Mattia Vitale

University of Manchester

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Jordi Bella

Manchester Academic Health Science Centre

Judith A. Hoyland

University of Manchester

Stephen M. Richardson

University of Manchester

Cosimo Ligorio

University of Manchester

Serena Pollino

Istituto Ortopedico Rizzoli

Maria Serena Benassi

Istituto Ortopedico Rizzoli

Laura Pazzaglia

Istituto Ortopedico Rizzoli

Bethan S. McAvan

Henry Royce Institute

Piero Picci

Istituto Ortopedico Rizzoli

Chris Allan

Biogelx (United Kingdom)

Cooperative Institutions

Istituto Ortopedico Rizzoli

Istituti di Ricovero e Cura a Carattere Scientifico

University of Manchester

Henry Royce Institute

Manchester Academic Health Science Centre

Wellcome Centre for Cell-Matrix Research

Hospital Universitario Fundación Jiménez Díaz

University of Bologna

Medica (Italy)

Policlinico S.Orsola-Malpighi

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Role of OSCAR Signaling in Osteoclastogenesis and Bone Disease

Frontiers in Cell and Developmental Biology (2021)

Iva R. Nedeva Mattia Vitale Ari Elson Judith A. Hoyland Jordi Bella

Formation of mature bone-resorbing cells through osteoclastogenesis is required for the continuous remodeling and repair of bone tissue. In aging and disease this process may become aberrant, resulting in excessive bone degradation and fragility fractures. Interaction of receptor-activator of nuclear factor-κB (RANK) with its ligand RANKL activates the main signaling pathway for osteoclastogenesis. However, compelling evidence indicates that this pathway may not be sufficient for the production of mature osteoclast cells and that co-stimulatory signals may be required for both the expression of osteoclast-specific genes and the activation of osteoclasts. Osteoclast-associated receptor (OSCAR), a regulator of osteoclast differentiation, provides one such co-stimulatory pathway. This review summarizes our present knowledge of osteoclastogenesis signaling and the role of OSCAR in the normal production of bone-resorbing cells and in bone disease. Understanding the signaling mechanism through this receptor and how it contributes to the production of mature osteoclasts may offer a more specific and targeted approach for pharmacological intervention against pathological bone resorption.

RANK Ligand

Bone remodeling

10.3389/fcell.2021.641162

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Citations (44)

miR‑494.3p expression in synovial sarcoma: Role of CXCR4 as a potential target gene

International Journal of Oncology (2018)

Laura Pazzaglia Serena Pollino Mattia Vitale Elisa Bientinesi Stefania Benini

Synovial sarcoma (SS) is a rare tumour, with dismal survival when metastasis occurs. SS contains a characteristic translocation (X;18)(p11;q11) and the fusion genes appear to be mutually exclusive and concordant in primary and metastatic tumours. Novel prognostic and predictive factors are required. The C‑X‑C motif chemokine ligand 12 (CXCL12)/C‑X‑C chemokine receptor 4 (CXCR4) axis is involved in tumour development and metastatic spread in many types of cancer and previous data have demonstrated a pivotal role of CXCR4 in SS cell migration and invasion. Bioinformatics and biological data indicated CXCR4 is a possible candidate target of miR‑494.3p, known to be involved in tumour progression. In this study, we analysed the expression of miR‑494.3p and its potential target, CXCR4, in a series of SS specimens. A significantly lower miR‑494.3p expression was found in the tumour compared to normal tissue associated with higher levels of CXCR4 both at the gene and protein level. The role of CXCR4 as a potential target of miR‑494.3p was assessed in two SS cell lines (SW982 and SYO‑I). Transfection with miR‑494.3p expression plasmid led to a marked decrease in CXCR4 gene and protein expression, concomitant with a transitory decrease in cell proliferation and migration. The SYO‑I cells also responded with an increased apoptotic fraction. The data of this study also demonstrate that the downregulation of miR‑494.3p in SS surgical specimens, concomitant with an increased expression of its potential target, CXCR4, was more evident in the metastatic subset. In vitro experiments confirmed that miR‑494.3p functioned as a tumour suppressor through the involvement of CXCR4 and ongoing studies are directed to better clarify its role in SS therapeutic strategies.

Synovial Sarcoma

10.3892/ijo.2018.4627

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Hydroxyapatite-decorated Fmoc-hydrogel as a bone-mimicking substrate for osteoclast differentiation and culture

Acta Biomaterialia (2021)

Mattia Vitale Cosimo Ligorio Bethan S. McAvan Nigel W. Hodson Chris Allan

Hydrogels are water-swollen networks with great potential for tissue engineering applications. However, their use in bone regeneration is often hampered due to a lack of materials' mineralization and poor mechanical properties. Moreover, most studies are focused on osteoblasts (OBs) for bone formation, while osteoclasts (OCs), cells involved in bone resorption, are often overlooked. Yet, the role of OCs is pivotal for bone homeostasis and aberrant OC activity has been reported in several pathological diseases, such as osteoporosis and bone cancer. For these reasons, the aim of this work is to develop customised, reinforced hydrogels to be used as material platform to study cell function, cell-material interactions and ultimately to provide a substrate for OC differentiation and culture. Here, Fmoc-based RGD-functionalised peptide hydrogels have been modified with hydroxyapatite nanopowder (Hap) as nanofiller, to create nanocomposite hydrogels. Atomic force microscopy showed that Hap nanoparticles decorate the peptide nanofibres with a repeating pattern, resulting in stiffer hydrogels with improved mechanical properties compared to Hap- and RGD-free controls. Furthermore, these nanocomposites supported adhesion of Raw 264.7 macrophages and their differentiation in 2D to mature OCs, as defined by the adoption of a typical OC morphology (presence of an actin ring, multinucleation, and ruffled plasma membrane). Finally, after 7 days of culture OCs showed an increased expression of TRAP, a typical OC differentiation marker. Collectively, the results suggest that the Hap/Fmoc-RGD hydrogel has a potential for bone tissue engineering, as a 2D model to study impairment or upregulation of OC differentiation. STATEMENT OF SIGNIFICANCE: Altered osteoclasts (OC) function is one of the major cause of bone fracture in the most commonly skeletal disorders (e.g. osteoporosis). Peptide hydrogels can be used as a platform to mimic the bone microenvironment and provide a tool to assess OC differentiation and function. Moreover, hydrogels can incorporate different nanofillers to yield hybrid biomaterials with enhanced mechanical properties and improved cytocompatibility. Herein, Fmoc-based RGD-functionalised peptide hydrogels were decorated with hydroxyapatite (Hap) nanoparticles to generate a hydrogel with improved rheological properties. Furthermore, they are able to support osteoclastogenesis of Raw264.7 cells in vitro as confirmed by morphology changes and expression of OC-markers. Therefore, this Hap-decorated hydrogel can be used as a template to successfully differentiate OC and potentially study OC dysfunction.

10.1016/j.actbio.2021.11.011

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Abstract 2534: miRNA expression as potential biomarker for synovial sarcoma

Cancer Research (2017)

Laura Pazzaglia Serena Pollino Mattia Vitale Amalia Conti Piero Picci

Abstract Synovial sarcoma (SS) is a rare tumor, with dismal survival when metastatic. SS contains a characteristic translocation (X;18)(p11;q11), representing the fusion of SYT on chromosome 18 with either SSX1, SSX2, or rarely SSX4 on chromosome X The resulting fusion genes appear to be mutually exclusive and concordant in primary and metastatic tumours. New prognostic and predictive factors are needed. Chemokine receptor 4 (CXCR4) is a seven-transmembrane G protein-coupled chemokine receptor and it is the chemokine receptor most commonly expressed in tumour cells, involved in cell migration and invasion, as well as angiogenesis. microRNAs (miRNAs) are involved in post-transcriptional gene expression regulation and control important physiological processes like development, cell differentiation and cell signaling. Altered expression of miRNAs is strongly correlated with the malignant phenotype and there is data reporting a strong association between microRNA expression, patient age and STS prognosis. By three different databases (miRBase, TargetScan , miRanda) and by literature data we identified two miRNA regulators of CXCR4, miR-133b and miR-494. The expression of these miRNAs was evaluated by RT-PCR in 42 SS primary samples stored at Rizzoli biobank. 20 tissues from non oncologic patients were used as control. Our results showed a significant lower expression of miR-133b and miR-494 (respectively p=0.0005 and p=0.001) when compared to non tumor tissue. In vitro study on SW982 cell line with miR-133b precursor show a CXCR4 downregulation and a decrease of cell proliferation. Our preliminary data confirmed a miR-133b and miR-494 downregulation in SS. Correlation with clinical data, with CXCR4 expression and in vitro studies also with miR-494 in several SS cell lines are on-going to better investigate their role as potential prognostic and therapeutic markers. Citation Format: Laura Pazzaglia, Serena Pollino, Mattia Vitale, Amalia Conti, Piero Picci, Maria Serena Benassi. miRNA expression as potential biomarker for synovial sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2534. doi:10.1158/1538-7445.AM2017-2534

Synovial Sarcoma

MiRBase

10.1158/1538-7445.am2017-2534

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Incorporation of Natural and Recombinant Collagen Proteins within Fmoc-Based Self-Assembling Peptide Hydrogels

Gels (2022)

Mattia Vitale Cosimo Ligorio Ian P. Smith Stephen M. Richardson Judith A. Hoyland

Hydrogel biomaterials mimic the natural extracellular matrix through their nanofibrous ultrastructure and composition and provide an appropriate environment for cell–matrix and cell–cell interactions within their polymeric network. Hydrogels can be modified with different proteins, cytokines, or cell-adhesion motifs to control cell behavior and cell differentiation. Collagens are desirable and versatile proteins for hydrogel modification due to their abundance in the vertebrate extracellular matrix and their interactions with cell-surface receptors. Here, we report a quick, inexpensive and effective protocol for incorporation of natural, synthetic and recombinant collagens into Fmoc-based self-assembling peptide hydrogels. The hydrogels are modified through a diffusion protocol in which collagen molecules of different molecular sizes are successfully incorporated and retained over time. Characterization studies show that these collagens interact with the hydrogel fibers without affecting the overall mechanical properties of the composite hydrogels. Furthermore, the collagen molecules incorporated into the hydrogels are still biologically active and provide sites for adhesion and spreading of human fibrosarcoma cells through interaction with the α2β1 integrin. Our protocol can be used to incorporate different types of collagen molecules into peptide-based hydrogels without any prior chemical modification. These modified hydrogels could be used in studies where collagen-based substrates are required to differentiate and control the cell behavior. Our protocol can be easily adapted to the incorporation of other bioactive proteins and peptides into peptide-based hydrogels to modulate their characteristics and their interaction with different cell types.

3D cell culture

10.3390/gels8050254

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Citations (6)

Towards a "global" political risk analysis

Raffaele Marchetti Mattia Vitale

The purpose of this paper is to test the relevance of the globalization variable for Political Risk Analysis (PRA). The concept of political risk and the analysis methodology adopted and used in PRA are extremely heterogeneous, varying profoundly case by case. However a common pattern can be identified. In almost every definition or operational concept of political risk, the focus relies almost entirely on the internal dimension. The models developed by both public and private agencies and institutions tend in fact to base their models on variables and indicators internal to the country object of the analysis. In those few cases in which the external variables are taken into consideration, they refer to classical events such as wars. In our opinion this approach is limited because it does not capture the structural processes generated by the global transformations of the last decades. In today’s globalized and ever changing world, we think that in any political risk analysis model it is fundamental to include a transnational perspective. A transnational variable should accordingly be crafted in order to complement the national variable by weighting the effects of the international and global dimension on local and national socio-political events. By testing out hypotheses with reference to two indexes related respectively to stability and governance, we find evidence of a positive relationship between the level of global integration of a country and its degree of stability and even more its level of governance. While these results (to be further tested with more sophisticated statistical tools in the follow up of the research) remain preliminary, they are sufficient to delineate a new understanding of political risk analysis that – by taking into consideration current concepts of political risk and modern theories of globalization – integrates in a comprehensive framework the more traditional variables of political risk with a new transnational variable.

Political risk

Global Governance

Variables

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Hydroxyapatite-Decorated Fmoc-Hydrogel as a Bone-Mimicking Substrate for Osteoclast Differentiation and Culture

SSRN Electronic Journal (2021)

Mattia Vitale Cosimo Ligorio Bethan S. McAvan Nigel W. Hodson Chris Allan

10.2139/ssrn.3895614

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Citations (1)

Collagen-like Osteoclast-Associated Receptor (OSCAR)-Binding Motifs Show a Co-Stimulatory Effect on Osteoclastogenesis in a Peptide Hydrogel System

International Journal of Molecular Sciences (2023)

Mattia Vitale Cosimo Ligorio Stephen M. Richardson Judith A. Hoyland Jordi Bella

Osteoclastogenesis, one of the dynamic pathways underlying bone remodelling, is a complex process that includes many stages. This complexity, while offering a wealth of therapeutic opportunities, represents a substantial challenge in unravelling the underlying mechanisms. As such, there is a high demand for robust model systems to understand osteoclastogenesis. Hydrogels seeded with osteoclast precursors and decorated with peptides or proteins mimicking bone’s extracellular matrix could provide a useful synthetic tool to study pre-osteoclast-matrix interactions and their effect on osteoclastogenesis. For instance, fibrillar collagens have been shown to provide a co-stimulatory pathway for osteoclastogenesis through interaction with the osteoclast-associated receptor (OSCAR), a regulator of osteoclastogenesis expressed on the surface of pre-osteoclast cells. Based on this rationale, here we design two OSCAR-binding peptides and one recombinant OSCAR-binding protein, and we combine them with peptide-based hydrogels to study their effect on osteoclastogenesis. The OSCAR-binding peptides adopt the collagen triple-helical conformation and interact with OSCAR, as shown by circular dichroism spectropolarimetry and surface plasmon resonance. Furthermore, they have a positive effect on osteoclastogenesis, as demonstrated by appropriate gene expression and tartrate-resistant acid phosphatase staining typical of osteoclast formation. Combination of the OSCAR-binding peptides or the OSCAR-binding recombinant protein with peptide-based hydrogels enhances osteoclast differentiation when compared to the non-modified hydrogels, as demonstrated by multi-nucleation and by F-actin staining showing a characteristic osteoclast-like morphology. We envisage that these hydrogels could be used as a platform to study osteoclastogenesis and, in particular, to investigate the effect of costimulatory pathways involving OSCAR.

10.3390/ijms25010445

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CSR come driver strategico per le imprese: analisi del caso Volkswagen

Mattia Vitale

La corporate social responsability. Formalizzazione della CSR. CSR nel settore dell'automotive: il caso Volkswagen.

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