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Osteoblast-Derived Vesicle Protein Content Is Temporally Regulated University of Birmingham Osteoblast-derived vesicle protein content is temporally regulated during osteogenesis Davies, Owen G.; Cox, Sophie C.; Azoidis, Ioannis; McGuinness, Adam J.; Cooke, Megan; Heaney, Liam M.; Grover, Liam M. DOI: 10.3389/fbioe.2019.00092 License: Creative Commons: Attribution (CC BY) Document Version Publisher's PDF, also known as Version of record Citation for published version (Harvard): Davies, OG, Cox, SC, Azoidis, I, McGuinness, AJ, Cooke, M, Heaney, LM & Grover, LM 2019, 'Osteoblast- derived vesicle protein content is temporally regulated during osteogenesis: Implications for regenerative therapies', Frontiers in Bioengineering and Biotechnology, vol. 7, no. APR, 92. https://doi.org/10.3389/fbioe.2019.00092 Link to publication on Research at Birmingham portal Publisher Rights Statement: © 2019 Davies, Cox, Azoidis, McGuinness, Cooke, Heaney and Grover. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. General rights Unless a licence is specified above, all rights (including copyright and moral rights) in this document are retained by the authors and/or the copyright holders. The express permission of the copyright holder must be obtained for any use of this material other than for purposes permitted by law. •Users may freely distribute the URL that is used to identify this publication. •Users may download and/or print one copy of the publication from the University of Birmingham research portal for the purpose of private study or non-commercial research. •User may use extracts from the document in line with the concept of ‘fair dealing’ under the Copyright, Designs and Patents Act 1988 (?) •Users may not further distribute the material nor use it for the purposes of commercial gain. Where a licence is displayed above, please note the terms and conditions of the licence govern your use of this document. When citing, please reference the published version. Take down policy While the University of Birmingham exercises care and attention in making items available there are rare occasions when an item has been uploaded in error or has been deemed to be commercially or otherwise sensitive. If you believe that this is the case for this document, please contact [email protected] providing details and we will remove access to the work immediately and investigate. Download date: 25. Sep. 2021 ORIGINAL RESEARCH published: 01 May 2019 doi: 10.3389/fbioe.2019.00092 Osteoblast-Derived Vesicle Protein Content Is Temporally Regulated During Osteogenesis: Implications for Regenerative Therapies Owen G. Davies 1*, Sophie C. Cox 2, Ioannis Azoidis 2, Adam J. A. McGuinness 3, Megan Cooke 2,3, Liam M. Heaney 1 and Liam M. Grover 2 1 School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom, 2 School of Chemical Engineering, University of Birmingham, Birmingham, United Kingdom, 3 Physical Sciences for Health Doctoral Training Centre, University of Birmingham, Birmingham, United Kingdom Osteoblast-derived extracellular vesicles (EV) are a collection of secreted (sEVs) and matrix-bound nanoparticles that function as foci for mineral nucleation and accumulation. Edited by: Due to the fact sEVs can be isolated directly from the culture medium of mineralizing Martijn van Griensven, osteoblasts, there is growing interest their application regenerative medicine. However, Technische Universität München, Germany at present therapeutic advancements are hindered by a lack of understanding of their Reviewed by: precise temporal contribution to matrix mineralization. This study advances current Jeroen Van De Peppel, knowledge by temporally aligning sEV profile and protein content with mineralization Erasmus University Rotterdam, Netherlands status. sEVs were isolated from mineralizing primary osteoblasts over a period of 1, Marjolein Van Driel, 2, and 3 weeks. Bimodal particle distributions were observed (weeks 1 and 3: 44 Erasmus Medical Center, Netherlands and 164 nm; week 2: 59 and 220 nm), indicating a heterogeneous population with Rodolfo Enrique De La Vega, Mayo Clinic, United States dimensions characteristic of exosome- (44 and 59 nm) and microvesicle-like (164 and *Correspondence: 220nm) particles. Proteomic characterization by liquid chromatography tandem-mass Owen G. Davies spectrometry (LC-MS/MS) revealed a declining correlation in EV-localized proteins as [email protected] mineralization advanced, with Pearson correlation-coefficients of 0.79 (week 1 vs. 2), Specialty section: 0.6 (2 vs. 3) and 0.46 (1 vs. 3), respectively. Principal component analysis (PCA) This article was submitted to further highlighted a time-dependent divergence in protein content as mineralization Tissue Engineering and Regenerative Medicine, advanced. The most significant variations were observed at week 3, with a significant a section of the journal (p < 0.05) decline in particle concentration, visual evidence of EV rupture and enhanced Frontiers in Bioengineering and mineralization. A total of 116 vesicle-localized proteins were significantly upregulated at Biotechnology week 3 (56% non-specifically, 19% relative to week 1, 25% relative to week 2). Gene Received: 23 January 2019 Accepted: 12 April 2019 ontology enrichment analysis of these proteins highlighted overrepresentation of genes Published: 01 May 2019 associated with matrix organization. Of note, increased presence of phospholipid-binding Citation: and calcium channeling annexin proteins (A2, A5, and A6) indicative of progressive Davies OG, Cox SC, Azoidis I, McGuinness AJA, Cooke M, variations in the nucleational capacity of vesicles, as well as interaction with the Heaney LM and Grover LM (2019) surrounding ECM. We demonstrate sEV-mediated mineralization is dynamic process Osteoblast-Derived Vesicle Protein with variations in vesicle morphology and protein content having a potential influence Content Is Temporally Regulated During Osteogenesis: Implications for on developmental changes matrix organization. These findings have implications for the Regenerative Therapies. selection and application of EVs for regenerative applications. Front. Bioeng. Biotechnol. 7:92. doi: 10.3389/fbioe.2019.00092 Keywords: vesicle, mineralization, annexin, collagen, osteoblast, nano Frontiers in Bioengineering and Biotechnology | www.frontiersin.org 1 May 2019 | Volume 7 | Article 92 Davies et al. EVs Temporally Coordinate Mineralization INTRODUCTION the course of mineralization and better understand how their properties align with the more comprehensively characterized Bone formation is a carefully orchestrated and well-regulated MVs (Shapiro et al., 2015). process whereby inorganic mineral is deposited on a collagenous Vesicles derived from different tissue sources are uniquely matrix. Early mineral deposition is principally coordinated by adapted to fulfill the requirements of that tissue. As such, vesicles osteoblasts, which modulate local phosphate ion concentrations will contain specific protein, lipid and nucleic acid signatures and drive osteogenesis. Despite significant advancement indicative of their tissue of origin. Within developing bone, in musculoskeletal biology, current understanding of the osteoblast-derived vesicles have been shown to function in early processes by which mineral is first deposited and propagated mineralization events preceding endochondral ossification. To within the extracellular matrix (ECM) remain incompletely fulfill their function, these particles are enriched in membrane understood (Boskey, 1998). Early studies postulated that matrix lipids (e.g., cholesterol, sphingomyelin and phosphatidylserine), mineralization was largely a passive and cell-independent calcium binding proteins (e.g., annexins-A1, -A2,−5, and – process whereby non-collagenous proteins confined to gap zones A6) and phosphate converting enzymes (e.g., tissue non-specific function as sites for the localization of ions that drive mineral alkaline phosphatase, TNAP, and nucleotide pyrophosphatase nucleation (Bonucci, 2012). However, two highly significant phosphodiesterase, Enpp) (Kirsch et al., 2000; Davies et al., ultrastructural studies published in 1967 identified the active 2017). Together this specialized collection of lipids and contribution of nano-sized extracellular vesicles (EVs, 50– proteins comprises the nucleational-core-complex (NCC), which 400 nm), which functioned as loci for early mineral nucleation facilitates the uptake, binding and organization of calcium and and propagation in growth plate cartilage (Anderson, 1967; phosphate ions to initiate mineral formation, expansion and Bonucci, 1967). It was subsequently demonstrated that mineral crystallization (Wu et al., 1993). It is proposed that EVs bud crystallized in and around EVs, forming the spheroidal nodules from the osteoblast plasma membrane and accumulate calcium characteristic of mineralization both in vitro and in vivo. It and phosphate ions extracellularly, providing an optimized niche has since been shown that these particles are released into the for the transition to crystalline apatite that eventually ruptures developing ECM where they determine the specific and localized the vesicle
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