[en] Background: The inactive dephosphorylated and uncarboxylated form of the matrix Gla protein (dp-ucMGP) has been shown to be increased in plasma of inflammatory bowel disease (IBD) patients. Our aim was to assess if the plasmatic level of dp-ucMGP could reflect disease endoscopic activity, presence of strictures and cumulative structural bowel damage in Crohn’s disease (CD) patients. Methods: The plasmatic level of dp-ucMGP was measured in a monocentric cohort of prospectively recruited patients. The analysis was done by chemiluminescent immunoassay on blood samples collected the day of a planned ileocolonoscopy. In addition to classical clinical data (gender, age, body mass index (BMI), disease duration, current treatment), endoscopic data (disease location, Crohn’s Disease Endoscopic Index of Severity (CDEIS), mucosal healing (MH), presence of 9 CD lesion types) and biological markers (faecal calprotectin and C-reactive protein (CRP)) were collected. The association between dp-ucMGP level and Lémann index was also investigated. Univariate linear regression was used to investigate the relationship between dp-ucMGP level and different parameters collected. Results: A total of 82 ileocolonoscopies and dp-ucMGP assays were performed in 75 CD patients (45 females; 37 ileocolonic, 19 ileal and 19 colonic diseases) between October 2012 and November 2019. A total of 24 patients (29.3%) showed MH. The dp-ucMGP levels were not associated with MH, CDEIS, faecal calprotectin or CRP levels. Plasmatic dp-ucMGP levels increased significantly with age (p = 0.0032), disease duration (p = 0.0033), corticosteroids use (p = 0.019) and tended to increase in patients with intestinal strictures (p = 0.086) but not with the Lémann index. Conclusion: The significant increase of plasmatic dp-ucMGP levels with age, disease duration and the trend observed in patients with non-ulcerated strictures may suggest that this extracellular matrix protein could be a marker of tissue remodelling and physiological ageing of the gut.
Disciplines :
Gastroenterology & hepatology
Author, co-author :
VIEUJEAN, Sophie ; Centre Hospitalier Universitaire de Liège - CHU > > Service de gastroentérologie, hépatologie, onco. digestive
GILLARD, Romain ; Centre Hospitalier Universitaire de Liège - CHU > > Service médical de radiodiagnostic
Delanaye, Pierre ; Centre Hospitalier Universitaire de Liège - CHU > > Service de néphrologie
Seidel, Laurence ; Centre Hospitalier Universitaire de Liège - CHU > > Service des informations médico économiques (SIME)
Bequet, Emeline ; Université de Liège - ULiège > Département des sciences cliniques > Médecine générale
Cosnes J, Cattan S, Blain A, et al. Long-term evolution of disease behavior of crohn’s disease. Inflamm Bowel Dis. 2002; 8 (4): 244–250. doi: 10.1097/00054725-200207000-00002.
Cosnes J, Gower–Rousseau C, Seksik P, et al. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology. 2011; 140 (6): 1785–1794.e4. doi: 10.1053/j.gastro.2011.01.055.
Pariente B, Mary JY, Danese S, et al. Development of the lémann index to assess digestive tract damage in patients with crohn’s disease. Gastroenterology. 2015; 148 (1): 52–63.e3. doi: 10.1053/J.GASTRO.2014.09.015.
Klenske E, Bojarski C, Waldner M, et al. Targeting mucosal healing in crohn’s disease: what the clinician needs to know. Therap Adv Gastroenterol. 2019; 12. doi: 10.1177/1756284819856865.
Shah SC, Colombel JF, Sands BE, et al. Systematic review with meta-analysis: mucosal healing is associated with improved long-term outcomes in crohn’s disease. Aliment Pharmacol Ther. 2016; 43 (3): 317–333. doi: 10.1111/apt.13475.
Sandborn WJ, Hanauer S, Van Assche G, et al. Treating beyond symptoms with a view to improving patient outcomes in inflammatory bowel diseases. J Crohns Colitis. 2014; 8 (9): 927–935. doi: 10.1016/J.CROHNS.2014.02.021.
Neurath MF, Travis SPL. Mucosal healing in inflammatory bowel diseases: a systematic review. Gut. 2012; 61 (11): 1619–1635. doi: 10.1136/GUTJNL-2012-302830.
Rutgeerts P, Vermeire S, Van Assche G. Mucosal healing in inflammatory bowel disease: impossible ideal or therapeutic target? Gut. 2007; 56 (4): 453–455. doi: 10.1136/GUT.2005.088732.
Buisson A, Gonzalez F, Poullenot F, et al. Comparative acceptability and perceived clinical utility of monitoring tools: a nationwide survey of patients with inflammatory bowel disease. Inflamm Bowel Dis. 2017; 23 (8): 1425–1433. doi: 10.1097/MIB.0000000000001140.
Kim SY, Kim HS, Park HJ. Adverse events related to colonoscopy: global trends and future challenges. World J Gastroenterol. 2019; 25 (2): 190–204. doi: 10.3748/wjg.v25.i2.190.
State M, Voiosu T, Voiosu A, et al. Surrogate markers of mucosal healing in inflammatory bowel disease: a systematic review. World J Gastroenterol. 2021; 27 (16): 1828–1840. doi: 10.3748/wjg.v27.i16.1828.
Krzystek-Korpacka M, Kempiński R, Bromke M, et al. Biochemical biomarkers of mucosal healing for inflammatory bowel disease in adults. Diagnostics. 2020; 10 (6): 367. doi: 10.3390/DIAGNOSTICS10060367.
Laserna-Mendieta EJ, Lucendo AJ. Faecal calprotectin in inflammatory bowel diseases: a review focused on meta-analyses and routine usage limitations. Clin Chem Lab Med. 2019; 57 (9): 1295–1307. doi: 10.1515/CCLM-2018-1063.
Labaere D, Smismans A, Van Olmen A, et al. Comparison of six different calprotectin assays for the assessment of inflammatory bowel disease. United European Gastroenterol J. 2014; 2 (1): 30–37. doi: 10.1177/2050640613518201.
Amcoff K, Stridsberg M, Lampinen M, et al. Clinical implications of assay specific differences in f-calprotectin when monitoring inflammatory bowel disease activity over time. Scand J Gastroenterol. 2017; 52 (3): 344–350. doi: 10.1080/00365521.2016.1256424.
Af Björkesten CG, Nieminen U, Turunen U, et al. Surrogate markers and clinical indices, alone or combined, as indicators for endoscopic remission in anti-TNF-treated luminal crohn’s disease. Scand J Gastroenterol. 2012; 47 (5): 528–537. doi: 10.3109/00365521.2012.660542.
Ma C, Battat R, Parker CE, et al. Update on C-reactive protein and fecal calprotectin: are they accurate measures of disease activity in crohn’s disease? Expert Rev Gastroenterol Hepatol. 2019; 13 (4): 319–330. doi: 10.1080/17474124.2019.1563481.
Pierre N, Salée C, Vieujean S, et al. Review article: distinctions between ileal and colonic crohn’s disease: from physiology to pathology. Aliment Pharmacol Ther. 2021; 54 (6): 779–791. doi: 10.1111/apt.16536.
Shimshoni E, Adir I, Afik R, et al. Distinct extracellular–matrix remodeling events precede symptoms of inflammation. Matrix Biol. 2021; 96: 47–68. doi: 10.1016/j.matbio.2020.11.001.
Khokha R, Murthy A, Weiss A. Metalloproteinases and their natural inhibitors in inflammation and immunity. Nat Rev Immunol. 2013; 13 (9): 649–665. doi: 10.1038/nri3499.
Karamanos NK, Theocharis AD, Neill T, et al. Matrix modeling and remodeling: a biological interplay regulating tissue homeostasis and diseases. Matrix Biol. 2019; 75-76: 1–11. doi: 10.1016/j.matbio.2018.08.007.
Shimshoni E, Yablecovitch D, Baram L, et al. ECM remodelling in IBD: innocent bystander or partner in crime? The emerging role of extracellular molecular events in sustaining intestinal inflammation. Gut. 2015; 64 (3): 367–372. doi: 10.1136/GUTJNL-2014-308048.
Dong XY, Wu MX, Zhang HM, et al. Association between matrix gla protein and ulcerative colitis according to DNA microarray data. Gastroenterol Rep. 2020; 8 (1): 66–75. doi: 10.1093/gastro/goz038.
Brnic D, Martinovic D, Zivkovic PM, et al. Inactive matrix gla protein is elevated in patients with inflammatory bowel disease. World J Gastroenterol. 2020; 26 (32): 4866–4877. doi: 10.3748/WJG.V26.I32.4866.
G F, D A, A V, et al. 3rd european evidence-based consensus on the diagnosis and management of crohn’s disease 2016: part 1: diagnosis and medical management. J Crohns Colitis. 2017; 11 (1): 3–25. doi: 10.1093/ECCO-JCC/JJW168.
Bitoun A, Blanchi A, Contou JF, et al. Development and validation of an endoscopic index of the severity for crohn’s disease: a prospective multicentre study. Groupe d’Etudes thérapeutiques des affections inflammatoires du tube digestif (GETAID). Gut. 1989; 30 (7): 983–989. doi: 10.1136/GUT.30.7.983.
Turner D, Ricciuto A, Lewis A, et al. STRIDE-II: an update on the selecting therapeutic targets in inflammatory bowel disease (STRIDE) initiative of the international organization for the study of IBD (IOIBD): determining therapeutic goals for treat-to-Target strategies in IBD. Gastroenterology. 2021; 160 (5): 1570–1583. doi: 10.1053/J.GASTRO.2020.12.031.
Cellier C, Sahmoud T, Froguel E, et al. Correlations between clinical activity, endoscopic severity, and biological parameters in colonic or ileocolonic crohn’s disease. A prospective multicentre study of 121 cases. The groupe d’Etudes therapeutiques des affections inflammatoires digestives. Gut. 1994; 35 (2): 231–235. doi: 10.1136/gut.35.2.231.
Schurgers LJ, Barreto DV, Barreto FC, et al. The circulating inactive form of matrix gla protein is a surrogate marker for vascular calcification in chronic kidney disease: a preliminary report. Clin J Am Soc Nephrol. 2010; 5 (4): 568–575. doi: 10.2215/CJN.07081009.
Puzantian H, Akers SR, Oldland G, et al. Circulating Dephospho-Uncarboxylated matrix gla-protein is associated with kidney dysfunction and arterial stiffness. Am J Hypertens. 2018; 31 (9): 988–994. doi: 10.1093/AJH/HPY079.
Thamratnopkoon S, Susantitaphong P, Tumkosit M, et al. Correlations of plasma desphosphorylated uncarboxylated matrix gla protein with vascular calcification and vascular stiffness in chronic kidney disease. Nephron. 2017; 135 (3): 167–172. doi: 10.1159/000453368.
Roumeliotis S, Dounousi E, Eleftheriadis T, et al. Association of the inactive circulating matrix gla protein with vitamin K intake, calcification, mortality, and cardiovascular disease: a review. Int J Mol Sci. 2019; 20 (3): 628. doi: 10.3390/IJMS20030628.
Delanaye P, Krzesinski JM, Warling X, et al. Dephosphorylated-uncarboxylated matrix gla protein concentration is predictive of vitamin K status and is correlated with vascular calcification in a cohort of hemodialysis patients. BMC Nephrol. 2014; 15 (1): 145. doi: 10.1186/1471-2369-15-145.
Barrett H, O’Keeffe M, Kavanagh E, et al. Is matrix gla protein associated with vascular calcification? A systematic review. Nutrients. 2018; 10 (4): 415. doi: 10.3390/nu10040415.
Schlieper G, Westenfeld R, Krüger T, et al. Circulating nonphosphorylated carboxylated matrix gla protein predicts survival in ESRD. J Am Soc Nephrol. 2011; 22 (2): 387–395. doi: 10.1681/ASN.2010040339.
Jono S, Ikari Y, Vermeer C, et al. Matrix gla protein is associated with coronary artery calcification as assessed by electron-beam computed tomography. Thromb Haemost. 2004; 91 (4): 790–794. doi: 10.1160/th03-08-0572.
Silverberg MS, Satsangi J, Ahmad T, et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a working party of the 2005 montreal world congress of gastroenterology. Can J Gastroenterol. 2005; 19 (Suppl A): 5A–36A. doi: 10.1155/2005/269076.
Pariente B, Torres J, Burisch J, et al. Validation and update of the lémann index to measure cumulative structural bowel damage in crohn’s disease. Gastroenterology. 2021; 161 (3): 853–864.e13. doi: 10.1053/J.GASTRO.2021.05.049.
Hardie WD, Korfhagen TR, Sartor MA, et al. Genomic profile of matrix and vasculature remodeling in TGF-α-induced pulmonary fibrosis. Am J Respir Cell Mol Biol. 2007; 37 (3): 309–321. doi: 10.1165/rcmb.2006-0455OC.
Booth AJ, Hadley R, Cornett AM, et al. Acellular normal and fibrotic human lung matrices as a culture system for in vitro investigation. Am J Respir Crit Care Med. 2012; 186 (9): 866–876. doi: 10.1164/rccm.201204-0754OC.
De Brouwer B, Piscaer I, Von Der Thusen JH, et al. Should vitamin K be supplemented instead of antagonised in patients with idiopathic pulmonary fibrosis? Expert Rev Respir Med. 2018; 12 (3): 169–175. doi: 10.1080/17476348.2018.1424544.
Miyata KN, Nast CC, Dai T, et al. Renal matrix gla protein expression increases progressively with CKD and predicts renal outcome. Exp Mol Pathol. 2018; 105 (1): 120–129. doi: 10.1016/j.yexmp.2018.07.001.
Tveitarås MK, Skogstrand T, Leh S, et al. Matrix metalloproteinase-2 knockout and heterozygote mice are protected from hydronephrosis and kidney fibrosis after unilateral ureteral obstruction. PLoS One. 2015; 10 (12): e0143390. doi: 10.1371/journal.pone.0143390.
Jerala M, Hauptman N, Kojc N, et al. Expression of fibrosis-related genes in liver and kidney fibrosis in comparison to inflammatory bowel diseases. Cells. 2022; 11 (3): 314. doi: 10.3390/cells11030314.
Piscaer I, van den Ouweland JMW, Vermeersch K, et al. Low vitamin K status is associated with increased elastin degradation in chronic obstructive pulmonary disease. J Clin Med. 2019; 8 (8): 1116. doi: 10.3390/jcm8081116.
Janssen R, Vermeer C. Vitamin K deficit and elastolysis theory in pulmonary elasto-degenerative diseases. Med Hypotheses. 2017; 108: 38–41. doi: 10.1016/j.mehy.2017.07.029.
Maurice P, Blaise S, Gayral S, et al. Elastin fragmentation and atherosclerosis progression: the elastokine concept. Trends Cardiovasc Med. 2013; 23 (6): 211–221. doi: 10.1016/j.tcm.2012.12.004.
Robert L, Robert AM, Fülöp T. Rapid increase in human life expectancy: will it soon be limited by the aging of elastin? Biogerontology. 2008; 9 (2): 119–133. doi: 10.1007/s10522-007-9122-6.
Caluwé R, Verbeke F, De Vriese AS. Evaluation of vitamin K status and rationale for vitamin K supplementation in dialysis patients. Nephrol Dial Transplant. 2020; 35 (1): 23–33. doi: 10.1093/ndt/gfy373.
Schurgers LJ, Uitto J, Reutelingsperger CP. Vitamin K-dependent carboxylation of matrix gla-protein: a crucial switch to control ectopic mineralization. Trends Mol Med. 2013; 19 (4): 217–226. doi: 10.1016/j.molmed.2012.12.008.
Lee JS, Basalyga DM, Simionescu A, et al. Elastin calcification in the rat subdermal model is accompanied by up-regulation of degradative and osteogenic cellular responses. Am J Pathol. 2006; 168 (2): 490–498. doi: 10.2353/ajpath.2006.050338.
Krasinski SD, Russell RM, Furie BC, et al. The prevalence of vitamin K deficiency in chronic gastrointestinal disorders. Am J Clin Nutr. 1985; 41 (3): 639–643. doi: 10.1093/ajcn/41.3.639.
Fabisiak N, Fabisiak A, Watala C, et al. Fat-soluble vitamin deficiencies and inflammatory bowel disease: systematic review and Meta-Analysis. J Clin Gastroenterol. 2017; 51 (10): 878–889. doi: 10.1097/MCG.0000000000000911.
Kuwabara A, Tanaka K, Tsugawa N, et al. High prevalence of vitamin K and D deficiency and decreased BMD in inflammatory bowel disease. Osteoporos Int. 2009; 20 (6): 935–942. doi: 10.1007/S00198-008-0764-2.
Zallot C, Quilliot D, Chevaux JB, et al. Dietary beliefs and behavior among inflammatory bowel disease patients. Inflamm Bowel Dis. 2013; 19 (1): 66–72. doi: 10.1002/IBD.22965.
Lucendo AJ, De Rezende LC. Importance of nutrition in inflammatory bowel disease. World J Gastroenterol. 2009; 15 (17): 2081–2088. doi: 10.3748/WJG.15.2081.
Gilbert KA, Rannels SR. Glucocorticoid effects on vitamin K-dependent carboxylase activity and matrix gla protein expression in rat lung. Am J Physiol Lung Cell Mol Physiol. 2003; 285 (3): L569–77. doi: 10.1152/ajplung.00426.2002.
Wei FF, Huang QF, Zhang ZY, et al. Inactive matrix gla protein is a novel circulating biomarker predicting retinal arteriolar narrowing in humans. Sci Rep. 2018; 8 (1): 15088. doi: 10.1038/S41598-018-33257-6.
Pivin E, Ponte B, Pruijm M, et al. Inactive matrix gla-protein is associated with arterial stiffness in an adult Population-Based study. Hypertension. 2015; 66 (1): 85–92. doi: 10.1161/HYPERTENSIONAHA.115.05177.
Liabeuf S, Olivier B, Vemeer C, et al. Vascular calcification in patients with type 2 diabetes: the involvement of matrix gla protein. Cardiovasc Diabetol. 2014; 13 (1): 85. doi: 10.1186/1475-2840-13-85.
Wei FF, Thijs L, Zhang ZY, et al. The risk of nephrolithiasis is causally related to inactive matrix gla protein, a marker of vitamin K status: a mendelian randomization study in a flemish population. Nephrol Dial Transplant. 2018; 33 (3): 514–522. doi: 10.1093/NDT/GFX014.
Sardana M, Vasim I, Varakantam S, et al. Inactive matrix gla-protein and arterial stiffness in type 2 diabetes mellitus. Am J Hypertens. 2017; 30 (2): 196–201. doi: 10.1093/AJH/HPW146.
Dai L, Li L, Erlandsson H, et al. Functional vitamin K insufficiency, vascular calcification and mortality in advanced chronic kidney disease: a cohort study. PLoS One. 2021; 16 (2): e0247623. doi: 10.1371/JOURNAL.PONE.0247623.
Viegas CSB, Costa RM, Santos L, et al. Gla-rich protein function as an anti-inflammatory agent in monocytes/macrophages: implications for calcification-related chronic inflammatory diseases. PLoS One. 2017; 12 (5): e0177829. doi: 10.1371/journal.pone.0177829.
Feng Y, Liao Y, Huang W, et al. Mesenchymal stromal cells-derived matrix gla protein contribute to the alleviation of experimental colitis article. Cell Death Dis. 2018; 9 (6): 691. doi: 10.1038/s41419-018-0734-3.
Schurgers LJ, Vermeer C. Determination of phylloquinone and menaquinones in food: effect of food matrix on circulating vitamin K concentrations. Haemostasis. 2000; 30 (6): 298–307. doi: 10.1159/000054147.
