Cells

Research

14 pages, 3155 KiB

Open AccessArticle

Osteopontin is An Important Regulative Component of the Fetal Bone Marrow Hematopoietic Stem Cell Niche

by Huimin Cao, Benjamin Cao, Chad K. Heazlewood, Melanie Domingues, Xuan Sun, Emmanuel Debele, Narelle E. McGregor, Natalie A. Sims, Shen Y. Heazlewood and Susan K. Nilsson

Cells 2019, 8(9), 985; https://doi.org/10.3390/cells8090985 - 27 Aug 2019

Cited by 20 | Viewed by 4854

Abstract

Osteopontin (OPN) is an important component in both bone and blood regulation, functioning as a bridge between the two. Previously, thrombin-cleaved osteopontin (trOPN), the dominant form of OPN in adult bone marrow (BM), was demonstrated to be a critical negative regulator of adult [...] Read more.

Osteopontin (OPN) is an important component in both bone and blood regulation, functioning as a bridge between the two. Previously, thrombin-cleaved osteopontin (trOPN), the dominant form of OPN in adult bone marrow (BM), was demonstrated to be a critical negative regulator of adult hematopoietic stem cells (HSC) via interactions with α₄β₁ and α₉β₁ integrins. We now demonstrate OPN is also required for fetal hematopoiesis in maintaining the HSC and progenitor pool in fetal BM. Specifically, we showed that trOPN is highly expressed in fetal BM and its receptors, α₄β₁ and α₉β₁ integrins, are both highly expressed and endogenously activated on fetal BM HSC and progenitors. Notably, the endogenous activation of integrins expressed by HSC was attributed to high concentrations of three divalent metal cations, Ca²⁺, Mg²⁺ and Mn²⁺, which were highly prevalent in developing fetal BM. In contrast, minimal levels of OPN were detected in fetal liver, and α₄β₁ and α₉β₁ integrins expressed by fetal liver HSC were not in the activated state, thereby permitting the massive expansion of HSC and progenitors required during early fetal hematopoiesis. Consistent with these results, no differences in the number or composition of hematopoietic cells in the liver of fetal OPN^-/- mice were detected, but significant increases in the hematopoietic progenitor pool in fetal BM as well as an increase in the BM HSC pool following birth and into adulthood were observed. Together, the data demonstrates OPN is a necessary negative regulator of fetal and neonatal BM progenitors and HSC, and it exhibits preserved regulatory roles during early development, adulthood and ageing. Full article

(This article belongs to the Special Issue Adding New Pieces in the Osteopontin Puzzle)

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18 pages, 5063 KiB

Open AccessArticle

Osteopontin-Enhanced Autophagy Attenuates Early Brain Injury via FAK–ERK Pathway and Improves Long-Term Outcome after Subarachnoid Hemorrhage in Rats

by Chengmei Sun, Budbazar Enkhjargal, Cesar Reis, Tongyu Zhang, Qiquan Zhu, Keren Zhou, Zhiyi Xie, Lingyun Wu, Jiping Tang, Xiaodan Jiang and John H. Zhang

Cells 2019, 8(9), 980; https://doi.org/10.3390/cells8090980 - 27 Aug 2019

Cited by 25 | Viewed by 5042

Abstract

Osteopontin (OPN) enhances autophagy, reduces apoptosis, and attenuates early brain injury (EBI) after a subarachnoid hemorrhage (SAH). A total of 87 Sprague–Dawley rats were subjected to sham or SAH operations to further investigate the signaling pathway involved in osteopontin-enhanced autophagy during EBI, and [...] Read more.

Osteopontin (OPN) enhances autophagy, reduces apoptosis, and attenuates early brain injury (EBI) after a subarachnoid hemorrhage (SAH). A total of 87 Sprague–Dawley rats were subjected to sham or SAH operations to further investigate the signaling pathway involved in osteopontin-enhanced autophagy during EBI, and the potential effect of recombinant OPN (rOPN) administration to improve long-term outcomes after SAH. Rats were randomly divided into five groups: Sham, SAH + Vehicle (PBS, phosphate-buffered saline), SAH + rOPN (5 μg/rat recombinant OPN), SAH + rOPN + Fib-14 (30 mg/kg of focal adhesion kinase (FAK) inhibitor-14), and SAH + rOPN + DMSO (dimethyl sulfoxide). Short-term and long-term neurobehavior tests were performed, followed by a collection of brain samples for assessment of autophagy markers in neurons, pathway proteins expression, and delayed hippocampal injury. Western blot, double immunofluorescence staining, Nissl staining, and Fluoro-Jade C staining assay were used. Results showed that rOPN administration increased autophagy in neurons and improved neurobehavior in a rat model of SAH. With the administration of FAK inhibitor-14 (Fib-14), neurobehavioral improvement and autophagy enhancement induced by rOPN were abolished, and there were consistent changes in the phosphorylation level of ERK1/2. In addition, early administration of rOPN in rat SAH models improved long-term neurobehavior results, possibly by alleviating hippocampal injury. These results suggest that FAK–ERK signaling may be involved in OPN-enhanced autophagy in the EBI phase after SAH. Early administration of rOPN may be a preventive and therapeutic strategy against delayed brain injury after SAH. Full article

(This article belongs to the Special Issue Adding New Pieces in the Osteopontin Puzzle)

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10 pages, 399 KiB

Open AccessArticle

Osteopontin Gene Polymorphism and Urinary OPN Excretion in Patients with Immunoglobulin A Nephropathy

by Beata Kaleta, Natalia Krata, Radosław Zagożdżon and Krzysztof Mucha

Cells 2019, 8(6), 524; https://doi.org/10.3390/cells8060524 - 31 May 2019

Cited by 6 | Viewed by 2932

Abstract

Osteopontin (OPN) is a glycoprotein involved in the pathogenesis of multiple autoimmune and inflammatory conditions. However, the association of variants of secreted phosphoprotein 1 gene (SPP1), which encodes OPN, with immunoglobulin A nephropathy (IgAN) has not been examined up to date. [...] Read more.

Osteopontin (OPN) is a glycoprotein involved in the pathogenesis of multiple autoimmune and inflammatory conditions. However, the association of variants of secreted phosphoprotein 1 gene (SPP1), which encodes OPN, with immunoglobulin A nephropathy (IgAN) has not been examined up to date. Moreover, the role of OPN in disease pathogenesis and clinical manifestations is not fully known. Therefore, the aim of the study was to determine the frequency of four single nucleotide polymorphisms (SNiPs) of SPP1 gene, as well as the urinary OPN excretion in IgAN patients and healthy controls. In total, 58 Caucasian patients with biopsy-proven IgAN and 184 gender-, age-, and ethnically-matched healthy controls were genotyped for rs1126616, rs1126772, rs9138, and rs7687316/rs3841116 polymorphisms by real time polymerase chain reaction (RT-PCR). Urinary OPN concentration was determined by enzyme-linked immunosorbent assay (ELISA) in 58 IgAN patients and 19 controls. SPP1 SNiPs, as well as urinary OPN excretion, were analyzed in relation to their possible associations with the clinicopathological parameters. The frequency of the minor TT/CT genotypes of rs1126616 was significantly higher in IgAN patients compared to controls (P = 0.0217). Similarly, the minor (CC/AC) genotypes and the C allele of rs9138 were more frequent in IgAN patients (P = 0.0425 and P = 0.0112, respectively). Moreover, these two SNiPs were associated with the higher urinary OPN excretion (P < 0.05). These findings suggest that rs1126616, as well as rs9138, may be associated with IgAN development, however future studies in this field are required. Full article

(This article belongs to the Special Issue Adding New Pieces in the Osteopontin Puzzle)

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14 pages, 2007 KiB

Open AccessArticle

Characterisation of Osteopontin in an In Vitro Model of Embryo Implantation

by Stéphane C Berneau, Peter T Ruane, Daniel R Brison, Susan J Kimber, Melissa Westwood and John D Aplin

Cells 2019, 8(5), 432; https://doi.org/10.3390/cells8050432 - 09 May 2019

Cited by 24 | Viewed by 5429

Abstract

At the onset of pregnancy, embryo implantation is initiated by interactions between the endometrial epithelium and the outer trophectoderm cells of the blastocyst. Osteopontin (OPN) is expressed in the endometrium and is implicated in attachment and signalling roles at the embryo–epithelium interface. We [...] Read more.

At the onset of pregnancy, embryo implantation is initiated by interactions between the endometrial epithelium and the outer trophectoderm cells of the blastocyst. Osteopontin (OPN) is expressed in the endometrium and is implicated in attachment and signalling roles at the embryo–epithelium interface. We have characterised OPN in the human endometrial epithelial Ishikawa cell line using three different monoclonal antibodies, revealing at least nine distinct molecular weight forms and a novel secretory pathway localisation in the apical domain induced by cell organisation into a confluent epithelial layer. Mouse blastocysts co-cultured with Ishikawa cell layers served to model embryo apposition, attachment and initial invasion at implantation. Exogenous OPN attenuated initial, weak embryo attachment to Ishikawa cells but did not affect the attainment of stable attachment. Notably, exogenous OPN inhibited embryonic invasion of the underlying cell layer, and this corresponded with altered expression of transcription factors associated with differentiation from trophectoderm (Gata2) to invasive trophoblast giant cells (Hand1). These data demonstrate the complexity of endometrial OPN forms and suggest that OPN regulates embryonic invasion at implantation by signalling to the trophectoderm. Full article

(This article belongs to the Special Issue Adding New Pieces in the Osteopontin Puzzle)

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22 pages, 3519 KiB

Open AccessFeature PaperArticle

Untangling Extracellular Proteasome-Osteopontin Circuit Dynamics in Multiple Sclerosis

by Chiara Dianzani, Domizia Vecchio, Nausicaa Clemente, Annalisa Chiocchetti, Filippo Martinelli Boneschi, Daniela Galimberti, Umberto Dianzani, Cristoforo Comi, Michele Mishto and Juliane Liepe

Cells 2019, 8(3), 262; https://doi.org/10.3390/cells8030262 - 20 Mar 2019

Cited by 10 | Viewed by 4556

Abstract

The function of proteasomes in extracellular space is still largely unknown. The extracellular proteasome-osteopontin circuit has recently been hypothesized to be part of the inflammatory machinery regulating relapse/remission phase alternation in multiple sclerosis. However, it is still unclear what dynamics there are between [...] Read more.

The function of proteasomes in extracellular space is still largely unknown. The extracellular proteasome-osteopontin circuit has recently been hypothesized to be part of the inflammatory machinery regulating relapse/remission phase alternation in multiple sclerosis. However, it is still unclear what dynamics there are between the different elements of the circuit, what the role of proteasome isoforms is, and whether these inflammatory circuit dynamics are associated with the clinical severity of multiple sclerosis. To shed light on these aspects of this novel inflammatory circuit, we integrated in vitro proteasome isoform data, cell chemotaxis cell culture data, and clinical data of multiple sclerosis cohorts in a coherent computational inference framework. Thereby, we modeled extracellular osteopontin-proteasome circuit dynamics during relapse/remission alternation in multiple sclerosis. Applying this computational framework to a longitudinal study on single multiple sclerosis patients suggests a complex interaction between extracellular proteasome isoforms and osteopontin with potential clinical implications. Full article

(This article belongs to the Special Issue Adding New Pieces in the Osteopontin Puzzle)

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Graphical abstract

12 pages, 1282 KiB

Open AccessArticle

The Role of Osteopontin as a Diagnostic and Prognostic Biomarker in Sepsis and Septic Shock

by Luigi Mario Castello, Marco Baldrighi, Luca Molinari, Livia Salmi, Vincenzo Cantaluppi, Rosanna Vaschetto, Greta Zunino, Marco Quaglia, Mattia Bellan, Francesco Gavelli, Paolo Navalesi, Gian Carlo Avanzi and Annalisa Chiocchetti

Cells 2019, 8(2), 174; https://doi.org/10.3390/cells8020174 - 18 Feb 2019

Cited by 33 | Viewed by 4614

Abstract

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host-response to infections. Osteopontin (OPN) is an extracellular matrix protein involved in the inflammatory response. Our aim was to evaluate the diagnostic and prognostic performance in sepsis of a single OPN determination in [...] Read more.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host-response to infections. Osteopontin (OPN) is an extracellular matrix protein involved in the inflammatory response. Our aim was to evaluate the diagnostic and prognostic performance in sepsis of a single OPN determination in the Emergency Department (ED). We conducted a single-centre prospective observational study in an Italian ED where we enrolled 102 consecutive patients presenting with suspected infection and qSOFA ≥ 2. OPN plasma concentration was found to be an independent predictor of sepsis (OR = 1.020, 95% CI 1.002–1.039, p = 0.031) and the diagnostic receiver operating characteristic (ROC) curve resulted in an area under the curve (AUC) of 0.878. OPN levels were positively correlated to plasma creatinine (r = 0.401 with p = 0.0001), but this relation was not explained by the development of acute kidney injury (AKI), since no difference was found in OPN concentration between AKI and non-AKI patients. The analysis of 30-days mortality showed no significant difference in OPN levels between alive and dead patients (p = 0.482). In conclusion, a single determination of OPN concentration helped to identify patients with sepsis in the ED, but it was not able to predict poor prognosis in our cohort of patients. Full article

(This article belongs to the Special Issue Adding New Pieces in the Osteopontin Puzzle)

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Review

Jump to: Research, Other

14 pages, 1211 KiB

Open AccessReview

Osteopontin: A Promising Therapeutic Target in Cardiac Fibrosis

by Iman Abdelaziz Mohamed, Alain-Pierre Gadeau, Anwarul Hasan, Nabeel Abdulrahman and Fatima Mraiche

Cells 2019, 8(12), 1558; https://doi.org/10.3390/cells8121558 - 03 Dec 2019

Cited by 42 | Viewed by 5388

Abstract

Osteopontin (OPN) is recognized for its significant roles in both physiological and pathological processes. Initially, OPN was recognized as a cytokine with pro-inflammatory actions. More recently, OPN has emerged as a matricellular protein of the extracellular matrix (ECM). OPN is also known to [...] Read more.

Osteopontin (OPN) is recognized for its significant roles in both physiological and pathological processes. Initially, OPN was recognized as a cytokine with pro-inflammatory actions. More recently, OPN has emerged as a matricellular protein of the extracellular matrix (ECM). OPN is also known to be a substrate for proteolytic cleavage by several proteases that form an integral part of the ECM. In the adult heart under physiological conditions, basal levels of OPN are expressed. Increased expression of OPN has been correlated with the progression of cardiac remodeling and fibrosis to heart failure and the severity of the condition. The intricate process by which OPN mediates its effects include the coordination of intracellular signals necessary for the differentiation of fibroblasts into myofibroblasts, promoting angiogenesis, wound healing, and tissue regeneration. In this review, we discuss the role of OPN in contributing to the development of cardiac fibrosis and its suitability as a therapeutic target. Full article

(This article belongs to the Special Issue Adding New Pieces in the Osteopontin Puzzle)

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20 pages, 1301 KiB

Open AccessReview

Osteopontin as a Link between Inflammation and Cancer: The Thorax in the Spotlight

by Anne-Sophie Lamort, Ioanna Giopanou, Ioannis Psallidas and Georgios T. Stathopoulos

Cells 2019, 8(8), 815; https://doi.org/10.3390/cells8080815 - 02 Aug 2019

Cited by 98 | Viewed by 6390

Abstract

The glycoprotein osteopontin (OPN) possesses multiple functions in health and disease. To this end, osteopontin has beneficial roles in wound healing, bone homeostasis, and extracellular matrix (ECM) function. On the contrary, osteopontin can be deleterious for the human body during disease. Indeed, osteopontin [...] Read more.

The glycoprotein osteopontin (OPN) possesses multiple functions in health and disease. To this end, osteopontin has beneficial roles in wound healing, bone homeostasis, and extracellular matrix (ECM) function. On the contrary, osteopontin can be deleterious for the human body during disease. Indeed, osteopontin is a cardinal mediator of tumor-associated inflammation and facilitates metastasis. The purpose of this review is to highlight the importance of osteopontin in malignant processes, focusing on lung and pleural tumors as examples. Full article

(This article belongs to the Special Issue Adding New Pieces in the Osteopontin Puzzle)

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Other

Jump to: Research, Review

10 pages, 571 KiB

Open AccessBrief Report

Osteopontin in the Cerebrospinal Fluid of Patients with Severe Aneurysmal Subarachnoid Hemorrhage

by Maria Giulia Abate, Lorenza Moretto, Ilaria Licari, Teresa Esposito, Lorenzo Capuano, Carlo Olivieri, Arnaldo Benech, Matteo Brucoli, Gian Carlo Avanzi, Gianmaria Cammarota, Umberto Dianzani, Nausicaa Clemente, Gabriele Panzarasa, Giuseppe Citerio, Fabio Carfagna, Giuseppe Cappellano, Francesco Della Corte and Rosanna Vaschetto

Cells 2019, 8(7), 695; https://doi.org/10.3390/cells8070695 - 10 Jul 2019

Cited by 8 | Viewed by 2797

Abstract

Aneurysmal subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality. In SAH patients, plasma osteopontin (OPN) has been shown to independently predict poor outcome. The aim of the study is to investigate, in a selected population with severe SAH, OPN time course [...] Read more.

Aneurysmal subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality. In SAH patients, plasma osteopontin (OPN) has been shown to independently predict poor outcome. The aim of the study is to investigate, in a selected population with severe SAH, OPN time course in cerebrospinal fluid (CSF) and plasma during the first week after aneurism rupture, and OPN prognostic value. We included 44 patients with the following criteria: (1) age 18 and 80 years, (2) diagnosis of SAH from cerebral aneurysm rupture, (3) insertion of external ventricular drain. Plasma and CSF were sampled at day 1, 4, and 8. OPN levels, in CSF and plasma, displayed a weak correlation on day 1 and were higher, in CSF, in all time points. Only in poor prognosis patients, OPN levels in CSF significantly increased at day 4 and day 8. Plasma OPN at day 1 and 4 was predictor of poor outcome. In conclusion, plasma and CSF OPN displays a weak correlation, on day 1. The higher levels of OPN found in the CSF compared to plasma, suggest OPN production within the CNS after SAH. Furthermore, plasma OPN, at day 1 and 4, seems to be an independent predictor of poor outcome. Full article

(This article belongs to the Special Issue Adding New Pieces in the Osteopontin Puzzle)

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