- Open Access
YKL-40 - an emerging biomarker in cardiovascular disease and diabetes
© Rathcke and Vestergaard; licensee BioMed Central Ltd. 2009
- Received: 2 October 2009
- Accepted: 23 November 2009
- Published: 23 November 2009
Several inflammatory cytokines are involved in vascular inflammation resulting in endothelial dysfunction which is the earliest event in the atherosclerotic process leading to manifest cardiovascular disease. YKL-40 is an inflammatory glycoprotein involved in endothelial dysfunction by promoting chemotaxis, cell attachment and migration, reorganization and tissue remodelling as a response to endothelial damage. YKL-40 protein expression is seen in macrophages and smooth muscle cells in atherosclerotic plaques with the highest expression seen in macrophages in the early lesion of atherosclerosis. Several studies demonstrate, that elevated serum YKL-levels are independently associated with the presence and extent of coronary artery disease and even higher YKL-40 levels are documented in patients with myocardial infarction. Moreover, elevated serum YKL-40 levels have also been found to be associated with all-cause as well as cardiovascular mortality. Finally, YKL-40 levels are elevated both in patients with type 1 and type 2 diabetes, known to be at high risk for the development of cardiovascular diseases, when compared to non-diabetic persons. A positive association between elevated circulating YKL-40 levels and increasing levels of albuminuria have been described in patients with type 1 diabetes indicating a role of YKL-40 in the progressing vascular damage resulting in microvascular disease.
This review describes the present knowledge about YKL-40 and discusses its relation to endothelial dysfunction, atherosclerosis, cardiovascular disease and diabetes and look ahead on future perspectives of YKL-40 research.
- Endothelial Dysfunction
- Atherosclerotic Plaque
- Human Cartilage Glycoprotein
- Endothelial Cell Angiogenesis
- Subsequent Lipid Accumulation
Since the results of the Framingham Heart Study revealed C-reactive protein (CRP) as a cardiovascular marker even in ranges considered normal [1–3], several studies of biomarkers in cardiovascular disease (CVD) have been conducted. Until this day, CRP remains the most validated biomarker but substantial knowledge about CRP as a predictor of cardiovascular events is now complemented by studies of new emerging markers such as interleukin 18, matrix metalloproteinase 9, adiponectin and CD40 ligand . The present review focuses on the inflammatory protein YKL-40 and its role in atherosclerosis, CVD and diabetes.
YKL-40 - biology and physiology in general
YKL-40 is a 40 kDa heparin- and chitin-binding glycoprotein also known as human cartilage glycoprotein 39 (HC-gp39) , 38-kDa heparin-binding glycoprotein  or chitinase-3-like protein 1 (CHI3L1) . The abbreviation YKL-40 is based on the one letter code for the first three N-terminal amino acids, tyrosine (Y), lysine (K) and leucine (L) and the apparent molecular weight of YKL-40 .
The CHI3L1 gene for human YKL-40 is localized in a highly conserved area on chromosome 1q31-q32  and the crystal structure of YKL-40 has been described . YKL-40 belongs to the family 18 of glycosyl hydrolases comprising chitinases from various species , but YKL-40 is without any enzymatic properties [5, 12, 13].
YKL-40 is secreted in vitro by a variety of cells and seems especially involved in activation of the innate immune system and in cell processes in relation to extracellular matrix remodelling [11, 14]. YKL-40 induce the maturation of monocytes to macrophages, and is secreted by macrophages during late stages of differentiation and by activated macrophages [7, 15–18]. Studies show that the differentiation and maturation of CD14+ monocytes to CD14-, CD16+ macrophages are attended by an expression of YKL-40 from CD16+ macrophages . YKL-40 has also been shown to be an adhesion and migration factor for vascular cells and is secernated by differentiated vascular smooth muscle cells (VSMCs) [6, 19, 20]. In vivo YKL-40 protein expression is found in human VSMCs in adventitial vessels  and in subpopulations of macrophages and VSMCs in different tissues with inflammation and extracellular matrix remodelling as in atherosclerotic plaques [14, 19, 22].
The knowledge about the physiological function and the mechanisms by which YKL-40 mediates its effects is still scarce. Immunohistochemical studies of different types of normal human tissues show, that cells with a high cellular activity, e.g. a high level of metabolic activity and/or proliferation, have especially high YKL-40 expression [23, 24].
YKL-40 mRNA and protein expression are found in tissues from all germ layers and are present during the early development of the human musculoskeletal system where they seem associated with cell proliferation, differentiation and tissue morphogenesis . Other studies show, that YKL-40 stimulates the proliferation of human connective tissue cells (fibroblasts, chondrocytes, synovial cells) in a dose-dependent manner in a functional concentration range similar to that of insulin-like growth factor (IGF-1). When present in suboptimal concentrations, YKL-40 and IGF-1 work in a synergistic fashion [25, 26]. In mouse studies, YKL-40 stimulates the antigen-induced T-helper 2-response and seems to induce tissue inflammation and fibrosis mediated by IL-13. In this sense, YKL-40 plays an essential role in antigen sensitization and IgE induction as well as in activation of innate immune cells .
In fibroblasts and synovial cells YKL-40 mediates a mitogenic effect through initiation of mitogen-activated protein kinase (MAPK) and phosphoinoside-3 kinase (PI3K) signalling pathways by phosphorylation of the extracellular signal-regulated kinase-1 and 2 (ERK1/ERK2) and protein kinase B (AKT), respectively. Both pathways are required for the cells to complete mitosis and the activation of these pathways stimulates the growth of connective tissue cells .
In fibroblasts and chondrocytes YKL-40 reduces the activation of p38 and SAPK/JNK MAPKs which counteracts the inflammatory responses to TNFα and IL-1. This leads to reduced concentrations of matrix metalloproteinases (MMPs) and IL-8. The modulation of p38 and SAPK/JNK by YKL-40 is mediated through the PI3K  and the induction and continued secretion of YKL-40 require sustained activation of Nf-κB . YKL-40 has no effect on the signalling pathways p38 and SAPK/JNK MAPKs when present without the presence of TNFα and IL-1 and similar do not affect the MMP or IL-8 production. This suggests that YKL-40 expression is an anti-inflammatory counteract of the inflammatory response mediated by TNFα and IL-1  beside its apparent function as a growth factor . The activation of cytoplasmatic signal-transduction pathways suggests, that YKL-40 interacts with one or several signalling components on the plasma membrane. However, specific cell surface receptors or potential YKL-40 ligands remain to be determined.
No difference in serum or plasma YKL-40 levels has been found between genders . In serum, no significant diurnal, weekly or long-time variation in serum YKL-40 concentrations are found in healthy subjects . Similarly, serum YKL-40 concentrations are not affected by physical exercise . There seems to be no or only weak correlation between YKL-40 and hsCRP in studies of patients with diabetes, obesity or atrial fibrillation [31–34] whereas a positive correlation is found between YKL-40 and hsCRP in studies of patients with manifest coronary artery disease (CAD) [35, 36]. Opposite CRP which is a systemic inflammation marker primarily secreted by hepatocytes in response to proinflammatory mediators such as IL-6, YKL-40 is locally produced and secernated. However, all studies investigating the association between YKL-40 and IL-6 found a positive correlation between the two [34, 37, 38]. Furthermore, a tight association between monocyte chemoatractant protein-1 (MCP-1) and YKL-40 have been found in morbidly obese patients . MCP-1 is associated with monocyte trafficking and macrophage infiltration in adipose tissue  and it is also a strong predictor of cardiovascular death . YKL-40 levels are elevated in morbidly obese patients, but despite the apparent linkage between YKL-40 and macrophage maturation and activation, no studies have ever found and association between YKL-40 and body mass index [31, 33, 37].
YKL-40 in endothelial dysfunction and atherosclerosis
The participation of YKL-40 in inflammatory states and vascular processes implies that YKL-40 may play a role in endothelial dysfunction and atherosclerosis. In endothelial dysfunction, elevated YKL-40 levels seem to be involved in relation to cell migration, reorganization and tissue remodelling as a response to endothelial damage [6, 20, 41].
In vitro VSMCs from explants of swine thoracic aorta syntesize YKL-40 during the time of transition from monolayer culture to a non-proliferating differentiated multilayer culture [41, 42]. The YKL-40 secretion continues during the reorganisation of the cells where multicellular nodules are formed. In these nodules the cells re-express markers of differentiated VSMCs [6, 20, 41]. This in vitro nodule forming process mimics some of the characteristics of the in vivo changes that occur in VSMCs following injury, where media smooth muscle cells dedifferentiate, migrate and contribute to the process of restenosis and neointima formation .
In vitro studies also show that YKL-40 promotes chemotaxis, cell attachment, spreading and migration of vascular endothelial cells which suggest a role of YKL-40 in the atherosclerotic plaque formation, where smooth muscle cells are induced to migrate through the intima in response to exogenous signals . YKL-40 also modulates vascular endothelial cell morphology by promoting the formation of branching tubules, indicating that YKL-40 has a role in angiogenesis by stimulating the migration and reorganization of VSMCs . These in vitro studies are supported by immunohistochemical analysis which has shown in vivo protein expression of YKL-40 in human smooth muscle cells in atherosclerotic plaques .
YKL-40 mRNA expression is highly up-regulated in distinct subsets of macrophages in the atherosclerotic plaque, a plaque that is characterized by the infiltration of monocytes into the subendothelial space of the vessel wall and a subsequent lipid accumulation in the activated macrophages. Particularly macrophages that infiltrate deeper in the lesion show high YKL-40 mRNA expression and the highest expression is seen in macrophages in the early lesion of atherosclerosis . An in vitro study with emphasis on biomarker discovery for atherosclerosis by proteomics, show elevated YKL-40 levels in the supernatant of macrophages following treatment with oxidized low-density lipoprotein, a process that mimics the formation of "foam cells" . This also suggests a role of YKL-40 in the differentiation of monocytes to lipid-laden macrophages during formation of the atherosclerotic plaque.
YKL-40 in cardiovascular disease
In the last few years, several clinical studies have described elevated YKL-40 levels in several cardiovascular conditions as well as described an association between YKL-40 and mortality. Studies show, that elevated YKL-levels are independently associated with the presence of CAD [35, 36, 45]. One study even found, that YKL-40 levels increase with the extent of CAD defined by the number of stenosed vessels as assessed by coronary angiography . This findings indicate, that plasma YKL-40 levels could be a quantitative indicator of disease progression as well as of disease presence .
In patients suffering myocardial infarction (MI) even higher YKL-levels have been documented [36, 45, 46] and YKL-levels remain higher in patients with prior MI compaired to individuals without previous MI . There seems to be no difference in YKL-40 levels between MI patients with or without ST elevations, but higher YKL-40 levels were seen in thrombolyzed patients compared with non-thrombolyzed patients during the first 24 hours after the event  indicating that YKL-40 is released from the dissolved thrombosis. Lately, elevated YKL-40 levels have also been documented in individuals with atrial fibrillation (AF) where the highest YKL-40 levels were found in patients with permanent AF compared to patients with persistent AF suggesting an association between the chronicity of AF and the inflammatory burden .
Hazard ratios for cardiovascular and overall mortality at 5 years follow-up in accordance to baseline values of YKL-40 in a representative group of the general population without known cardiovascular disease or diabetes
HR (95% CI)
Age- and sex-adjusted
All together these findings suggest YKL-40 as a possible screening modality/diagnostic marker for progressing coronary atherosclerosis. It seems reasonable to speculate that serum YKL-40 could be used for monitoring the efficiency and sufficiency of medical treatment of patients with CAD and thereby assist the clinician in reducing the high occurrence of fatal cardiovascular events.
YKL-40 and diabetes
Individuals with diabetes have in general a 2- to 4-fold increased risk of subsequent CVD . Persistent microalbuminuria is associated with an increased risk of CVD in both patients with type 1 and type 2 diabetes [48–50]. Patients with type 1 diabetes have up to a 9-fold increased mortality risk from ischemic heart disease, excessively higher in patients under 30 years of age .
It has been demonstrated, that patients with type 1 diabetes as well as patients with type 2 diabetes have elevated plasma YKL-40 levels [31–33, 37, 52]. In type 2 diabetes patients YKL-40 levels are correlated with insulin resistance [31, 37] and in a single study also with the diabetic lipid profile . Some studies have also shown a correlation between YKL-40 and glycemic parameters such as hemoglobin A1c  and fasting glucose  whereas others have not [31, 33].
Unadjusted cumulative cardiovascular and overall mortality according to YKL-40 levels and UACR above and below median at baseline in a representative group of the general population without diabetes, hypertension or CVD
Cardiovascular mortality*, %
Overall mortality*, %
YKL-40 < median, UACR ≤ median
YKL-40 > median, UACR ≤ median
YKL-40 ≤ median, UACR > median
YKL-40 > median, UACR > median
A study of polymorphisms of the CHI3L1 locus encoding the inflammatory protein YKL-40 did not show any association between certain gene polymorphisms and the risk of type 2 diabetes. It therefore seems reasonable, that it is the low grade inflammation and endothelial dysfunction progressing to later micro- and macrovascular complications that account for the elevated YKL-40 levels in diabetic patients.
YKL-40 in other clinical conditions
Serum YKL-40 levels have been found to be elevated in other clinical conditions not directly related to atherosclerosis or cardiovascular disease. Several studies describe elevated YKL-40 levels in patients with different types of cancer [9, 11, 53]. YKL-40 levels seem to be related to tumor grade and burden, short recurrence-free interval and short disease-free and overall survival . The exact biological function of YKL-40 in cancer is unknown, but YKL-40 seems to play an important role in tumor invasion. The signalling pathways MAPK/ERK1/2 and PI3K/AKT which YKL-40 has been demonstrated to mediate its effects through in other conditions [26, 28] are critical in the malignant phenotype of glioblastoma and have been shown to govern proliferation and survival, invasiveness and radiation resistance . Furthermore, activation of the PI3K/AKT-pathway is correlated with increased tumor grade, lesser likelihood of apoptosis and decreased overall survival . However, the functional ligand for the chitin-binding site in YKL-40 in relation to cancer is not presently known.
Recently, an in vitro study has shown, that ectopic expression of YKL-40 in breast and colon cancer cells respectively led to tumor formation with an extensive angiogenic phenotype and that recombinant YKL-40 protein promoted vascular endothelial cell angiogenesis whereas blockade of YKL-40 suppressed tumor angiogenesis both in vitro and in vivo . Furthermore, immunohistochemical analysis of human breast cancer showed a correlation between YKL-40 expression and blood vessel density . Therefore, the occurrence of high YKL-40 levels in highly differentiated and advanced cancers and recurrent cancer states could be explained by the role of YKL-40 in both angiogenesis and fibrogenesis, since highly differentiated tumours are characterized by high vascularization and a high turnover of extracellular matrix.
YKL-40 is not tumor specific and the studies of YKL-40 as a screening marker for cancer and as a marker useful for monitoring therapeutic results differ . Furthermore, YKL-40 seems not suited as a tumor marker due to low specificity and sensitivity .
Substantial evidence supports a role of YKL-40 in endothelial dysfunction, atherosclerosis and manifest CVD. Clinical studies have demonstrated, that YKL-40 levels are associated with the presence and extent of CAD, are even higher in patients with MI and are associated with all-cause as well as cardiovascular mortality. YKL-40 plays a role in relation to cell migration, reorganization and tissue remodelling during atherogenesis and seems to play a pivotal role in the differentiation of monocytes to activated macrophages in tissues characterized by inflammation. However, the YKL-40 receptor(s) still remain to be isolated and described.
YKL-40 has emerged as a promising marker of cardiovascular disease. It seems to be useful for screening because it is detectable in early stage subclinical disease, and it also seems to have the potential of becoming a prognosticator of cardiovascular events and mortality. Future research around YKL-40 should concentrate further on establishing whether YKL-40 could assess the value of a cardiovascular biomarker in clinical practice. Therefore, further investigations of YKL-40 in relation to CAD, MI and diabetes are needed as well as intervention studies describing possible changes in serum/plasma YKL concentrations concomitant with optimized medical treatment of conditions such as e.g. angina pectoris and diabetes. Furthermore, to assess the value as a useful marker in clinical practice, both specificity and sensitivity of YKL-40 in relation to CVD need to be clarified and optimized.
Studies in obese with and without complications such as CVD and/or diabetes are few. Such studies could also contribute in establishing YKL-40 as a useful cardiovascular biomarker, since the weight loss following bariatric surgery is accompanied by a reduced risk of CVD in these patients. One study has described significantly reduced YKL-40 levels in obese having bariatric surgery indicating an association between serum YKL-40 levels and adipose tissue/weight loss/reduced cardiovascular risk that still remains to be clarified . Cardiovascular follow-up in these patients should be done.
Finally, elevated YKL-40 levels have also been observed in patients with highly differentiated and advanced cancers of various types as well as recurrent cancer states, but recent studies show that this could be explained by the role of YKL-40 in cancer angiogenesis and fibrogenesis.
CNR is one of the leading scientists worldwide in the field of YKL-40 in releation to diabetes, atherosclerosis and cardiovascular disease. CNR was the first to describe elevated YKL-40 levels in patients with type 2 diabetes and is the only scientist who has examined YKL-40 levels in patients with type 1 diabetes. Beside clinical studies in patients with diabetes and/or cardiovascular disease, CNR conduct cellular studies which hopefully will elucidate the mechanisms by which YKL-40 mediates its function. CNR obtain a Ph.D on this research field in january 2010.
HV is chief scientist with primary focus on diabetes and micro- and macrovascular complications. HV is supervisor of CNR and has made substantial contributions to concept and design of the YKL-40 studies conducted by the research group.
- Rutter MK, Meigs JB, Sullivan LM, D'Agostino RB, Wilson PW: C-reactive protein, the metabolic syndrome, and prediction of cardiovascular events in the Framingham Offspring Study. Circulation. 2004, 110: 380-385. 10.1161/01.CIR.0000136581.59584.0E.View ArticlePubMedGoogle Scholar
- Libby P, Willerson JT, Braunwald E: C-reactive protein and coronary heart disease. N Engl J Med. 2004, 351: 295-298. 10.1056/NEJM200407153510318.View ArticlePubMedGoogle Scholar
- Libby P, Ridker PM: Inflammation and atherosclerosis: role of C-reactive protein in risk assessment. Am J Med. 2004, 116 (Suppl 6A): 9S-16S. 10.1016/j.amjmed.2004.02.006.View ArticlePubMedGoogle Scholar
- Packard RR, Libby P: Inflammation in atherosclerosis: from vascular biology to biomarker discovery and risk prediction. Clin Chem. 2008, 54: 24-38. 10.1373/clinchem.2007.097360.View ArticlePubMedGoogle Scholar
- Hakala BE, White C, Recklies AD: Human cartilage gp-39, a major secretory product of articular chondrocytes and synovial cells, is a mammalian member of a chitinase protein family. J Biol Chem. 1993, 268: 25803-25810.PubMedGoogle Scholar
- Shackelton LM, Mann DM, Millis AJ: Identification of a 38-kDa heparin-binding glycoprotein (gp38k) in differentiating vascular smooth muscle cells as a member of a group of proteins associated with tissue remodeling. J Biol Chem. 1995, 270: 13076-13083. 10.1074/jbc.270.22.13076.View ArticlePubMedGoogle Scholar
- Rehli M, Krause SW, Andreesen R: Molecular characterization of the gene for human cartilage gp-39(CHI3L1), a member of the chitinase protein family and marker for late stages of macrophage differentiation. Genomics. 1997, 43: 221-225. 10.1006/geno.1997.4778.View ArticlePubMedGoogle Scholar
- Hauschka PV, Mann KG, Price P, Termine JD: Report of the Ad Hoc Committee on Nomenclature and Standards for Bone Proteins and Growth Factors. J Bone Miner Res. 1986, 1: 485-486.View ArticlePubMedGoogle Scholar
- Johansen JS, Jensen BV, Roslind A, Nielsen D, Price PA: Serum YKL-40, a new prognostic biomarker in cancer patients?. Cancer Epidemiol Biomarkers Prev. 2006, 15: 194-202. 10.1158/1055-9965.EPI-05-0011.View ArticlePubMedGoogle Scholar
- Fusetti F, Pijning T, Kalk KH, Bos E, Dijkstra BW: Crystal structure and carbohydrate-binding properties of the human cartilage glycoprotein-39. J Biol Chem. 2003, 278: 37753-37760. 10.1074/jbc.M303137200.View ArticlePubMedGoogle Scholar
- Johansen JS: Studies on serum YKL-40 as a biomarker in diseases with inflammation, tissue remodelling, fibroses and cancer. Dan Med Bull. 2006, 53: 172-209.PubMedGoogle Scholar
- Renkema GH, Boot RG, Au FL, Donker-Koopman WE, Strijland A, Muijsers AO, Hrebicek M, Aerts JM: Chitotriosidase, a chitinase, and the 39-kDa human cartilage glycoprotein, a chitin-binding lectin, are homologues of family 18 glycosyl hydrolases secreted by human macrophages. Eur J Biochem. 1998, 251: 504-509. 10.1046/j.1432-1327.1998.2510504.x.View ArticlePubMedGoogle Scholar
- Boot RG, Renkema GH, Strijland A, van Zonneveld AJ, Aerts JM: Cloning of a cDNA encoding chitotriosidase, a human chitinase produced by macrophages. J Biol Chem. 1995, 270: 26252-26256. 10.1074/jbc.270.5.2198.View ArticlePubMedGoogle Scholar
- Rathcke CN, Vestergaard H: YKL-40, a new inflammatory marker with relation to insulin resistance and with a role in endothelial dysfunction and atherosclerosis. Inflamm Res. 2006, 55: 221-227. 10.1007/s00011-006-0076-y.View ArticlePubMedGoogle Scholar
- Kirkpatrick RB, Matico RE, McNulty DE, Strickler JE, Rosenberg M: An abundantly secreted glycoprotein from Drosophila melanogaster is related to mammalian secretory proteins produced in rheumatoid tissues and by activated macrophages. Gene. 1995, 153: 147-154. 10.1016/0378-1119(94)00756-I.View ArticlePubMedGoogle Scholar
- Krause SW, Rehli M, Kreutz M, Schwarzfischer L, Paulauskis JD, Andreesen R: Differential screening identifies genetic markers of monocyte to macrophage maturation. J Leukoc Biol. 1996, 60: 540-545.PubMedGoogle Scholar
- Baeten D, Boots AM, Steenbakkers PG, Elewaut D, Bos E, Verheijden GF, Berheijden G, Miltenburg AM, Rijnders AW, Veys EM, de Keyser F: Human cartilage gp-39+, CD16+ monocytes in peripheral blood and synovium: correlation with joint destruction in rheumatoid arthritis. Arthritis Rheum. 2000, 43: 1233-1243. 10.1002/1529-0131(200006)43:6<1233::AID-ANR6>3.0.CO;2-9.View ArticlePubMedGoogle Scholar
- Rehli M, Niller HH, Ammon C, Langmann S, Schwarzfischer L, Andreesen R, Krause SW: Transcriptional regulation of CHI3L1, a marker gene for late stages of macrophage differentiation. J Biol Chem. 2003, 278: 44058-44067. 10.1074/jbc.M306792200.View ArticlePubMedGoogle Scholar
- Nishikawa KC, Millis AJ: gp38k (CHI3L1) is a novel adhesion and migration factor for vascular cells. Exp Cell Res. 2003, 287: 79-87. 10.1016/S0014-4827(03)00069-7.View ArticlePubMedGoogle Scholar
- Malinda KM, Ponce L, Kleinman HK, Shackelton LM, Millis AJ: Gp38k, a protein synthesized by vascular smooth muscle cells, stimulates directional migration of human umbilical vein endothelial cells. Exp Cell Res. 1999, 250: 168-173. 10.1006/excr.1999.4511.View ArticlePubMedGoogle Scholar
- Johansen JS, Baslund B, Garbarsch C, Hansen M, Stoltenberg M, Lorenzen I, Price PA: YKL-40 in giant cells and macrophages from patients with giant cell arteritis. Arthritis Rheum. 1999, 42: 2624-2630. 10.1002/1529-0131(199912)42:12<2624::AID-ANR17>3.0.CO;2-K.View ArticlePubMedGoogle Scholar
- Boot RG, van Achterberg TA, van Aken BE, Renkema GH, Jacobs MJ, Aerts JM, de Vries CJ: Strong induction of members of the chitinase family of proteins in atherosclerosis: chitotriosidase and human cartilage gp-39 expressed in lesion macrophages. Arterioscler Thromb Vasc Biol. 1999, 19: 687-694.View ArticlePubMedGoogle Scholar
- Johansen JS, Hoyer PE, Larsen LA, Price PA, Mollgard K: YKL-40 protein expression in the early developing human musculoskeletal system. J Histochem Cytochem. 2007, 55: 1213-1228. 10.1369/jhc.7A7245.2007.View ArticlePubMedGoogle Scholar
- Ringsholt M, Hogdall EV, Johansen JS, Price PA, Christensen LH: YKL-40 protein expression in normal adult human tissues--an immunohistochemical study. J Mol Histol. 2007, 38: 33-43. 10.1007/s10735-006-9075-0.View ArticlePubMedGoogle Scholar
- De CF, Gaufillier S, Bonnaud A, Sabatini M, Lesur C, Pastoureau P: YKL-40(cartilage gp-39) induces proliferative events in cultured chondrocytes and synoviocytes and increases glycosaminoglycan synthesis in chondrocytes. Biochem Biophys Res Commun. 2001, 285: 926-931. 10.1006/bbrc.2001.5253.View ArticleGoogle Scholar
- Recklies AD, White C, Ling H: The chitinase 3-like protein human cartilage glycoprotein 39(HC-gp39) stimulates proliferation of human connective-tissue cells and activates both extracellular signal-regulated kinase- and protein kinase B-mediated signalling pathways. Biochem J. 2002, 365: 119-126. 10.1042/BJ20020075.PubMed CentralView ArticlePubMedGoogle Scholar
- Lee CG, Hartl D, Lee GR, Koller B, Matsuura H, Da Silva CA, Sohn MH, Cohn L, Homer RJ, Kozhich AA, Humbles A, Kearley J, Coyle A, Chupp G, Reed J, Flavell RA, Elias JA: Role of breast regression protein 39(BRP-39)/chitinase 3-like-1 in Th2 and IL-13-induced tissue responses and apoptosis. J Exp Med. 2009, 206: 1149-1166. 10.1084/jem.20081271.PubMed CentralView ArticlePubMedGoogle Scholar
- Ling H, Recklies AD: The chitinase 3-like protein human cartilage glycoprotein 39 inhibits cellular responses to the inflammatory cytokines interleukin-1 and tumour necrosis factor-alpha. Biochem J. 2004, 380: 651-659. 10.1042/BJ20040099.PubMed CentralView ArticlePubMedGoogle Scholar
- Recklies AD, Ling H, White C, Bernier SM: Inflammatory cytokines induce production of CHI3L1 by articular chondrocytes. J Biol Chem. 2005, 280: 41213-41221. 10.1074/jbc.M510146200.View ArticlePubMedGoogle Scholar
- Johansen JS, Lottenburger T, Nielsen HJ, Jensen JE, Svendsen MN, Kollerup G, Christensen IJ: Diurnal, weekly, and long-time variation in serum concentrations of YKL-40 in healthy subjects. Cancer Epidemiol Biomarkers Prev. 2008, 17: 2603-2608. 10.1158/1055-9965.EPI-07-2766.View ArticlePubMedGoogle Scholar
- Rathcke CN, Johansen JS, Vestergaard H: YKL-40, a biomarker of inflammation, is elevated in patients with type 2 diabetes and is related to insulin resistance. Inflamm Res. 2006, 55: 53-59. 10.1007/s00011-005-0010-8.View ArticlePubMedGoogle Scholar
- Rathcke CN, Raymond I, Kistorp C, Hildebrandt P, Faber J, Vestergaard H: Low grade inflammation as measured by levels of YKL-40: Association with an increased overall and cardiovascular mortality rate in an elderly population. Int J Cardiol. 2009.Google Scholar
- Hempen M, Kopp HP, Elhenicky M, Hobaus C, Brix JM, Koppensteiner R, Schernthaner G, Schernthaner GH: YKL-40 is Elevated in Morbidly Obese Patients and Declines After Weight Loss. Obes Surg. 2009, 19 (11): 1557-63. 10.1007/s11695-009-9917-4.View ArticlePubMedGoogle Scholar
- Henningsen KM, Therkelsen SK, Johansen JS, Bruunsgaard H, Svendsen JH: Plasma YKL-40, a new biomarker for atrial fibrillation?. Europace. 2009, 11: 1032-1036. 10.1093/europace/eup103.View ArticlePubMedGoogle Scholar
- Kucur M, Isman FK, Karadag B, Vural VA, Tavsanoglu S: Serum YKL-40 levels in patients with coronary artery disease. Coron Artery Dis. 2007, 18: 391-396. 10.1097/MCA.0b013e328241d991.View ArticlePubMedGoogle Scholar
- Wang Y, Ripa RS, Johansen JS, Gabrielsen A, Steinbruchel DA, Friis T, Bindslev L, Haack-Sorensen M, Jorgensen E, Kastrup J: YKL-40 a new biomarker in patients with acute coronary syndrome or stable coronary artery disease. Scand Cardiovasc J. 2008, 42: 295-302. 10.1080/14017430802220567.View ArticlePubMedGoogle Scholar
- Nielsen AR, Erikstrup C, Johansen JS, Fischer CP, Plomgaard P, Krogh-Madsen R, Taudorf S, Lindegaard B, Pedersen BK: Plasma YKL-40: a BMI-independent marker of type 2 diabetes. Diabetes. 2008, 57: 3078-3082. 10.2337/db08-0182.PubMed CentralView ArticlePubMedGoogle Scholar
- Johansen JS, Pedersen AN, Schroll M, Jorgensen T, Pedersen BK, Bruunsgaard H: High serum YKL-40 level in a cohort of octogenarians is associated with increased risk of all-cause mortality. Clin Exp Immunol. 2008, 151: 260-266.PubMed CentralView ArticlePubMedGoogle Scholar
- Kralisch S, Bluher M, Paschke R, Stumvoll M, Fasshauer M: Adipokines and adipocyte targets in the future management of obesity and the metabolic syndrome. Mini Rev Med Chem. 2007, 7: 39-45. 10.2174/138955707779317821.View ArticlePubMedGoogle Scholar
- de Lemos JA, Morrow DA, Sabatine MS, Murphy SA, Gibson CM, Antman EM, McCabe CH, Cannon CP, Braunwald E: Association between plasma levels of monocyte chemoattractant protein-1 and long-term clinical outcomes in patients with acute coronary syndromes. Circulation. 2003, 107: 690-695. 10.1161/01.CIR.0000049742.68848.99.View ArticlePubMedGoogle Scholar
- Millis AJ, Hoyle M, Reich E, Mann DM: Isolation and characterization of a Mr = 38,000 protein from differentiating smooth muscle cells. J Biol Chem. 1985, 260: 3754-3761.PubMedGoogle Scholar
- Millis AJ, Hoyle M, Kent L: In vitro expression of a 38,000 dalton heparin-binding glycoprotein by morphologically differentiated smooth muscle cells. J Cell Physiol. 1986, 127: 366-372. 10.1002/jcp.1041270304.View ArticlePubMedGoogle Scholar
- Schwartz SM: Smooth muscle migration in vascular development and pathogenesis. Transpl Immunol. 1997, 5: 255-260. 10.1016/S0966-3274(97)80005-6.View ArticlePubMedGoogle Scholar
- Fach EM, Garulacan LA, Gao J, Xiao Q, Storm SM, Dubaquie YP, Hefta SA, Opiteck GJ: In vitro biomarker discovery for atherosclerosis by proteomics. Mol Cell Proteomics. 2004, 3: 1200-1210. 10.1074/mcp.M400160-MCP200.View ArticlePubMedGoogle Scholar
- Kastrup J, Johansen JS, Winkel P, Hansen JF, Hildebrandt P, Jensen GB, Jespersen CM, Kjoller E, Kolmos HJ, Lind I, Nielsen H, Gluud C: High serum YKL-40 concentration is associated with cardiovascular and all-cause mortality in patients with stable coronary artery disease. Eur Heart J. 2009, 30: 1066-1072. 10.1093/eurheartj/ehp049.View ArticlePubMedGoogle Scholar
- Nojgaard C, Host NB, Christensen IJ, Poulsen SH, Egstrup K, Price PA, Johansen JS: Serum levels of YKL-40 increases in patients with acute myocardial infarction. Coron Artery Dis. 2008, 19: 257-263. 10.1097/MCA.0b013e3282f40dd5.View ArticlePubMedGoogle Scholar
- Stamler J, Vaccaro O, Neaton JD, Wentworth D: Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. 1993, 16: 434-444. 10.2337/diacare.16.2.434.View ArticlePubMedGoogle Scholar
- Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S, Schroll M, Jensen JS: Urinary albumin excretion. An independent predictor of ischemic heart disease. Arterioscler Thromb Vasc Biol. 1999, 19: 1992-1997.View ArticlePubMedGoogle Scholar
- Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF, Hoogwerf B, Halle JP, Young J, Rashkow A, Joyce C, Nawaz S, Yusuf S: Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA. 2001, 286: 421-426. 10.1001/jama.286.4.421.View ArticlePubMedGoogle Scholar
- Rossing P, Hougaard P, Parving HH: Progression of microalbuminuria in type 1 diabetes: ten-year prospective observational study. Kidney Int. 2005, 68: 1446-1450. 10.1111/j.1523-1755.2005.00556.x.View ArticlePubMedGoogle Scholar
- Laing SP, Swerdlow AJ, Slater SD, Burden AC, Morris A, Waughn NR, Gatling W, Bingley PJ, Patterson CC: Mortality from heart disease in a cohort of 23,000 patients with insulin-treated diabetes. Diabetologia. 2003, 46: 760-765. 10.1007/s00125-003-1116-6.View ArticlePubMedGoogle Scholar
- Rathcke CN, Persson F, Tarnow L, Rossing P, Vestergaard H: YKL-40, a marker of inflammation and endothelial dysfunction, is elevated in patients with type 1 diabetes and increases with levels of albuminuria. Diabetes Care. 2009, 32: 323-328. 10.2337/dc08-1144.PubMed CentralView ArticlePubMedGoogle Scholar
- Roslind A, Johansen JS: YKL-40: a novel marker shared by chronic inflammation and oncogenic transformation. Methods Mol Biol. 2009, 511: 159-184. full_text.View ArticlePubMedGoogle Scholar
- Pelloski CE, Lin E, Zhang L, Yung WK, Colman H, Liu JL, Woo SY, Heimberger AB, Suki D, Prados M, Chang S, Barjer FG, Fuller GN, Aldape KD: Prognostic associations of activated mitogen-activated protein kinase and Akt pathways in glioblastoma. Clin Cancer Res. 2006, 12: 3935-3941. 10.1158/1078-0432.CCR-05-2202.View ArticlePubMedGoogle Scholar
- Shao R, Hamel K, Petersen L, Cao QJ, Arenas RB, Bigelow C, Bentley B, Yan W: YKL-40, a secreted glycoprotein, promotes tumor angiogenesis. Oncogene. 2009.Google Scholar
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