Increased circulating osteopontin levels in adult patients with type 1 diabetes mellitus and association with dysmetabolic profile

in European Journal of Endocrinology
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  • 1 Internal Medicine Unit, Rheumatology, Department of Ophthalmology, Endocrinology and Diabetes, Department of Internal Medicine and Medical Specialties

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Objective

Osteopontin (OPN) is a sialoprotein implicated in different immunity and metabolic pathways. Capable of activating dendritic cells and inducing Th1-Th17-mediated tissue damage, OPN plays a significant role in the development/progression of several autoimmune diseases; interestingly, it was also shown that OPN participates in the acute pancreatic islets response to experimentally induced diabetes in non-obese diabetic (NOD) mice. Furthermore, OPN promotes adipose tissue dysfunction, systemic inflammation and insulin resistance. Our aims of this study were to evaluate circulating OPN levels in adult patients with type 1 diabetes mellitus (T1DM) compared to non-diabetic control participants and to unravel clinical and biochemical correlates of OPN concentration.

Design

Case–control study.

Methods

We enrolled 54 consecutive T1DM patients referred to our diabetes outpatient clinic at Sapienza University of Rome and 52 healthy sex and age-comparable controls. The study population underwent clinical evaluation, blood sampling for biochemistry and complete screening for diabetes complications. Serum OPN levels were measured by MILLIPLEX Multiplex Assays Luminex.

Results

T1DM patients had significantly higher serum OPN levels than controls (17.2±12.9 vs 10.5±11.6 mg/ml, P=0.009). OPN levels correlated with T1DM, higher blood pressure, BMI, creatinine, γ-GT, ALP and lower HDL; the association between high OPN levels and T1DM was independent from all confounders. No correlation was shown between OPN and HbA1c, C-peptide, insulin requirement, co-medications and diabetes duration.

Conclusions

This study demonstrates for the first time in a case–control study that adults with T1DM have increased serum OPN levels, and that higher OPN concentrations are associated with an unfavorable metabolic profile in these patients.

Abstract

Objective

Osteopontin (OPN) is a sialoprotein implicated in different immunity and metabolic pathways. Capable of activating dendritic cells and inducing Th1-Th17-mediated tissue damage, OPN plays a significant role in the development/progression of several autoimmune diseases; interestingly, it was also shown that OPN participates in the acute pancreatic islets response to experimentally induced diabetes in non-obese diabetic (NOD) mice. Furthermore, OPN promotes adipose tissue dysfunction, systemic inflammation and insulin resistance. Our aims of this study were to evaluate circulating OPN levels in adult patients with type 1 diabetes mellitus (T1DM) compared to non-diabetic control participants and to unravel clinical and biochemical correlates of OPN concentration.

Design

Case–control study.

Methods

We enrolled 54 consecutive T1DM patients referred to our diabetes outpatient clinic at Sapienza University of Rome and 52 healthy sex and age-comparable controls. The study population underwent clinical evaluation, blood sampling for biochemistry and complete screening for diabetes complications. Serum OPN levels were measured by MILLIPLEX Multiplex Assays Luminex.

Results

T1DM patients had significantly higher serum OPN levels than controls (17.2±12.9 vs 10.5±11.6 mg/ml, P=0.009). OPN levels correlated with T1DM, higher blood pressure, BMI, creatinine, γ-GT, ALP and lower HDL; the association between high OPN levels and T1DM was independent from all confounders. No correlation was shown between OPN and HbA1c, C-peptide, insulin requirement, co-medications and diabetes duration.

Conclusions

This study demonstrates for the first time in a case–control study that adults with T1DM have increased serum OPN levels, and that higher OPN concentrations are associated with an unfavorable metabolic profile in these patients.

Background

Osteopontin (OPN), or early T-lymphocyte activation-1, is a sialoprotein originated by the bone and by a large number of other tissues and cells. OPN has been described as a secreted protein involved in a wide spectrum of physiopathological processes, as OPN expression was demonstrated in the nucleus and cytoplasm of several different cells. The term ‘osteopontin’ takes origin from the role of this protein in bone metabolism, as OPN exerts a major function in controlling biomineralization and stimulating adhesion, migrations and bone resorption by osteoclasts (1, 2, 3).

Among its non-bone related functions, OPN plays a pivotal role in the regulation of immune cell functions including monocyte adhesion, migration, differentiation and phagocytosis (4, 5, 6, 7). It also exerts an influence on T-helper (Th) cells polarization to Th1 or Th2 phenotypes, a critical aspect of cell-mediated immunity, by enhancing Th1 and inhibiting Th2 cytokine expression (8).

OPN was also demonstrated to induce adipose tissue inflammation, increase pro-inflammatory cytokines release in the bloodstream and, consequently, promote the development of insulin resistance (IR)-related conditions (9, 10, 11). Increased OPN levels were found in obese participants (12, 13) and predicted coronary calcification, nephropathy and coronary artery disease in patients with type 2 diabetes, independent of traditional risk factors (14, 15).

For its action in the regulation of immune system, OPN has been recognized to have a role in the development/progression of several autoimmune diseases, such as multiple sclerosis (16, 17, 18, 19) rheumatoid arthritis (20, 21), psoriasis (22) and Graves' disease (23).

Interestingly, OPN was shown to influence the acute pancreatic islets' response to experimentally induced diabetes in non-obese diabetic (NOD) mice, and genetic studies of single nucleotide polymorphisms (SNPs) in humans suggest that the OPN encoding gene might be associated with an increased susceptibility to the development of type 1 diabetes mellitus (T1DM) (24, 25). Moreover, serum OPN levels were demonstrated to strongly predict incipient diabetic nephropathy (DN), cardiovascular events and all-cause mortality in patients with T1DM (26) and were associated with renal failure and left ventricular hypertrophy in patients affected by systemic hypertension (27, 28). Furthermore, in a recent study, obese individuals exhibited significantly increased blood OPN levels and higher adipose tissue/peripheral blood mononuclear cells OPN expression compared with lean individuals; OPN also correlated with fasting blood glucose (FBG) and BMI (13).

However, so far no study has investigated whether OPN serum levels in adult T1DM patients are increased compared with non-diabetic controls or which variables may be associated with increased OPN levels.

Therefore, the aims of this study were to evaluate circulating OPN levels in an adult population of T1DM patients compared to non-diabetic participants and to explore clinical and biochemical correlates of OPN concentration.

Subjects and methods

This is an observational case–control study. For our purposes, we enrolled 54 consecutive patients with T1DM (M/F: 36/18, mean±s.d. age: 36.2±12 years, mean±s.d. diabetes' duration: 13.2±13.3 years) among those referring to our diabetes outpatient clinics at Sapienza University of Rome and 52 control participants comparable for sex and age (M/F: 33/19, mean±s.d. age: 39.3±7.4 years, P value: 0.87 and 0.16 respectively) without T1DM or other chronic diseases selected among Sapienza University employees undergoing clinical evaluation for the Occupational Medicine Service. Participants' recruitment took place between June 2013 and February 2014.

Each participant underwent a medical history collection and physical examination (height, weight, waist circumference, systolic and diastolic blood pressure (SBP, DBP, mmHg) measurement and BMI (kg/m2) calculation) as well as, where appropriate, a clinical/instrumental assessment for diabetes complications, daily insulin requirement (IU/kg per day) and concomitant medications at the time of study enrollment (statins, angiotensin converting enzyme inhibitors (ACE-I)).

Ophthalmoscopy was performed on T1D patients by the same ophthalmologist experienced in diabetes. One drop of atropine was put in each eye and left for 20–30 min for the pupil to dilate. Ophthalmoscopy was followed by retinal fluorangiography, when indicated. Retinal examination was used to identify and quantify diabetic retinopathy (DR) according to the International Clinical Diabetic Retinopathy Disease Severity Scale (29).

DN was defined as persistent microalbuminuria (30–300 mg/day) or macroalbuminuria (>300 mg/day) in at least two of three urine samples collected over 24 h.

All study participants underwent blood sampling for biochemistry after an overnight fasting. FBG (mg/dl), HbA1c (% – mmol/mol), C-peptide (ng/ml), total cholesterol (mg/dl), HDL-cholesterol (mg/dl), triglycerides (mg/dl), blood urea nitrogen (BUN, mg/dl), creatinine (mg/dl), aspartate aminotransferase (AST, IU/l), alanine aminotransferase (ALT, IU/l), alkaline phosphatase (ALP, IU/l) and gamma-glutamyl transpeptidase (γ-GT, IU/l) were measured by standard laboratory methods after an overnight fasting. LDL-cholesterol (mg/dl) value was obtained using Friedewald formula. The glomerular filtration rate (GFR, ml/min) `was estimated by means of Cockcroft-Gault formula. Serum parathyroid hormone (PTH, pg/ml) and OPN (μg/l) levels were measured by MILLIPLEX Multiplex Assays Luminex in sera frozen immediately after separation and stored at −25 °C for two weeks.

Statistical analysis

SPSS version 17 statistical package was used to perform the analyses. Student's t test for continuous variables and χ2 test for categorical variables were used to compare mean values between two independent groups. As OPN, BMI, triglycerides, AST, ALT, BUN, HDL, FBG, HbA1c, ALP, PTH and γ-GT were skewed variables, we used natural logarithmic transformation to normalize the distribution of these parameters before all analyses. For statistical analyses, the presence of DR was categorized as follows: 0=absence of DR, 1=non-proliferative DR, 2=proliferative DR; DN was considered on the basis of the absence (DN=0) or the presence of persistent microalbuminuria (DN=1) or macroalbuminuria (DN=2) in at least two of three urine samples collected over 24 h.

Bivariate and multivariate linear regression analyses were used to detect the association between serum OPN levels, considered as a continuous variable, and all possible determinants. Correlations between continuous variables were calculated by Pearson's coefficient, whereas Spearman's coefficient was used for dichotomic/ordinal parameters. A multiple liner regression analysis, including all variables significantly associated with OPN levels at the bivariate analyses, was performed to confirm the independence of the association between OPN (considered as dependent variable) and the diagnosis of T1DM.

Data are shown as mean±s.d., median (min–max) or as percentage in both text and tables, as appropriate. For all of the above, P<0.05 was considered statistically significant.

This study was approved by the local ethical committee, Sapienza University of Rome, functioning according to the 3rd edition of the Guidelines on the Practice of Ethical Committees in Medical Research issued by the Royal College of Physicians of London. Written consent was obtained from each patient and control participant after a full explanation of the purpose and nature of all procedures used.

Results

Clinical and biochemical characteristics of study cohorts are shown in Tables 1 and 2. Patients with T1DM had significantly higher serum OPN levels compared with controls (mean±s.d.: 17.2±12.9, (median (min–max): 13.6 (1.4–62.9)) μg/l vs mean±s.d.: 10.5±11.6, (median (min–max): 5.7 (0.2–76.89) μg/l, P=0.009); they also showed lower BMI, waist circumference, triglycerides, higher FBG and ALP than the control group.

Table 1

Clinical and biochemical characteristics of T1D patients and control participants. Values are expressed by mean±s.d., median (min–max) or rate of subjects, as appropriate.

ParameterT1DM (n=54)Controls (n=52)P value
Age (years)36.2±1239.3±7.40.16
Sex (M/F)36/1833/190.87*
BMI (kg/m2)22.9 (17.4–35.9)24.4 (18.6–40.2)0.04
Waist circumference (cm)77.5±10.587.5±16.40.01
SBP (mmHg)119.4±12.7120.7±14.60.66
DBP (mmHg)77.9±10.477.1±8.70.74
FBG (mg/dl)116.5 (86–385)91 (74–120)<0.001
BUN (mg/dl)38 (9–61)34 (19–65)0.78
Creatinine (mg/dl)0.96±0.30.92±0.20.42
GFR (ml/min)122±37.3135.2±31.20.056
Total cholesterol (mg/dl)187.4±32.7195.8±39.40.27
HDL cholesterol (mg/dl)54 (31–93)54.5 (31–79)0.81
LDL cholesterol (mg/dl)115.9±28.2116.7±35.20.90
Triglycerides (mg/dl)75 (29–323)83 (35–295)0.02
AST (IU/l)19 (12–50)17.5 (11–35)0.056
ALT (IU/l)20.5 (7.59)18 (1050)0.047
ALP (IU/l)73.5 (56–354)62.5 (10–109)0.006
γ-GT (IU/l)15 (8–244)18 (6–62)0.31
PTH (pg/ml)25.7 (3.6–443)52.5 (1–287)0.68
OPN (μg/l)13.6 (1.4–62.9)5.7 (0.2–76.8)0.009

T test for independent samples test applied. *χ2 test applied. P values <0.05 are considered statistically significant.

Table 2

Characteristics of T1DM patients. Values are expressed by mean±s.d., range or number/percentage, as appropriate.

ParameterValues
Disease duration (years)13.2±13.3
 Median (min–max; years)7 (<1–40)
HbA1c (mmol/mol, %)54±10 to 7.1±1.7
IR (U/kg per day)0.45±0.5
Fasting C-peptide (ng/ml; (range))0.1±0.3 (0–1)
Microalbuminuria (mg/day; (range))9.6±16.5 (0–76)
Prevalence of DR % (n)20% (11)
Prevalence of DN % (n)20% (11)
 Microalbuminuria73% (8)
 Macroalbuminuria27% (3)
Use of statins % (n)22% (12)
Use of antihypertensive agents % (n)35% (19)

In the overall study population (n=106) circulating OPN levels correlated with higher SBP (correlation coefficient: 0.35, P=0.001), DBP (correlation coefficient: 0.23, P=0.03), BMI (correlation coefficient: 0.22, P=0.02), BUN (correlation coefficient: 0.26, P=0.02), serum creatinine (correlation coefficient: 0.25, P=0.02), γ-GT (correlation coefficient: 0.31, P=0.006), ALP (correlation coefficient: 0.27, P=0.04), PTH (correlation coefficient: 0.37, P<0.001), lower HDL (correlation coefficient: −0.25, P=0.02) and the diagnosis of T1DM (correlation coefficient: 0.32, P<0.001). No correlation was found between OPN levels and HbA1c, C-peptide, GFR, microalbuminuria, IR, diabetes complications and disease duration in T1DM patients.

To rule out an influence of chronic ACE-I treatment on OPN levels, as previously suggested by studies in experimental models, circulating OPN levels were also evaluated separately in T1DM patients according to the use of ACE-Is and no difference was detected between T1DM patients with (n=19) and without (n=35) ACE-I therapy (T1DM treated with ACE-I OPN: 15.9±11.3 μg/l, T1DM participants without ACE-I OPN: 17.3±18.5 μg/l, P=0.98).

Finally, the multivariate linear regression analysis demonstrated that higher circulating OPN levels were associated with the diagnosis of T1DM independent of all possible confounders (P=0.03; Table 3).

Table 3

Multivariate linear regression analysis. OPN is considered as the dependent variable of the model.

VariableNon-standardized βStandard errorStandardized βtP-value
Constant−26.47720.909−1.2660.213
PTH−0.0050.023−0.033−0.2200.827
HDL−0.0540.125−0.064−0.4310.669
Creatinine10.1598.8950.1701.1420.261
DBP−0.2940.368−0.205−0.7990.429
SBP0.4720.2650.4711.7770.084
γ-GT0.0030.0730.0110.0370.971
ALP−0.0400.100−0.126−0.3960.695
T1D (yes/no)10.9965.0380.3702.1830.035

Discussion

Our study demonstrates that circulating OPN levels are significantly higher in adult patients with T1DM compared to healthy participants and that the association between diabetes and increased OPN levels is independent from clinical and biochemical confounders. Furthermore, circulating OPN levels directly correlate with several cardio-metabolic risk factors, such as higher BMI, SBP and DBP and lower HDL, but not with diabetes complications, IR, C-peptide and disease duration.

Recently, increased OPN levels were observed in sera of pediatric patients with T1DM compared with healthy children in an Iranian study conducted by Karamizadeh et al. (30), but the presence of clinical and biochemical determinants of high OPN levels were not explored.

Moreover, in a large population of T1DM patients from the FinnDiane study cohort with a median disease duration of 20 years, Gordin et al. (26) demonstrated that serum OPN concentration was an independent predictor of DN, cardiovascular events and all-cause mortality after a 10-year follow-up. These authors also found an association between higher OPN levels and micro- and macroalbuminuria at baseline and, in agreement with our results, did not find any relationship between OPN levels and glycemic control. However, in this study (26) OPN levels at baseline were not compared with a control population, thus no inference can be made if the range of OPN levels detected in T1DM patients are comparable to those present in normal individuals. In our study sample, the median diabetes duration was 7 years and the prevalence of DN was 20%; among patients with stable albuminuria, <30% had macroalbuminuria. Indeed, we observed a direct correlation between OPN levels, BUN and serum creatinine, but this association disappeared after adjusting for other confounders at multivariate analysis.

Interestingly, in our study population, higher OPN levels correlated with a dysmetabolic profile. Our findings are in line with data from type 2 diabetic patients in which elevated circulating OPN levels were associated with the presence and development of coronary artery disease and artery calcification (14, 15). Several studies described OPN as a key regulator of adipose tissue inflammation and IR; notably, both serum levels and adipose tissue expression of the number of pro-inflammatory cytokines, such as IL6, TNFα, MCP-1 and iNOS, were significantly reduced in experimental models of mice lacking the OPN gene (11). In these studies, OPN deficiency led to reduced adipose tissue inflammation and increased insulin sensitivity (10, 11).

In agreement with the results obtained in our study, circulating OPN levels were also associated with a dysmetabolic profile in other autoimmune diseases, such as psoriasis and rheumatoid arthritis (22, 31); in these cohorts, higher OPN concentrations correlated with hypertension and increased arterial stiffness. The hypothesis of a direct role of OPN in atherosclerosis is supported by the occurrence of more severe cardiovascular disease and restenosis after percutaneous coronary intervention in patients with elevated OPN levels, independent of traditional cardiovascular risk factors (32, 33).

In conclusion, this study shows for the first time in a cross-sectional setting that increased OPN levels are independently associated with T1DM and identify patients with an unfavorable metabolic profile. Therefore, our results provide further support to the hypothesis that OPN may have a role in the prediction of micro- and macro-vascular diabetes complications. Future studies are warranted to evaluate OPN as a possible novel marker/mediator of increased cardiovascular risk and a useful tool for risk stratification in T1DM patients.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This work was funded by research grants from the Sapienza Ateneo Scientific Research 2010 to C Alessandri, M Di Franco and M G Cavallo and from the Regione Autonoma della Sardegna RAS 2007 (number CRP-59453) to M G Baroni.

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  • 31

    Bazzichi L, Ghiadoni L, Rossi A, Bernardini M, Lanza M, De Feo F, Giacomelli C, Mencaroni I, Raimo K, Rossi M et al.. Osteopontin is associated with increased arterial stiffness in rheumatoid arthritis. Molecular Medicine 2009 15 402406. (doi:10.2119/molmed.2009.00052).

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  • 32

    Momiyama Y, Ohmori R, Fayad ZA, Kihara T, Tanaka N, Kato R, Taniguchi H, Nagata M, Nakamura H, Ohsuzu F. Associations between plasma osteopontin levels and the severities of coronary and aortic atherosclerosis. Atherosclerosis 2010 210 668670. (doi:10.1016/j.atherosclerosis.2009.12.024).

    • Search Google Scholar
    • Export Citation
  • 33

    Kato R, Momiyama Y, Ohmori R, Tanaka N, Taniguchi H, Arakawa K, Kusuhara M, Nakamura H, Ohsuzu F. High plasma levels of osteopontin in patients with restenosis after percutaneous coronary intervention. Arteriosclerosis Thrombosis and Vascular Biology 2006 26 e1e2. (doi:10.1161/01.ATV.0000194157.26665.e6).

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     European Society of Endocrinology

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  • 1

    Hunter GK, Hauschka PV, Poole AR, Rosenberg LC, Goldberg HA. Nucleation and inhibition of hydroxyapatite formation by mineralized tissue proteins. Biochemistry Journal 1996 317 5964. (doi:10.1042/bj3170059).

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  • 2

    Scatena M, Liaw L, Giachelli CM. Osteopontin: a multifunctional molecule regulating chronic inflammation and vascular disease. Arteriosclerosis Thrombosis and Vascular Biology 2007 27 23022309. (doi:10.1161/ATVBAHA.107.144824).

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  • 3

    Chellaiah MA, Kizer N, Biswas R, Alvarez U, Strauss-Schoenberger J, Rifas L, Rittling SR, Denhardt DT, Hruska KA. Osteopontin deficiency produces osteoclast dysfunction due to reduced CD44 surface expression. Molecular Biology of the Cell 2003 14 173189. (doi:10.1091/mbc.E02-06-0354).

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  • 4

    Giachelli CM, Lombardi D, Johnson RJ, Murry CE, Almeida M. Evidence for a role of osteopontin in macrophage infiltration in response to pathological stimuli in vivo. American Journal of Pathology 1998 152 353358.

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  • 5

    Weber GF, Zawaideh S, Hikita S, Kumar VA, Cantor H, Ashkar S. Phosphorylation-dependent interaction of osteopontin with its receptors regulates macrophage migration and activation. Journal of Leukocyte Biology 2002 72 752761.

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  • 6

    Crawford HC, Matrisian LM, Liaw L. Distinct roles of osteopontin in host defense activity and tumor survival during squamous cell carcinoma progression in vivo. Cancer Research 1998 15 52065215.

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  • 7

    O'Regan AW, Chupp GL, Lowry JA, Goetschkes M, Mulligan N, Berman JS. Osteopontin is associated with T cells in sarcoid granulomas and has T cell adhesive and cytokine-like properties in vitro. Journal of Immunology 1999 162 10241031.

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  • 8

    Ashkar S, Weber GF, Panoutsakopoulou V, Sanchirico ME, Jansson M, Zawaideh S, Rittling SR, Denhardt DT, Glimcher MJ, Cantor H. Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. Science 2000 287 860864. (doi:10.1126/science.287.5454.860).

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  • 9

    Ahlqvist E, Osmark P, Kuulasmaa T, Pilgaard K, Omar B, Brøns C, Kotova O, Zetterqvist AV, Stancáková A, Jonsson A et al.. Link between GIP and osteopontin in adipose tissue and insulin resistance. Diabetes 2013 62 20882094. (doi:10.2337/db12-0976).

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  • 10

    Kiefer FW, Zeyda M, Todoric J, Huber J, Geyeregger R, Weichhart T, Aszmann O, Ludvik B, Silberhumer GR, Prager G et al.. Osteopontin expression in human and murine obesity: extensive local up-regulation in adipose tissue but minimal systemic alterations. Endocrinology 2008 149 13501357. (doi:10.1210/en.2007-1312).

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  • 11

    Nomiyama T, Perez-Tilve D, Ogawa D, Gizard F, Zhao Y, Heywood EB, Jones KL, Kawamori R, Cassis LA, Tschöp MH et al.. Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice. Journal of Clinical Investigation 2007 117 28772888. (doi:10.1172/JCI31986).

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  • 12

    Gomez-Ambrosi J, Catalan V, Ramirez B, Rodriguez A, Colina I, Silva C, Rotellar F, Mugueta C, Gil MJ, Cienfuegos JA et al.. Plasma osteopontin levels and expression in adipose tissue are increased in obesity. Journal of Clinical Endocrinology and Metabolism 2007 92 37193727. (doi:10.1210/jc.2007-0349).

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  • 13

    Ahmad R, Al-Mass A, Al-Ghawas D, Shareif N, Zghoul N, Melhem M, Hasan A, Al-Ghimlas F, Dermime S, Behbehani K. Interaction of osteopontin with IL18 in obese individuals: implications for insulin resistance. PLoS ONE 2013 8 e63944. (doi:10.1371/journal.pone.0063944).

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  • 14

    Berezin AE, Kremzer AA. Circulating osteopontin as a marker of early coronary vascular calcification in type two diabetes mellitus patients with known asymptomatic coronary artery disease. Atherosclerosis 2013 229 475481. (doi:10.1016/j.atherosclerosis.2013.06.003).

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  • 15

    Yan X, Sano M, Lu L, Wang W, Zhang Q, Zhang R, Wang L, Chen Q, Fukuda K, Shen W. Plasma concentrations of osteopontin, but not thrombin-cleaved osteopontin, are associated with the presence and severity of nephropathy and coronary artery disease in patients with type 2 diabetes mellitus. Cardiovascular Diabetology 2010 9 70. (doi:10.1186/1475-2840-9-70).

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  • 16

    Kivisäkk P, Healy BC, Francois K, Gandhi R, Gholipour T, Egorova S, Sevdalinova V, Quintana F, Chitnis T, Weiner HL et al.. Evaluation of circulating osteopontin levels in an unselected cohort of patients with multiple sclerosis: relevance for biomarker development. Multiple Sclerosis 2014 20 438444. (doi:10.1177/1352458513503052).

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  • 17

    Shimizu Y, Ota K, Ikeguchi R, Kubo S, Kabasawa C, Uchiyama S. Plasma osteopontin levels are associated with disease activity in the patients with multiple sclerosis and neuromyelitis optica. Journal of Neuroimmunology 2013 263 148151. (doi:10.1016/j.jneuroim.2013.07.005).

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  • 18

    Comi C, Cappellano G, Chiocchetti A, Orilieri E, Buttini S, Ghezzi L, Galimberti D, Guerini F, Barizzone N, Perla F et al.. The impact of osteopontin gene variations on multiple sclerosis development and progression. Clinical and Developmental Immunology 2012 2012 212893. (doi:10.1155/2012/212893).

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  • 19

    Wen SR, Liu GJ, Feng RN, Gong FC, Zhong H, Duan SR, Bi S. Increased levels of IL-23 and osteopontin in serum and cerebrospinal fluid of multiple sclerosis patients. Journal of Neuroimmunology 2012 244 9496. (doi:10.1016/j.jneuroim.2011.12.004).

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  • 20

    Iwadate H, Kobayashi H, Kanno T, Asano T, Saito R, Sato S, Suzuki E, Watanabe H, Ohira H. Plasma osteopontin is correlated with bone resorption markers in rheumatoid arthritis patients. International Journal of Rheumatic Diseases 2014 17 5056. (doi:10.1111/1756-185X.12115).

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  • 21

    Ji HI, Lee SH, Song R, Yang HI, Lee YA, Hong SJ, Kim S, Park YB, Lee SK, Yoo MC et al.. Serum level of osteopontin as an inflammatory marker does not indicate disease activity or responsiveness to therapeutic treatments in patients with rheumatoid arthritis. Clinical Rheumatology 2014 33 397402. (doi:10.1007/s10067-013-2375-3).

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  • 22

    Chen YJ, Shen JL, Wu CY, Chang YT, Chen CM, Lee FY. Elevated plasma osteopontin level is associated with occurrence of psoriasis and is an unfavorable cardiovascular risk factor in patients with psoriasis. Journal of the American Academy of Dermatology 2009 60 225230. (doi:10.1016/j.jaad.2008.09.046).

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  • 23

    Xu L, Ma X, Wang Y, Li X, Qi Y, Cui B, Li X, Ning G, Wang S. The expression and pathophysiological role of osteopontin in Graves' disease. Journal of Clinical Endocrinology and Metabolism 2011 96 E1866E1870. (doi:10.1210/jc.2011-1339).

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  • 24

    Chiocchetti A, Orilieri E, Cappellano G, Barizzone N, D' Alfonso S, D' Annunzio G, Lorini R, Ravazzolo R, Cadario F, Martinetti M et al.. The osteopontin gene +1239A/C single nucleotide polymorphism is associated with type 1 diabetes mellitus in the Italian population. International Journal of Immunopathology and Pharmacology 2010 23 263269.

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  • 25

    Marciano R, D'Annunzio G, Minuto N, Pasquali L, Santamaria A, Di Duca M, Ravazzolo R, Lorini R. Association of alleles at polymorphic sites in the Osteopontin encoding gene in young type 1 diabetic patients. Clinical Immunology 2009 131 8491. (doi:10.1016/j.clim.2008.11.004).

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  • 26

    Gordin D, Forsblom C, Panduru NM, Thomas MC, Bjerre M, Soro-Paavonen A, Tolonen N, Sandholm N, Flyvbjerg A, Harjutsalo V et al.. Osteopontin is a strong predictor of incipient diabetic nephropathy, cardiovascular disease, and all-cause mortality in patients with type 1 diabetes. Diabetes Care 2014 37 25932600. (doi:10.2337/dc14-0065).

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  • 27

    Xu TY, Zhang Y, Li Y, Zhu DL, Gao PJ. The association of serum inflammatory biomarkers with chronic kidney disease in hypertensive patients. Renal Failure 2014 36 666672. (doi:10.3109/0886022X.2014.890002).

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  • 28

    Hou X, Hu Z, Huang X, Chen Y, He X, Xu H, Wang N. Serum osteopontin, but not OPN gene polymorphism, is associated with LVH in essential hypertensive patients. Journal of Molecular Medicine 2014 92 487495. (doi:10.1007/s00109-013-1099-9).

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  • 29

    Wilkinson CP, Ferris FL III, Klein RE, Lee PP, Agardh CD, Davis M, Dills D, Kampik A, Pararajasegaram R, Verdaguer JT et al.. Proposed international clinical retinopathy and diabetic macular edema disease severity scales. Ophthalmology 2003 110 16771682. (doi:10.1016/S0161-6420(03)00475-5).

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  • 30

    Karamizadeh Z, Kamali Sarvestani E, Saki F, Karamifar H, Amirhakimi GH, Namavar Shooshtarian MH, Ashkani-Esfahani S. Investigation of osteopontin levels and genomic variation of osteopontin and its receptors in type 1 diabetes mellitus. Journal of Endocrinological Investigation 2013 36 10901093. (doi:10.3275/9098).

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  • 31

    Bazzichi L, Ghiadoni L, Rossi A, Bernardini M, Lanza M, De Feo F, Giacomelli C, Mencaroni I, Raimo K, Rossi M et al.. Osteopontin is associated with increased arterial stiffness in rheumatoid arthritis. Molecular Medicine 2009 15 402406. (doi:10.2119/molmed.2009.00052).

    • Search Google Scholar
    • Export Citation
  • 32

    Momiyama Y, Ohmori R, Fayad ZA, Kihara T, Tanaka N, Kato R, Taniguchi H, Nagata M, Nakamura H, Ohsuzu F. Associations between plasma osteopontin levels and the severities of coronary and aortic atherosclerosis. Atherosclerosis 2010 210 668670. (doi:10.1016/j.atherosclerosis.2009.12.024).

    • Search Google Scholar
    • Export Citation
  • 33

    Kato R, Momiyama Y, Ohmori R, Tanaka N, Taniguchi H, Arakawa K, Kusuhara M, Nakamura H, Ohsuzu F. High plasma levels of osteopontin in patients with restenosis after percutaneous coronary intervention. Arteriosclerosis Thrombosis and Vascular Biology 2006 26 e1e2. (doi:10.1161/01.ATV.0000194157.26665.e6).

    • Search Google Scholar
    • Export Citation