D.a and David A. Fox M. Advances in the Medical Treatment of Rheumatoid Arthritis. NIH Public Access. 2011;27(1):11–20.Wilder RL, Sternberg EM. Neuroendocrine hormonal factors in rheumatoid arthritis and related conditions. Curr Opin Rheumatol [Internet]. 1990 Jun;2(3):436–40Ahmed SA, Hissong BD, Verthelyi D, Donner K, Becker K, KarpuzogluSahin E. Gender and risk of autoimmune diseases: Possible role of estrogenic compounds. Environ Health Perspect. 1999;107(SUPPL. 5):681–6.THU0070 RANKL, OPG and OSCAR but Not Dkk-1 Predict Radiographic Progression in An Inception Cohort of Seropositive Rheumatoid Arthritis (RA) Treated-To-Target with Combination Conventional DMARD Therapy. 2018.Rossini M, Viapiana O, Adami S, Fracassi E, Idolazzi L, Dartizio C et al. In patients with rheumatoid arthritis, Dickkopf-1 serum levels are correlated with parathyroid hormone, bone erosions and bone mineral density. Clin Exp Rheumatol. 2015;33(1):77-83Leech MT, Bartold PM. The association between rheumatoid arthritis and periodontitis. Best Pract Res Clin Rheumatol. 2015;29(2):189– 201.Pischon N, Pischon T, Kröger J, Gülmez E, Kleber B-M, Bernimoulin J-P, et al. Association among rheumatoid arthritis, oral hygiene, and periodontitis. J Periodontol. 2008;79(6):979–86.Äyräväinen L, Leirisalo-Repo M, Kuuliala A, Ahola K, Koivuniemi R, Meurman JH, et al. Periodontitis in early and chronic rheumatoid arthritis: a prospective follow-up study in Finnish population. BMJ Open [Internet]. 2017;7(1):e011916Pons-Fuster A et al. Clinical evaluation of periodontal disease in patients with rheumatoid arthritis: A cross-sectional study. Quintessence Int. 2015;46:817-22Scher J et al. Periodontal disease and the oral microbiota in newonset rheumatoid arthritis. Arthritis Rheumatol 2012;64:3083-309Napimoga M, Nametala C, Silva F et al. Involvement of the Wntβcatenin signalling antagonists, sclerostin and dickkopf-related protein 1, in chronic periodontitis. J Clin Periodontol; 2014;41:550–7Bello-Gualtero J, etal. Periodontal disease in subjects with genetic risk to develop arthritis and early rheumatoid arthritis: a cross sectional study. J periodontol 2016;87:346-456.EnfermedadNaturaleza autoinmuneEULAR/ACRArtritis reumatoideProteína DKK-1ORIGINALpresentación-sustentación-angelaarias. artrits.pdfpresentación-sustentación-angelaarias. artrits.pdfapplication/pdf2138302https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3762/1/presentaci%c3%b3n-sustentaci%c3%b3n-angelaarias.%20artrits.pdf0ade6161367f13862e80edba8415b460MD51open accessPROYECTO ArtritisDKK-1 Angela-Arias Cartas Derechos de Autor.pdfPROYECTO ArtritisDKK-1 Angela-Arias Cartas Derechos de Autor.pdfapplication/pdf196571https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3762/2/PROYECTO%20ArtritisDKK-1%20Angela-Arias%20Cartas%20Derechos%20de%20Autor.pdf4319bcc1d98a124144e1905dcd8ecc0fMD52metadata only accessPROYECTO ArtritisDKK-1 Angela-Arias..pdfPROYECTO ArtritisDKK-1 Angela-Arias..pdfapplication/pdf1044373https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3762/3/PROYECTO%20ArtritisDKK-1%20Angela-Arias..pdf4366de7171eb44077e9248b745d362ffMD53open accessLICENSElicense.txtlicense.txttext/plain; charset=utf-814828https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3762/4/license.txt2f9959eaf5b71fae44bbf9ec84150c7aMD54open accessTEXTpresentación-sustentación-angelaarias. artrits.pdf.txtpresentación-sustentación-angelaarias. artrits.pdf.txtExtracted texttext/plain13168https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3762/5/presentaci%c3%b3n-sustentaci%c3%b3n-angelaarias.%20artrits.pdf.txt5392cb208dc04be25aaef3012f6dc54fMD55open accessPROYECTO ArtritisDKK-1 Angela-Arias Cartas Derechos de Autor.pdf.txtPROYECTO ArtritisDKK-1 Angela-Arias Cartas Derechos de Autor.pdf.txtExtracted texttext/plain17https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3762/7/PROYECTO%20ArtritisDKK-1%20Angela-Arias%20Cartas%20Derechos%20de%20Autor.pdf.txtf9a8e002ebec227d74399f9906f369c3MD57metadata only accessPROYECTO ArtritisDKK-1 Angela-Arias..pdf.txtPROYECTO ArtritisDKK-1 Angela-Arias..pdf.txtExtracted texttext/plain118143https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3762/9/PROYECTO%20ArtritisDKK-1%20Angela-Arias..pdf.txta1e0587ff7cd57a076dde4040eeab2ceMD59open accessTHUMBNAILpresentación-sustentación-angelaarias. artrits.pdf.jpgpresentación-sustentación-angelaarias. artrits.pdf.jpgGenerated Thumbnailimage/jpeg5598https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3762/6/presentaci%c3%b3n-sustentaci%c3%b3n-angelaarias.%20artrits.pdf.jpg69b763e29c478617c351993a8e254cf6MD56open accessPROYECTO ArtritisDKK-1 Angela-Arias Cartas Derechos de Autor.pdf.jpgPROYECTO ArtritisDKK-1 Angela-Arias Cartas Derechos de Autor.pdf.jpgGenerated Thumbnailimage/jpeg6764https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3762/8/PROYECTO%20ArtritisDKK-1%20Angela-Arias%20Cartas%20Derechos%20de%20Autor.pdf.jpg222a742d0efebae6fb2e9283f7756ba2MD58metadata only accessPROYECTO ArtritisDKK-1 Angela-Arias..pdf.jpgPROYECTO ArtritisDKK-1 Angela-Arias..pdf.jpgGenerated Thumbnailimage/jpeg8321https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/3762/10/PROYECTO%20ArtritisDKK-1%20Angela-Arias..pdf.jpg4482ac8d595cf0362aaa55b676c13917MD510open accessunicolmayor/3762oai:repositorio.unicolmayor.edu.co:unicolmayor/37622021-12-03 03:01:22.374An error occurred on the license name.|||https://creativecommons.org/licenses/by-nc-sa/4.0/open accessBiblioteca Digital Unicolmayorrepositorio@unicolmayor.edu.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 |