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Pyrophosphate Stimulates Differentiation, Matrix Gene Expression and Alkaline Phosphatase Activity in Osteoblasts
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, e0163530Article in journal (Refereed) Published
Abstract [en]

Pyrophosphate is a potent mitogen, capable of stimulating proliferation in multiple cell types, and a critical participant in bone mineralization. Pyrophosphate can also affect the resorption rate and bioactivity of orthopedic ceramics. The present study investigated whether calcium pyrophosphate affected proliferation, differentiation and gene expression in early (MC3T3 pre-osteoblast) and late stage (SAOS-2 osteosarcoma) osteoblasts. Pyrophosphate stimulated peak alkaline phosphatase activity by 50% and 150% at 100 mu M and 0.1 mu M in MC3T3, and by 40% in SAOS-2. The expression of differentiation markers collagen 1 (COL1), alkaline phosphatase (ALP), osteopontin (OPN), and osteocalcin (OCN) were increased by an average of 1.5, 2, 2 and 3 fold, by high concentrations of sodium pyrophosphate (100 mu M) after 7 days of exposure in MC3T3. COX-2 and ANK expression did not differ significantly from controls in either treatment group. Though both high and low concentrations of pyrophosphate stimulate ALP activity, only high concentrations (100 mu M) stimulated osteogenic gene expression. Pyrophosphate did not affect proliferation in either cell type. The results of this study confirm that chronic exposure to pyrophosphate exerts a physiological effect upon osteoblast differentiation and ALP activity, specifically by stimulating osteoblast differentiation markers and extracellular matrix gene expression.

Place, publisher, year, edition, pages
2016. Vol. 11, no 10, e0163530
National Category
Biomaterials Science Engineering and Technology
Identifiers
URN: urn:nbn:se:uu:diva-307554DOI: 10.1371/journal.pone.0163530ISI: 000385696900011PubMedID: 27701417OAI: oai:DiVA.org:uu-307554DiVA: diva2:1047196
Available from: 2016-11-17 Created: 2016-11-17 Last updated: 2017-04-16Bibliographically approved
In thesis
1. The biological and physical performance of high strength dicalcium phosphate cement in physiologically relevant models
Open this publication in new window or tab >>The biological and physical performance of high strength dicalcium phosphate cement in physiologically relevant models
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The chemical properties of calcium phosphate cements (CPCs) are very similar to the mineral phase of bone. CPCs are, consequently, very effective substrates (scaffolds) for tissue engineering; bone and stem cells attach readily, and can proliferate and differentiate to form new bone tissue. Unlike other CPCs that may remain largely unchanged in the body for years, such as hydroxyapatite, dicalcium phosphates are remodelled by the body and rapidly converted to new bone. Unfortunately, the dicalcium phosphates are also typically too weak to support load bearing in the human body. Our laboratory has recently developed a novel, high strength brushite CPC, (hsCPC), which can reach 10-50 fold higher failure strength than many commercially available CPCs. The aim of this thesis was to investigate the physical, chemical and biological performance of hsCPCs in physiologically relevant model of drug release, load bearing, osteoconductivity, and as a scaffold for bone tissue engineering.

Multiple CPCs were compared in a model of screw augmentation to determine whether the physical properties of the cement, such as bulk strength and porosity, affected orthopedic screw holding strength. In an in vitro model of bone regeneration stem cells were grown on macroporous scaffolds that were fabricated from hsCPC. Drug releasing scaffolds were fabricated to examine whether the low porosity of hsCPC impeded drug release during a 4 week incubation period. The biological activity of an incorporated drug, Rebamipide, was examined after acute and chronic incubation periods. In the drug release study it was noted that the biological response to hsCPC was significantly better than tissue culture grade polystyrene, even in groups without drug. The mechanism underlying this biological response was further investigated by testing the effect of pyrophosphate, a common cement additive, on bone cell proliferation and differentiation. This thesis concludes that a high strength cement can produce significant improvement in screw augmentation strength, if there is sufficient cortical bone near the augmentation site. The hsCPC is also cytocompatible, and can support bone and stem cell proliferation and differentiation. hsCPC scaffolds stimulated osteogenic gene expression comparable to native bone scaffolds. hsCPC scaffolds are also capable of delivering drug for up to 4 weeks, in vitro. Finally, a cement additive, pyrophosphate, stimulated differentiation, but not proliferation of bone cells.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 78 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1502
Keyword
biomaterial, bioceramic, osteoinduction, calcium phosphate, cement, osteoblast, pyrophosphate, Rebamipide, drug delivery, screw augmentation
National Category
Medical Materials
Research subject
Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-319495 (URN)978-91-554-9885-6 (ISBN)
Public defence
2017-06-02, Å2001, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, 09:15 (English)
Opponent
Supervisors
Funder
Swedish Research Council, GA 621-2011-3399EU, FP7, Seventh Framework Programme, 262948
Available from: 2017-05-05 Created: 2017-04-06 Last updated: 2017-08-09Bibliographically approved
2.
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