30 Years of OPN Milestones and Future Avenues 2.0

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 15840

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Department of Health Sciences, Center for Translational Research on Autoimmune and Allergic Disease-CAAD, Università del Piemonte Orientale, 28100 Novara, Italy
Interests: autoimmune diseases; liquid biopsy biomarkers; immunology; nanomaterial biocompatibility; flow cytometry; microvesicles
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Special Issue Information

Dear Colleagues,

This Commemorative Issue will collect all contributions pertaining the multifaceted roles of osteopontin (OPN), discovered 30 years ago. In the nineties, OPN was identified in human bone as an immobilized extracellular matrix protein, but since then, further studies have shown that OPN also acts as a soluble cytokine in body fluids, and it has been linked to various physiological and pathological processes. OPN mediates bone remodeling, macrophage response, cell migration and adhesion, inflammation and Th1 and Th17 cell differentiation. Moreover, OPN is involved in tumor angiogenesis and metastatic dissemination. To date, investigations have been based on the paradigm that molecular mediators of OPN functions are two classes of receptors, namely integrins and CD44. The recent finding of an additional cell receptor, i.e., ICOSL, opens a new scenario in which OPN may modulate the function of all of the cell types expressing ICOSL, and this interaction may be functionally modulated by ICOS.

Understanding how OPN is processed and interacts with its natural ligands is of paramount importance for elucidating the complex role that this protein plays in human diseases.

Herein, in this Commemorative Issue, authors are invited to review recent work or submit original studies in all areas of recent and current OPN research, with an emphasis on work providing molecular insight, including, but not limited to, novel physiological and pathological functions, or regulatory mechanisms.

Thus, let us stop counting OPN years and start making them count!

Dr. Giuseppe Cappellano
Guest Editor

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Keywords

  • osteopontin
  • inflammation
  • autoimmunity
  • biomarker
  • cancer
  • therapeutics

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Published Papers (11 papers)

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Research

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20 pages, 4031 KiB  
Article
Preliminary Study of the Relationship between Osteopontin and Relapsed Hodgkin’s Lymphoma
by Valli De Re, Egesta Lopci, Giulia Brisotto, Caterina Elia, Lara Mussolin, Maurizio Mascarin, Emanuele Stefano Giovanni d’Amore and AIEOP The Hodgkin’s Lymphoma Research Network
Biomedicines 2024, 12(1), 31; https://doi.org/10.3390/biomedicines12010031 - 21 Dec 2023
Viewed by 784
Abstract
The primary objective of this study was to investigate the potential role of tissue osteopontin, also known as secreted phosphoprotein 1 (SPP1), as a contributing factor to an unfavorable prognosis in classical Hodgkin’s lymphoma (HL) patients who received the same treatment [...] Read more.
The primary objective of this study was to investigate the potential role of tissue osteopontin, also known as secreted phosphoprotein 1 (SPP1), as a contributing factor to an unfavorable prognosis in classical Hodgkin’s lymphoma (HL) patients who received the same treatment protocol. The study involved 44 patients aged 4–22 years, with a median follow-up period of 3 years. Patients with higher levels of SPP1 were associated with tissue necrosis and inflammation, and there was a trend toward a poorer prognosis in this group. Before therapy, we found a correlation between positron emission tomography (PET) scans and logarithmic SPP1 levels (p = 0.035). However, the addition of SPP1 levels did not significantly enhance the predictive capacity of PET scans for recurrence or progression. Elevated SPP levels were associated with tissue mRNA counts of chemotactic and inflammatory chemokines, as well as specific monocyte/dendritic cell subtypes, defined by IL-17RB, PLAUR, CXCL8, CD1A, CCL13, TREM1, and CCL24 markers. These findings contribute to a better understanding of the potential factors influencing the prognosis of HL patients and the potential role of SPP1 in the disease. While the predictive accuracy of PET scans did not substantially improve during the study, the results underscore the complexity of HL and highlight the relationships between SPP1 and other factors in the context of HL relapse. Full article
(This article belongs to the Special Issue 30 Years of OPN Milestones and Future Avenues 2.0)
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13 pages, 3056 KiB  
Article
A Dual Role of Osteopontin in Modifying B Cell Responses
by Rittika Chunder, Verena Schropp, Manuel Marzin, Sandra Amor and Stefanie Kuerten
Biomedicines 2023, 11(7), 1969; https://doi.org/10.3390/biomedicines11071969 - 12 Jul 2023
Cited by 2 | Viewed by 810
Abstract
The occurrence of B cell aggregates within the central nervous system (CNS) has prompted the investigation of the potential sources of pathogenic B cell and T cell responses in a subgroup of secondary progressive multiple sclerosis (MS) patients. Nevertheless, the expression profile of [...] Read more.
The occurrence of B cell aggregates within the central nervous system (CNS) has prompted the investigation of the potential sources of pathogenic B cell and T cell responses in a subgroup of secondary progressive multiple sclerosis (MS) patients. Nevertheless, the expression profile of molecules associated with these aggregates and their role in aggregate development and persistence is poorly described. Here, we focused on the expression pattern of osteopontin (OPN), which is a well-described cytokine, in MS brain tissue. Autopsied brain sections from MS cases with and without B cell pathology were screened for the presence of CD20+ B cell aggregates and co-expression of OPN. To demonstrate the effect of OPN on B cells, flow cytometry, ELISA and in vitro aggregation assays were conducted using the peripheral blood of healthy volunteers. Although OPN was expressed in MS brain tissue independent of B cell pathology, it was also highly expressed within B cell aggregates. In vitro studies demonstrated that OPN downregulated the co-stimulatory molecules CD80 and CD86 on B cells. OPN-treated B cells produced significantly lower amounts of IL-6. However, OPN-treated B cells also exhibited a higher tendency to form homotypic cell aggregates in vitro. Taken together, our data indicate a conflicting role of OPN in modulating B cell responses. Full article
(This article belongs to the Special Issue 30 Years of OPN Milestones and Future Avenues 2.0)
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7 pages, 1005 KiB  
Communication
Plasma Osteopontin Reflects Tissue Damage in Acute Pancreatitis
by Lina Wirestam, Pernilla Benjaminsson Nyberg, Todor Dzhendov, Thomas Gasslander, Per Sandström, Christopher Sjöwall and Bergthor Björnsson
Biomedicines 2023, 11(6), 1627; https://doi.org/10.3390/biomedicines11061627 - 03 Jun 2023
Viewed by 1012
Abstract
Several scoring systems for clinical prediction of the severity of acute pancreatitis (AP) have been proposed. Yet, there is still a need for an easy-to-measure biomarker. Osteopontin (OPN) may be released to the circulation early during tissue injury, but the significance of OPN [...] Read more.
Several scoring systems for clinical prediction of the severity of acute pancreatitis (AP) have been proposed. Yet, there is still a need for an easy-to-measure biomarker. Osteopontin (OPN) may be released to the circulation early during tissue injury, but the significance of OPN in AP has not yet been established. We aimed to evaluate plasma levels of OPN in relation to the severity of AP. In 39 individuals with confirmed AP, plasma was collected on the day of admission and consecutively for three days thereafter. Sex- and age-matched healthy blood donors (n = 39) served as controls. Plasma OPN was measured by a commercial enzyme-linked immunosorbent assay. At admission, patients with AP displayed higher OPN, 156.4 ng/mL (IQR 111.8–196.2) compared to controls, 37.4 ng/mL (IQR 11.7–65.7) (p < 0.0001). However, OPN levels on admission could not discriminate between mild and moderate-to-severe disease (132.6 ng/mL vs. 163.4 ng/mL). Nevertheless, the changes in OPN within 24 h of admission and Day 2/3 were higher among patients with moderate/severe AP (33.7%) compared to mild AP (−8.1%) (p = 0.01). This indicates that OPN is a relevant biomarker reflecting tissue injury in AP. The increase in OPN over time suggests that serial OPN measurements could contribute to the early detection of at-risk patients. Prospective studies assessing OPN in relation to outcome in AP are warranted. Full article
(This article belongs to the Special Issue 30 Years of OPN Milestones and Future Avenues 2.0)
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12 pages, 2446 KiB  
Article
Angiogenesis in the Outer Membrane of Chronic Subdural Hematomas through Thrombin-Cleaved Osteopontin and the Integrin α9 and Integrin β1 Signaling Pathways
by Koji Osuka, Yusuke Ohmichi, Mika Ohmichi, Satoru Honma, Chiharu Suzuki, Masahiro Aoyama, Kenichiro Iwami, Yasuo Watanabe and Shigeru Miyachi
Biomedicines 2023, 11(5), 1440; https://doi.org/10.3390/biomedicines11051440 - 13 May 2023
Cited by 1 | Viewed by 1108
Abstract
Background: A chronic subdural hematoma (CSDH) is considered to be an inflammatory and angiogenic disease. The CSDH outer membrane, which contains inflammatory cells, plays an important role in CSDH development. Osteopontin (OPN) is an extracellular matrix protein that is cleaved by thrombin, generating [...] Read more.
Background: A chronic subdural hematoma (CSDH) is considered to be an inflammatory and angiogenic disease. The CSDH outer membrane, which contains inflammatory cells, plays an important role in CSDH development. Osteopontin (OPN) is an extracellular matrix protein that is cleaved by thrombin, generating the N-terminal half of OPN, which is prominently involved in integrin signal transduction. We explored the expression of the N-terminal half of OPN in CSDH fluid and the expression of integrins α9 and β1 and the downstream components of the angiogenic signaling pathways in the outer membrane of CSDHs. Methods: Twenty samples of CSDH fluid and eight samples of CSDH outer membrane were collected from patients suffering from CSDHs. The concentrations of the N-terminal half of OPN in CSDH fluid samples were measured using ELISA kits. The expression levels of integrins α9 and β1, vinculin, talin-1, focal adhesion kinase (FAK), paxillin, α-actin, Src and β-actin were examined by Western blot analysis. The expression levels of integrins α9 and β1, FAK and paxillin were also examined by immunohistochemistry. We investigated whether CSDH fluid could activate FAK in cultured endothelial cells in vitro. Results: The concentration of the N-terminal half of OPN in CSDH fluid was significantly higher than that in the serum. Western blot analysis confirmed the presence of these molecules. In addition, integrins α9 and β1, FAK and paxillin were localized in the endothelial cells of vessels within the CSDH outer membrane. FAK was significantly phosphorylated immediately after treatment with CSDH fluid. Conclusion: Our data suggest that the N-terminal half of OPN in CSDH fluid promotes neovascularization in endothelial cells through integrins α9 and β1. The N-terminal half of OPN, which is part of the extracellular matrix, plays a critical role in the promotion of CSDHs. Full article
(This article belongs to the Special Issue 30 Years of OPN Milestones and Future Avenues 2.0)
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17 pages, 2555 KiB  
Article
Increased Circulating Osteopontin Levels Promote Primary Tumour Growth, but Do Not Induce Metastasis in Melanoma
by Rafael Saup, Nidhi Nair, Jingyi Shen, Anja Schmaus, Wilko Thiele, Boyan K. Garvalov and Jonathan P. Sleeman
Biomedicines 2023, 11(4), 1038; https://doi.org/10.3390/biomedicines11041038 - 28 Mar 2023
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Abstract
Osteopontin (OPN) is a phosphoprotein with diverse functions in various physiological and pathological processes. OPN expression is increased in multiple cancers, and OPN within tumour tissue has been shown to promote key stages of cancer development. OPN levels are also elevated in the [...] Read more.
Osteopontin (OPN) is a phosphoprotein with diverse functions in various physiological and pathological processes. OPN expression is increased in multiple cancers, and OPN within tumour tissue has been shown to promote key stages of cancer development. OPN levels are also elevated in the circulation of cancer patients, which in some cases has been correlated with enhanced metastatic propensity and poor prognosis. However, the precise impact of circulating OPN (cOPN) on tumour growth and progression remains insufficiently understood. To examine the role of cOPN, we used a melanoma model, in which we stably increased the levels of cOPN through adeno-associated virus-mediated transduction. We found that increased cOPN promoted the growth of primary tumours, but did not significantly alter the spontaneous metastasis of melanoma cells to the lymph nodes or lungs, despite an increase in the expression of multiple factors linked to tumour progression. To assess whether cOPN has a role at later stages of metastasis formation, we employed an experimental metastasis model, but again could not detect any increase in pulmonary metastasis in animals with elevated levels of cOPN. These results demonstrate that increased levels of OPN in the circulation play distinct roles during different stages of melanoma progression. Full article
(This article belongs to the Special Issue 30 Years of OPN Milestones and Future Avenues 2.0)
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Review

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21 pages, 1420 KiB  
Review
Contextualizing the Role of Osteopontin in the Inflammatory Responses of Alzheimer’s Disease
by Roshni C. Lalwani, Claude-Henry Volmar, Claes Wahlestedt, Keith A. Webster and Lina A. Shehadeh
Biomedicines 2023, 11(12), 3232; https://doi.org/10.3390/biomedicines11123232 - 06 Dec 2023
Cited by 1 | Viewed by 1208
Abstract
Alzheimer’s disease (AD) is characterized by progressive accumulations of extracellular amyloid-beta (Aβ) aggregates from soluble oligomers to insoluble plaques and hyperphosphorylated intraneuronal tau, also from soluble oligomers to insoluble neurofibrillary tangles (NFTs). Tau and Aβ complexes spread from the entorhinal cortex of the [...] Read more.
Alzheimer’s disease (AD) is characterized by progressive accumulations of extracellular amyloid-beta (Aβ) aggregates from soluble oligomers to insoluble plaques and hyperphosphorylated intraneuronal tau, also from soluble oligomers to insoluble neurofibrillary tangles (NFTs). Tau and Aβ complexes spread from the entorhinal cortex of the brain to interconnected regions, where they bind pattern recognition receptors on microglia and astroglia to trigger inflammation and neurotoxicity that ultimately lead to neurodegeneration and clinical AD. Systemic inflammation is initiated by Aβ’s egress into the circulation, which may be secondary to microglial activation and can confer both destructive and reparative actions. Microglial activation pathways and downstream drivers of Aβ/NFT neurotoxicity, including inflammatory regulators, are primary targets for AD therapy. Osteopontin (OPN), an inflammatory cytokine and biomarker of AD, is implicated in Aβ clearance and toxicity, microglial activation, and inflammation, and is considered to be a potential therapeutic target. Here, using the most relevant works from the literature, we review and contextualize the evidence for a central role of OPN and associated inflammation in AD. Full article
(This article belongs to the Special Issue 30 Years of OPN Milestones and Future Avenues 2.0)
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17 pages, 710 KiB  
Review
The Role of Osteopontin in Atherosclerosis and Its Clinical Manifestations (Atherosclerotic Cardiovascular Diseases)—A Narrative Review
by Nikolaos P. E. Kadoglou, Elina Khattab, Nikolaos Velidakis and Evangelia Gkougkoudi
Biomedicines 2023, 11(12), 3178; https://doi.org/10.3390/biomedicines11123178 - 29 Nov 2023
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Abstract
Atherosclerotic cardiovascular diseases (ASCVDs) are the most common and severe public health problem nowadays. Osteopontin (OPN) is a multifunctional glycoprotein highly expressed at atherosclerotic plaque, which has emerged as a potential biomarker of ASCVDs. OPN may act as an inflammatory mediator and/or a [...] Read more.
Atherosclerotic cardiovascular diseases (ASCVDs) are the most common and severe public health problem nowadays. Osteopontin (OPN) is a multifunctional glycoprotein highly expressed at atherosclerotic plaque, which has emerged as a potential biomarker of ASCVDs. OPN may act as an inflammatory mediator and/or a vascular calcification (VC) mediator, contributing to atherosclerosis progression and eventual plaque destabilization. In this article, we discuss the complex role of OPN in ASCVD pathophysiology, since many in vitro and in vivo experimental data indicate that OPN contributes to macrophage activation and differentiation, monocyte infiltration, vascular smooth muscle cell (VSMC) migration and proliferation and lipid core formation within atherosclerotic plaques. Most but not all studies reported that OPN may inhibit atherosclerotic plaque calcification, making it “vulnerable”. Regarding clinical evidence, serum OPN levels may become a biomarker of coronary artery disease (CAD) presence and severity. Significantly higher OPN levels have been found in patients with acute coronary syndromes than those with stable CAD. In limited studies of patients with peripheral artery disease, circulating OPN concentrations may be predictive of future major adverse cardiovascular events. Overall, the current literature search suggests the contribution of OPN to atherosclerosis development and progression, but more robust evidence is required. Full article
(This article belongs to the Special Issue 30 Years of OPN Milestones and Future Avenues 2.0)
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19 pages, 1486 KiB  
Review
The Multifaceted Role of Osteopontin in Prostate Pathologies
by Samara V. Silver and Petra Popovics
Biomedicines 2023, 11(11), 2895; https://doi.org/10.3390/biomedicines11112895 - 26 Oct 2023
Viewed by 1092
Abstract
The prostate gland, located beneath the bladder and surrounding the proximal urethra in men, plays a vital role in reproductive physiology and sexual health. Despite its importance, the prostate is vulnerable to various pathologies, including prostatitis, benign prostatic hyperplasia (BPH) and prostate cancer [...] Read more.
The prostate gland, located beneath the bladder and surrounding the proximal urethra in men, plays a vital role in reproductive physiology and sexual health. Despite its importance, the prostate is vulnerable to various pathologies, including prostatitis, benign prostatic hyperplasia (BPH) and prostate cancer (PCa). Osteopontin (OPN), a versatile protein involved in wound healing, inflammatory responses, and fibrotic diseases, has been implicated in all three prostate conditions. The role of OPN in prostatic pathophysiology, affecting both benign and malignant prostate conditions, is significant. Current evidence strongly suggests that OPN is expressed at a higher level in prostate cancer and promotes tumor progression and aggressiveness. Conversely, OPN is primarily secreted by macrophages and foam cells in benign prostate conditions and provokes inflammation and fibrosis. This review discusses the accumulating evidence on the role of OPN in prostatic diseases, cellular sources, and potential roles while also highlighting areas for future investigations. Full article
(This article belongs to the Special Issue 30 Years of OPN Milestones and Future Avenues 2.0)
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19 pages, 4659 KiB  
Review
Osteopontin in Pulmonary Hypertension
by Argen Mamazhakypov, Abdirashit Maripov, Akpay S. Sarybaev, Ralph Theo Schermuly and Akylbek Sydykov
Biomedicines 2023, 11(5), 1385; https://doi.org/10.3390/biomedicines11051385 - 07 May 2023
Cited by 1 | Viewed by 1805
Abstract
Pulmonary hypertension (PH) is a pathological condition with multifactorial etiology, which is characterized by elevated pulmonary arterial pressure and pulmonary vascular remodeling. The underlying pathogenetic mechanisms remain poorly understood. Accumulating clinical evidence suggests that circulating osteopontin may serve as a biomarker of PH [...] Read more.
Pulmonary hypertension (PH) is a pathological condition with multifactorial etiology, which is characterized by elevated pulmonary arterial pressure and pulmonary vascular remodeling. The underlying pathogenetic mechanisms remain poorly understood. Accumulating clinical evidence suggests that circulating osteopontin may serve as a biomarker of PH progression, severity, and prognosis, as well as an indicator of maladaptive right ventricular remodeling and dysfunction. Moreover, preclinical studies in rodent models have implicated osteopontin in PH pathogenesis. Osteopontin modulates a plethora of cellular processes within the pulmonary vasculature, including cell proliferation, migration, apoptosis, extracellular matrix synthesis, and inflammation via binding to various receptors such as integrins and CD44. In this article, we provide a comprehensive overview of the current understanding of osteopontin regulation and its impact on pulmonary vascular remodeling, as well as consider research issues required for the development of therapeutics targeting osteopontin as a potential strategy for the management of PH. Full article
(This article belongs to the Special Issue 30 Years of OPN Milestones and Future Avenues 2.0)
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20 pages, 1111 KiB  
Review
Osteopontin as a Biomarker in Chronic Kidney Disease
by Satyesh K. Sinha, Michael Mellody, Maria Beatriz Carpio, Robert Damoiseaux and Susanne B. Nicholas
Biomedicines 2023, 11(5), 1356; https://doi.org/10.3390/biomedicines11051356 - 04 May 2023
Cited by 6 | Viewed by 2226
Abstract
Osteopontin (OPN) is a ubiquitously expressed protein with a wide range of physiological functions, including roles in bone mineralization, immune regulation, and wound healing. OPN has been implicated in the pathogenesis of several forms of chronic kidney disease (CKD) where it promotes inflammation [...] Read more.
Osteopontin (OPN) is a ubiquitously expressed protein with a wide range of physiological functions, including roles in bone mineralization, immune regulation, and wound healing. OPN has been implicated in the pathogenesis of several forms of chronic kidney disease (CKD) where it promotes inflammation and fibrosis and regulates calcium and phosphate metabolism. OPN expression is increased in the kidneys, blood, and urine of patients with CKD, particularly in those with diabetic kidney disease and glomerulonephritis. The full-length OPN protein is cleaved by various proteases, including thrombin, matrix metalloproteinase (MMP)-3, MMP-7, cathepsin-D, and plasmin, producing N-terminal OPN (ntOPN), which may have more detrimental effects in CKD. Studies suggest that OPN may serve as a biomarker in CKD, and while more research is needed to fully evaluate and validate OPN and ntOPN as CKD biomarkers, the available evidence suggests that they are promising candidates for further investigation. Targeting OPN may be a potential treatment strategy. Several studies show that inhibition of OPN expression or activity can attenuate kidney injury and improve kidney function. In addition to its effects on kidney function, OPN has been linked to cardiovascular disease, which is a major cause of morbidity and mortality in patients with CKD. Full article
(This article belongs to the Special Issue 30 Years of OPN Milestones and Future Avenues 2.0)
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18 pages, 1219 KiB  
Review
Osteopontin and Cancer: Insights into Its Role in Drug Resistance
by Chengcheng Hao, Jane Lane and Wen G. Jiang
Biomedicines 2023, 11(1), 197; https://doi.org/10.3390/biomedicines11010197 - 12 Jan 2023
Cited by 9 | Viewed by 2092
Abstract
Cancer is one of the leading causes of mortality worldwide. Currently, drug resistance is the main obstacle in cancer treatments with the underlying mechanisms of drug resistance yet to be fully understood. Osteopontin (OPN) is a member of the integrin binding glycophosphoprotein family [...] Read more.
Cancer is one of the leading causes of mortality worldwide. Currently, drug resistance is the main obstacle in cancer treatments with the underlying mechanisms of drug resistance yet to be fully understood. Osteopontin (OPN) is a member of the integrin binding glycophosphoprotein family that is overexpressed in several tumour types. It is involved in drug transport, apoptosis, stemness, energy metabolism, and autophagy, which may contribute to drug resistance. Thus, understanding the role of OPN in cancer drug resistance could be important. This review describes the OPN-based mechanisms that might contribute to cancer drug resistance, demonstrating that OPN may be a viable target for cancer therapy to reduce drug resistance in sensitive tumours. Full article
(This article belongs to the Special Issue 30 Years of OPN Milestones and Future Avenues 2.0)
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