High Osteopontin Research Articles

Abstract 1415: Osteopontin and matrix metalloproteinase 2 plasma levels are elevated in colorectal cancer (CRC) vs benign disease; The 2 protein combination improves specificity as regards CRC diagnosis

Abstract Introduction: Expression of Osteopontin (OPN) and Matrix Metalloproteinase 2 (MMP 2) are elevated in CRC. OPN is an integrin binding phosphorylated glycoprotein implicated in cell-mediated immunity, inflammation, tumor progression, and cell viability. OPN is secreted by macrophages and leukocytes. OPN activity is associated with the PI3K/AKT and ERK pathways and VEGF mediated tumor angiogenesis. MMP-2 degrades type IV collagen and facilitates tumor cell invasion and metastasis. MMP-2 also promotes tumor angiogenesis. This study’s first purpose was to compare preoperative (PreOp) plasma OPN and MMP2 levels in CRC and benign pathology (BP) patients (pts); the 2nd purpose was to assess the combination of these proteins for diagnosis. Method: PreOp plasma samples obtained from consenting CRC and BP pts undergoing surgery were used for this study. Prospectively gathered demographic, clinical and pathologic data were analyzed. Plasma levels of OPN and MMP2 (ng/ml) were measured via ELISA and reported as median + 95% CI. The receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) were used to evaluate the diagnostic value of each protein alone and in combination. Expression levels of OPN and MMP2 were determined in tumor and normal tissue for a subset of pts by QRT-PCR. The Mann-Whitney test was used for analysis. Results: Plasma from 156 CRC (73% colon, 27% rectal) and 102 BP (polyp 32%, diverticulitis 56%, other 12%) pts was studied. CRC stage breakdown was: 1, 26%; 2, 33%, 3, 29%, 4, 12%. CRC median preop plasma levels were significantly higher vs. the BP group for both proteins [OPN; 82.4,CI:75.4, 89.5 vs 59.2, CI:53.8,63.3;MMP2; 203.6,CI:195.0,214.5 vs 160.2,CI:151.9,172.2; P<0.0001). Higher OPN levels were noted in stg 3(p=0.04) and Stg 4(p=0.01) vs stg 1 pts. The AUC value for the ROC curve for OPN and MMP2 were 0.73 and 0.73 respectively with 61% and 70% specificity. The AUC for the 2 protein combination was 0.80 with 65% sensitivity and 80% specificity. OPN and MMP2 expression was elevated in 75% and 50% of CRC tumors tested, respectively (n=12). Conclusion: Median CRC OPN and MMP2 levels were significantly higher (39% and 27%) than BP levels. OPN and MMP2 expression was confirmed in a subset of pts. This 2 protein combination improved the AUC and specificity for CRC diagnosis. Further study with more protein combinations is warranted. Citation Format: Chandana S. k. Herath Mudiyanselage, Hiromichi Miyagaki, Neil Mitra, Yanni Hedjar, Xiaohong Yan, Vesna Cekic, Joseph Martz, Jennifer Agnew, Richard L. Whelan. Osteopontin and matrix metalloproteinase 2 plasma levels are elevated in colorectal cancer (CRC) vs benign disease; The 2 protein combination improves specificity as regards CRC diagnosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1415.

Osteopontin-induced vascular hyperpermeability through tight junction disruption in diabetic retina

Diabetic retinopathy is a major cause of blindness in developed countries, and is characterized by deterioration of barrier function causing vascular hyperpermeability and retinal edema. Vascular endothelial growth factor (VEGF) is a major mediator of diabetic macular edema. Although anti-VEGF drugs are the first-line treatment for diabetic macular edema, some cases are refractory to anti-VEGF therapy. Osteopontin (OPN) is a phosphoglycoprotein with diverse functions and expressed in various cells and tissues. Elevated OPN level has been implicated in diabetic retinopathy, but whether OPN is involved in hyperpermeability remains unclear. Using streptozotocin-induced diabetic mice (STZ mice) and human retinal endothelial cells (HRECs), we tested the hypothesis that up-regulated OPN causes tight junction disruption, leading to vascular hyperpermeability. The serum and retinal OPN concentrations were elevated in STZ mice compared to controls. Intravitreal injection of anti-OPN neutralizing antibody (anti-OPN Ab) suppressed vascular hyperpermeability and prevented decreases in claudin-5 and ZO-1 gene expression levels in the retina of STZ mice. Immunohistochemical staining of retinal vessels in STZ mice revealed claudin-5 immunoreactivity with punctate distribution and attenuated ZO-1 immunoreactivity, and these changes were prevented by anti-OPN Ab. Intravitreal injection of anti-OPN Ab did not change VEGF gene expression or protein concentration in retina of STZ mice. In an in vitro study, HRECs were exposed to normal glucose or high glucose with or without OPN for 48 h, and barrier function was evaluated by transendothelial electrical resistance and Evans blue permeation. Barrier function deteriorated under high glucose condition, and was further exacerbated by the addition of OPN. Immunofluorescence localization of claudin-5 and ZO-1 demonstrated punctate appearance with discontinuous junction in HRECs exposed to high glucose and OPN. There were no changes in VEGF and VEGF receptor-2 expression levels in HRECs by exposure to OPN. Our results suggest that OPN induces tight junction disruption and vascular hyperpermeability under diabetic conditions. Targeting OPN may be an effective approach to manage diabetic retinopathy.

Outcome of Patients With Head and Neck Squamous Cell Carcinoma Can be Predicted by Expression of eIF4E and Osteopontin in Free Surgical Margins.

Squamous cell carcinoma of the head and neck (HNSCC) is recognized as the third most common cause of death. Incomplete resection of the primary tumor is the main cause of local recurrence and poor prognosis in HNSCC. Histologic assessment in order to determine "tumor-free" margins could be inadequate because of malignant transformation occurs at the molecular level earlier than the morphologic level. The present study aimed to evaluate the prognostic significance of eukaryotic initiation factor 4E (eIF4E) and Osteopontin in the tumor cells and histologically tumor free surgical margins of HNSCC. This cohort study was performed on 60 cases of HNSCC diagnosed at the Department of Pathology and treated at the Clinical Oncology Department, Faculty of Medicine, Zagazig University. Our enrolled formalin fixed paraffin embedded biopsy specimens with their matched tumor free surgical margins from resected head and neck squamous cell carcinoma were immunostaind for eIF4E and Osteopontin markers. 65% of our HNSCC patients had eIF4 E positive cytoplasmic immunostaining and 70% of them exhibited Osteopontin staining. Two-thirds of the dead patients exhibited high Osteopontin positive staining, whereas the surviving group did not exhibit this high expression. Concerning eIF4E, 85% and 5% of the dead patients showed high and low eIF4E expression, respectively. Disease-free survival (DFS) and overall survival were significantly (P=0.000) different between high and negative expression of Osteopontin, high and negative expression of eIF4E. 84% of patients with eIF4E positive margins and 75% with Osteopontin positive margins had local recurrence. In addition, negative expression of eIF4E is associated with highly significant better DFS and overall survival (P=0.000 and 0.001), respectively, in the margin negative expression status, while negative expression of Osteopontin was significantly associated with better DFS but of no significance in overall survival outcome. Our findings suggest that tumor-free surgical margins in HNSCC may be redefined as histologically Osteopontin and eIF4E negative resection margins. However, multicenter prospective studies are required to further evaluate their clinical utility in the surgical management of primary HNSCC.

Qualitative and Quantitative Estimation of Osteopontin in Bull Semen and its Effect on Sperm Quality Parameters and Fertility Rate In vivo

Background: Osteopontin plays a crucial role in fertilization and subsequent embryonic development. Methods: The fresh semen samples were collected from crossbred Jersey and Haryana breeding bulls. The proteins in the seminal plasma and sperm membrane were precipitated and analysed by SDS-PAGE followed by western blotting. Based on the concentration of osteopontin in the seminal plasma, the bulls were grouped as high (≥20 pg/ml), medium (10-20 pg/ml) and low (≤10 pg/ml) OPN groups. Result: Total 13 and 14 different proteins were identified in the seminal plasma and sperm membrane, respectively. The sperm velocity parameters (straight line velocity and straightness) and functional membrane integrity showed significant difference among high, medium and low OPN groups. Significant difference (P less than 0.05) was observed in malondialdehyde, SOD and glutathione reductase levels. Bulls which are having high osteopontin concentration in the semen had less sperm abnormality, less apoptotic cells, better resistance to cryopreservation, less damaged chromatin and higher conception rate (64.80±1.09) than bulls having low osteopontin concentration in their semen. Therefore, osteopontin may be a valuable protein marker to predict fertility in bulls.

A Retrospective Cohort Study of the Association between Serum Osteopontin Levels and Aortic Stiffness in Hypertensive Patients.

By suppressing mineralization and preventing ectopic calcium deposits, osteopontin (OPN) has an inhibitory effect on vascular calcification. Also, there is an association between OPN and aortic stiffness (AS). We aimed to investigate the association between serum OPN levels and AS measured by carotid–femoral pulse wave velocity (cfPWV) in hypertensive patients. Baseline characteristics and fasting blood sampling of 120 participants with hypertension and 120 participants without hypertension were acquired. Serum OPN concentrations were determined by enzyme-linked immunosorbent assay. In total, 43 (35.9%) participants were assigned to the AS group with cfPWV of >10 m/s in hypertensive patients. There were more patients with diabetes mellitus, old age, high systolic blood pressure, high serum intact parathyroid hormone (iPTH), elevated C-reactive protein, and high OPN levels in the AS group compared with the control group in hypertensive participants. A multivariate logistic regression analysis discloses that age, SBP, serum OPN, and iPTH levels were independently associated with AS in hypertensive patients. Moreover, according to a multivariate forward stepwise linear regression analysis, OPN level is positively associated with cfPWV. In conclusion, serum OPN level is assumed to be a potential biomarker to predict AS and is positively associated with cfPWV in patients with hypertension.

Osteopontin targeted theranostic nanoprobes for laser-induced synergistic regression of vulnerable atherosclerotic plaques

Vulnerable atherosclerotic plaque (VASPs) is the major pathological cause of acute cardiovascular event. Early detection and precise intervention of VASP hold great clinical significance, yet remain a major challenge. Photodynamic therapy (PDT) realizes potent ablation efficacy under precise manipulation of laser irradiation. In this study, we constructed theranostic nanoprobes (NPs), which could precisely regress VASPs through a cascade of synergistic events triggered by local irradiation of lasers under the guidance of fluorescence/MR imaging. The NPs were formulated from human serum albumin (HSA) conjugated with a high affinity-peptide targeting osteopontin (OPN) and encapsulated with photosensitizer IR780 and hypoxia-activatable tirapazamine (TPZ). After intravenous injection into atherosclerotic mice, the OPN-targeted NPs demonstrated high specific accumulation in VASPs due to the overexpression of OPN in activated foamy macrophages in the carotid artery. Under the visible guidance of fluorescence and MR dual-model imaging, the precise near-infrared (NIR) laser irradiation generated massive reactive oxygen species (ROS), which resulted in efficient plaque ablation and amplified hypoxia within VASPs. In response to the elevated hypoxia, the initially inactive TPZ was successively boosted to present potent biological suppression of foamy macrophages. After therapeutic administration of the NPs for 2 weeks, the plaque area and the degree of carotid artery stenosis were markedly reduced. Furthermore, the formulated NPs displayed excellent biocompatibility. In conclusion, the developed HSA-based NPs demonstrated appreciable specific identification ability of VASPs and realized precise synergistic regression of atherosclerosis.

TAMI-38. TUMOR-ASSOCIATED NEUTROPHILS IN GLIOBLASTOMA PROMOTE THE PERIVASCULAR GLIOMA STEM-LIKE CELL NICHE VIA OSTEOPONTIN SECRETION

Abstract Among clinical analyses, elevated neutrophil-lymphocyte ratio has been correlated with poor outcomes of glioblastoma patients independent of other prognostic factors. Additionally, our flow cytometric studies of primary patient samples found neutrophil percentage to be significantly higher in higher-grade glioma versus lower-grade glioma. Tumor-associated neutrophils (TANs) comprise less than 2% of the glioblastoma microenvironment. While TANs were initially considered passive bystanders due to their short-lived nature, investigation of TANs in other cancers revealed distinct pro-tumoral roles. Therefore, we transcriptomically characterized glioblastoma TANs and defined their oncologic effects. Transcriptomic analysis of patient-matched TANs versus peripheral blood neutrophils revealed that functionally quiescent circulating neutrophils infiltrate IDH1-wild type glioblastoma via leukotriene B4 chemoattraction, where tumor cells morphologically and transcriptomically activate them to become TANs. Single-cell RNA-sequencing of patient-matched TANs and peripheral blood neutrophils revealed a subset of tumor-activated neutrophils which adopt a pro-tumoral secretory phenotype, marked by activation of the IL-17 signaling pathway and high osteopontin production. Using immunofluorescence stains of primary patient glioblastoma sections, we demonstrated that activated, myeloperoxidase-positive TANs reside in the perivascular niche of glioblastoma in close proximity to glioblastoma stem-like cells (GSCs) and CD31-positive endothelial cells. Further analysis in culture demonstrated that TAN-secreted osteopontin drives the formation, self-renewal, and proliferation of GSC-containing neurospheres. These results were validated using a syngeneic stem cell-derived IDH1-wild type murine glioblastoma model in vivo. Thus, while TANs are rare in glioblastoma, their enrichment in the glioblastoma perivascular niche uniquely positions them to support the GSCs that are crucial to therapeutic resistance of GBM.

Osteopontin Expression in Thyroid Cancer: Deciphering EMT-Related Molecular Mechanisms.

Thyroid cancer is the most common tumor arising from the endocrine system and generally presents good prognosis. However, its aggressive subtypes are related to therapeutic resistance and early metastasis. Epithelial–mesenchymal transition (EMT) and its reverse process, the mesenchymal–epithelial transition (MET), are key events mediating cancer progression, including in thyroid cancer. The matricellular protein osteopontin (OPN) has been reported as a master regulator of EMT in many tumor types. Although high OPN expression has been described and associated with important aspects of thyroid cancer progression, there is no clear evidence regarding OPN as a regulator of EMT in thyroid cancer. Thus, taking together the known roles of OPN in the modulation of EMT in cancer and the information reporting the expression of OPN in thyroid tumor progression, this review aims at summarizing and discussing data related to EMT in thyroid cancer and its putative relation to the roles of OPN in the development of thyroid cancer. These data provide new insights into the molecular mechanisms by which OPN could potentially modulate EMT in thyroid tumors, generating evidence for future studies that may contribute to new therapeutic, prognostic and/or diagnostic tools.

Serum osteopontin can improve papillary thyroid cancer risk assessment of Bethesda III thyroid nodules: a preliminary study.

Thyroid cancer can be detected in 5-10% of patients with thyroid nodules. Management may be a challenge if fine-needle aspiration biopsy yields Bethesda III findings. Most of these cases undergo surgery and are ultimately found benign. Our aim was to evaluate whether serum osteopontin can accurately estimate thyroid cancer risk in cases with cytologically Bethesda III thyroid nodules and, thereby, decrease the number of unnecessary surgical interventions. We obtained blood samples of cases with repeated cytologically Bethesda III thyroid nodules before surgery, and followed up the pathology results after thyroidectomy. We evaluated serum osteopontin from 36 patients with papillary thyroid cancer and compared them with 40 benign cases. Serum osteopontin levels in patients with papillary thyroid cancer are significantly higher than in benign cases (mean serum osteopontin: 10.48 ± 3.51 ng/mL vs6.14 ± 2.29 ng/mL, P < 0.001). The area under the receiver operating characteristics curve was 0.851, suggesting that serum osteopontin could have considerable discriminative performance. In our preliminary study, high serum osteopontin levels can predict the risk of papillary thyroid cancer in thyroid nodules with Bethesda III cytology. Further studies are necessary to confirm these findings.

Dipeptidyl peptidase 3, a marker of the antagonist pathway of the renin-angiotensin-aldosterone system in patients with heart failure.

AimsRecently, dipeptidyl peptidase 3 (DPP3) has been discovered as the peptidase responsible for cleavage of angiotensin (1–7) [Ang (1–7)]. Ang (1–7) is part of the angiotensin‐converting enzyme–Ang (1–7)–Mas pathway which is considered to antagonize the renin–angiotensin–aldosterone system (RAAS). Since DPP3 inhibits the counteracting pathway of the RAAS, we hypothesize that DPP3 might be deleterious in the setting of heart failure. However, no data are available on DPP3 in chronic heart failure. We therefore investigated the clinical characteristics and outcome related to elevated DPP3 concentrations in patients with worsening heart failure.Methods and resultsDipeptidyl peptidase 3 was measured in 2156 serum samples of patients with worsening heart failure using luminometric immunoassay (DPP3‐LIA) by 4TEEN4 Pharmaceuticals GmbH, Hennigsdorf, Germany. Predictors of DPP3 levels were selected using multiple linear regression with stepwise backward selection. Median DPP3 concentration was 11.45 ng/mL with a range from 2.8 to 84.9 ng/mL. Patients with higher DPP3 concentrations had higher renin [78.3 (interquartile range, IQR 26.3–227.7) vs. 120.7 IU/mL (IQR 34.74–338.9), P < 0.001, for Q1–3 vs. Q4] and aldosterone [88 (IQR 44–179) vs. 116 IU/mL (IQR 46–241), P < 0.001, for Q1–3 vs. Q4] concentrations. The strongest independent predictors for higher concentration of DPP3 were log‐alanine aminotransferase, log‐total bilirubin, the absence of diabetes, higher osteopontin, fibroblast growth factor‐23 and N‐terminal pro‐B‐type natriuretic peptide concentrations (all P < 0.001). In univariable survival analysis, DPP3 was associated with mortality and the combined endpoint of death or heart failure hospitalization (P < 0.001 for both). After adjustment for confounders, this association was no longer significant.ConclusionsIn patients with worsening heart failure, DPP3 is a marker of more severe disease with higher RAAS activity. It may be deleterious in heart failure by counteracting the Mas receptor pathway. Procizumab, a specific antibody against DPP3, might be a potential future treatment option for patients with heart failure.

Salivary Osteopontin as a Potential Biomarker for Oral Mucositis.

Osteopontin (OPN), a multifunctional phosphoglycoprotein also presents in saliva, plays a crucial role in tumour progression, inflammation and mucosal protection. Mucosal barrier injury due to high-dose conditioning regimen administered during autologous and allogeneic peripheral stem cell transplantation (APSCT) has neither efficient therapy nor established biomarkers. Our aim was to assess the biomarker role of OPN during APSCT, with primary focus on oral mucositis (OM). Serum and salivary OPN levels were determined by ELISA in 10 patients during APSCT at four stages of transplantation (day −3/−7, 0, +7, +14), and in 23 respective healthy controls. Results: There was a negative correlation between both salivary and serum OPN levels and grade of OM severity during APSCT (r = −0.791, p = 0.019; r = −0.973, p = 0.001). Salivary OPN increased at days +7 (p = 0.011) and +14 (p = 0.034) compared to controls. Among patients, it was higher at day +14 compared to the time of admission (day −3/−7) (p = 0.039) and transplantation (day 0) (p = 0.011). Serum OPN remained elevated at all four stages of transplantation compared to controls (p = 0.013, p = 0.02, p = 0.011, p = 0.028). During APSCT elevated salivary OPN is a potential non-invasive biomarker of oral mucositis whereas the importance of high serum OPN warrants further studies.

Plasma osteopontin as a biomarker of Alzheimer\u2019s disease and vascular cognitive impairment

Cerebrovascular disease (CeVD) and neurodegenerative dementia such as Alzheimer’s disease (AD) are frequently associated comorbidities in the elderly, sharing common risk factors and pathophysiological mechanisms including neuroinflammation. Osteopontin (OPN) is an inflammatory marker found upregulated in vascular diseases as well as in AD. However, its involvement in vascular dementia (VaD) and pre-dementia stages, namely cognitive impairment no dementia (CIND), both of which fall under the spectrum of vascular cognitive impairment (VCI), has yet to be examined. Its correlations with inflammatory cytokines in cognitive impairment also await investigation. 80 subjects with no cognitive impairment (NCI), 160 with CIND and 144 with dementia were included in a cross-sectional study on a Singapore-based memory clinic cohort. All subjects underwent comprehensive clinical, neuropsychological and brain neuroimaging assessments, together with clinical diagnoses based on established criteria. Blood samples were collected and OPN as well as inflammatory cytokines interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF) were measured using immunoassays. Multivariate regression analyses showed significant associations between increased OPN and VCI groups, namely CIND with CeVD, AD with CeVD and VaD. Interestingly, higher OPN was also significantly associated with AD even in the absence of CeVD. We further showed that increased OPN significantly associated with neuroimaging markers of CeVD and neurodegeneration, including cortical infarcts, lacunes, white matter hyperintensities and brain atrophy. OPN also correlated with elevated levels of IL-6, IL-8 and TNF. Our findings suggest that OPN may play a role in both VCI and neurodegenerative dementias. Further longitudinal analyses are needed to assess the prognostic utility of OPN in disease prediction and monitoring.

Expression of osteopontin in hepatocellular carcinoma

Introduction Hepatocellular carcinoma (HCC) is a complex disease entity with multiple steps and associated with many risk factors and cofactors. Osteopontin (OPN) is a secreted glycosylated phosphoprotein encoded by the secreted phosphoprotein 1 gene. OPN has been implicated as an essential mediator and potential therapeutic target of cancer metastasis. Objectives This study aimed to determine the expression of OPN in HCC and to correlate the findings with different clinicopathological characteristics as well as p53 expression. Materials and methods HCC specimens (n=84) were immunostained using antibodies against OPN and p53. The association between OPN and clinicopathological parameters including grade, number of tumors, tumor size, and vascular invasion as well as p53 expression were evaluated. Results OPN showed positivity (+1 and +2) in 53 (63.1%) cases. OPN expression was directly proportional with tumor size, tumor grade, and vascular invasion, as high OPN expression showed a highly significant association with large-sized tumors (&gt;5 cm in diameter), high-grade HCC, and vascular invasion. No significant association was detected between OPN expression and age (P=0.738), sex (P=0.835), and number of tumors (P=0.358). OPN expression was directly proportional to p53 expression, as p53 positivity was observed in high-grade tumors with vascular invasion (P&lt;0.001). Conclusion OPN expression may have prognostic significance in HCC, as overexpression of OPN is associated with high-grade, large-size tumors and vascular invasion as well as high p53 expression.

The Relationship between Circulating Levels of Osteopontin with Carotid Intima-Media Thickness in Children on Regular Hemodialysis

Background: Chronic kidney disease (CKD) is associated with cardiovascular morbidity and mortality. Osteopontin (OPN) is a critical factor in developing atherosclerosis and increases the risk for a major adverse cardiovascular event. Aim: To investigate osteopontin serum levels in hemodialysis children and detect the association between the main arteries’ intimal medial thickness (IMT) and peak systolic velocity. Material and Methods: This case-control study included 30 children on regular hemodialysis and 30 children age and sex-matched as controls their age range from 4 to 18 years; we investigated osteopontin serum level in addition to the Doppler ultrasound assessment of intimal medial thickness and peak systolic velocity (PSV) of the main arteries in the same line with the traditional markers of the routine investigations of children on regular hemodialysis. Results: Significantly high osteopontin level in hemodialysis children than the controls was (0.85 ± 0.21 ng/ml) (0.69 ± 0.26 ng/ml), respectively (p = 0.026). A significant increase in the (IMT) of the main arteries, including the carotid and femoral arteries, in the patient’s group than the controls, was (0.51 ± 0.01 mm) (0. 69. ± 0.01 mm) (0.32 ± 0.036 mm) (0.55 ± 0.01), respectively (p = 0.001). There is a strong correlation between (OPN) with the (IMT) of carotid and femoral arteries, a significant positive correlation between (OPN) with urea, creatinine, triglyceride, PTH, ferritin, CRP, and ESR, and a negative correlation with RBCs count and carotid PSV. Conclusion: High osteopontin level is consistent with the increased IMT of the main arteries in hemodialysis children that seem to play a significant role in developing and propagating atherosclerosis in hemodialysis children, evidenced by significant association with inflammatory markers and uremic toxins.

High levels of osteopontin associated with polymorphisms in its gene are a risk factor for development of autoimmunity/lymphoproliferation

AbstractThe autoimmune/lymphoproliferative syndrome (ALPS) displays defective function of Fas, autoimmunities, lymphadenopathy/splenomegaly, and expansion of CD4/CD8 double-negative (DN) T cells. Dianzani autoimmune/lymphoproliferative disease (DALD) is an ALPS variant lacking DN cells. Both forms have been ascribed to inherited mutations hitting the Fas system but other factors may be involved. A pilot cDNA array analysis on a DALD patient detected overexpression of the cytokine osteopontin (OPN). This observation was confirmed by enzyme-linked immunosorbent assay (ELISA) detection of higher OPN serum levels in DALD patients (n = 25) than in controls (n = 50). Analysis of the OPN cDNA identified 4 polymorphisms forming 3 haplotypes (A, B, and C). Their overall distribution and genotypic combinations were different in patients (N = 26) and controls (N = 158) (P < .01). Subjects carrying haplotype B and/or C had an 8-fold higher risk of developing DALD than haplotype A homozygotes. Several data suggest that these haplotypes influence OPN levels: (1) in DALD families, high levels cosegregated with haplotype B or C; (2) in healthy controls, haplotype B or C carriers displayed higher levels than haplotype A homozygotes; and (3) in AB and AC heterozygotes, mRNA for haplotype B or C was more abundant than that for haplotype A. In vitro, exogenous OPN decreased activation-induced T-cell death, which suggests that high OPN levels are involved in the apoptosis defect.

Osteopontin as novel biomarker for reversibility of pressure overload induced left ventricular hypertrophy.

Aim: The aim of this study was to evaluate the prognostic value of osteopontin (OPN) as a marker for left ventricular (LV)hypertrophy and its reversibility after surgical aortic valve replacement (SAVR). Patients & methods: Echocardiographic data and OPN plasma levels of 149 consecutive patients undergoing SAVR were obtained preoperatively and 3 months postoperatively. OPN was measured by Quantikine Human OPN immunoassay. Results: There was a significant correlation between higher OPN plasma levels and lower LV-mass regression. In patients receiving SAVR combined with coronary artery bypass grafting, high OPN plasma levels were also an indicator for eccentric hypertrophy phenotype. Conclusion: OPN may be a useful indicator for LV hypertrophy phenotype and could have a prognostic value to estimate LV-mass regression after SAVR.

Osteopontin in vitreous and idiopathic epiretinal membranes.

To investigate osteopontin (OPN) expression in vitreous and in related idiopathic epiretinal membranes (ERMs), with respect to VEGF-A, IL8, MIP1α, IL6, and IL33, and correlate OPN expression with disease staging. Fifteen (15) vitreous and allied ERMs were collected at the time of therapeutic vitreoretinal surgery. Additional 5 vitreous and 10 ERMs (historical collection) were used. Biochemical and molecular analysis of OPN was performed in clear vitreous, vitreal pelleted cells, and ERMs. Double-immunofluorescence analysis (OPN - GFAP and OPN - αSMA) was performed on paraffin and whole-mounted ERMs. Vitreal OPN levels were correlated to those of VEGF-A, IL8, MIP1α, IL6, and IL33. High OPN levels were observed in vitreal samples, and OPN transcripts were amplified in vitreal cells and related ERMs. OPN immunoreactivity was found in ERMs, mainly in GFAP-bearing (Muller cells) and to a less extend in αSMA-expressing (myofibroblasts) cells. OPN levels were highest at early stages of ERM formation and positively correlated to VEGF-A and MIP1α. High OPN levels in vitreous, OPN transcripts in vitreal cells/ERMs, OPN immunoreactivity in activated Müller cells and contractile myofibroblasts, as well as the correlation with VEGF-A and MIP1α fulfill the potential involvement of OPN in both inflammation and tissue remodeling that takes part in vitreoretinal interface disorders. The highest OPN levels at early stages of ERM formation would prospect OPN as a potential biomarker for disease severity.

Plasma levels of osteopontin from birth to adulthood.

Osteopontin (OPN) has been investigated as a biomarker for cancer and nonmalignant diseases during the last decades. Data about OPN as a potential biomarker in childhood diseases are still sparse, and reference values are not available in children. We aimed to establish reference values for children from birth to young adulthood and evaluate whether there are age-, gender-, and weight-specific differences. Umbilical cord blood and blood plasma samples of 117 children were collected in the Children's Hospital of Saarland University in Homburg/Saar. OPN levels were measured by ELISA, and statistical analysis was performed using SPSS software. Neonates, infants, toddlers, young children, adolescents, and adults were divided into the following six age groups: newborns (birth), infancy and toddlers (0-24 months), early childhood (3-6 years), middle childhood (7-11 years), adolescence (12-18 years), and adults (>18 years). Highest blood OPN levels were found in the group of 0-1 years of age. OPN blood levels declined significantly with age (Spearman r=-0.874; P<0.001). Our work is the first prospective and systematic study analyzing OPN cord blood and blood plasma levels in children of all ages. It is the first study yielding reference values for different age groups from birth to young adulthood. Our data give insight on how OPN in umbilical cord blood and OPN in blood plasma are physiologically influenced during childhood development and growth with high OPN levels after birth and a constant age-related decline until the age of 14, when OPN levels reach similar values to those measured in adults.

Osteopontin expression and its relationship with prognostic biomarkers in canine mammary carcinomas

ABSTRACT: Osteopontin is a glycophosphoprotein implicated in different physiologic and pathologic processes and is known to be involved in progression and metastasis of various cancers in humans, but this relation is still little explored in the veterinary. The aim was to evaluate the expression of osteopontin in canine mammary carcinomas and its relation with well-established canine mammary tumor biomarkers. For that, expression of OPN, EGFR, HER2, and c-Kit were evaluated along with Ki67 rate in 43 mammary carcinomas. Osteopontin was demonstrated to be expressed by neoplastic epithelial cells in all carcinomas as well as in stromal cells from the tumor microenvironment. Relation between high osteopontin expression and EGFR positivity (P&lt;0.001) and HER2 overexpression (P=0.012) was demonstrated. In conclusion, high OPN expression seems to be related to poor prognosis and MAPK pathway activation, given the association with EGFR and HER2, members of the MAPK signaling pathway.

Increased osteopontin expression in endometrial carcinoma is associated with better survival outcome

Osteopontin (OPN) is a key extracellular matrix protein that is involved in cancer progression. The aim of the current study is to investigate the relation of OPN immunostaining in endometrial carcinoma with clinicopathological parameters. Archival 71 endometrial carcinomas and 30 non-neoplastic endometrial tissues were obtained from the Department of Pathology at King Abdulaziz University Jeddah, Saudi Arabia. Tissue microarrays were constructed. Tissue sections were stained using anti-human OPN monoclonal antibody. Immunostaining results were recorded and analysed. In non-neoplastic endometrial tissues, high (increased) OPN immunostaining was observed in 100%. In endometrial carcinoma, high (increased) OPN immunostaining was seen in 64.8% of cases. High (increased) OPN immunostaining was more frequent in non-neoplastic tissues than in endometrial carcinoma (p < 0.001). OPN immunostaining showed no association with histological type, FIGO tumour grade, tumour size, myometrial invasion, lymphovascular invasion, surgical resection margin or lymph node metastasis. On the other hand, high (increased) OPN immunostaining was associated with better overall survival [Log Rank (Mantel-Cox) = 4.385, p = 0.003]. In endometrial carcinoma, immunohistochemical staining of OPN could be a helpful tool in the prediction survival pattern. OPN immunostaining showed no association with most clinicopathological features. Further investigations both clinical and molecular are needed to explore the downstream of OPN in endometrial carcinoma.