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The chemical NMP as a potent BMP enhancer for bone tissue regeneration


San Miguel, B; Ghayor, C; Ehrbar, M; Jung, R E; Zwahlen, R A; Hortschansky, P; Schmökel, H G; Weber, F E (2009). The chemical NMP as a potent BMP enhancer for bone tissue regeneration. Tissue Engineering. Part A, 15(10):2955-2963.

Abstract

In medicine N-methylpyrrolidone (NMP) has a long track record as constituent in FDA approved medical devices and thus can be considered as safe and biological inactive small chemical. In the present study we report on the newly discovered pharmaceutical properties of NMP as it enhances bone regeneration in a rabbit calvarial defect model in vivo. At the cellular level, the pharmaceutical effect of NMP was confirmed, in particular, in combination with BMP-2, as NMP increased early and late markers for maturation of preosteoblasts and human bone marrow derived stem cells in vitro. When we used the multipotent cell line C2C12 lacking autologous BMP expression, NMP alone had no effect on alkaline phosphatase activity, a marker for osteogenic transdifferentiation. Nevertheless, in combination with low BMP-2-doses alkaline phosphatase activity was increased more than 8 fold. Thus, the pharmaceutical NMP mode of action is that of an enhancer of BMP activity. The dependency of the effects of NMP on BMP was confirmed in preosteoblasts as noggin, an extracellular BMP-inhibitor, suppressed NMP-induced increase in early markers for osteoblast maturation in vitro. At the molecular level, NMP was shown to have no effect on the binding of BMP-2 to the ectodomain of the high affinity BMP receptor IA. However, NMP further increased the phosphorylation of p38 and Smad1,5,8 induced by BMP-2. Thus, the small chemical NMP enhances BMP activity by increasing the kinase activity of the BMP receptor complex for Smad1,5,8 and p38 and could be employed as a potent drug for bone tissue regeneration and engineering.

In medicine N-methylpyrrolidone (NMP) has a long track record as constituent in FDA approved medical devices and thus can be considered as safe and biological inactive small chemical. In the present study we report on the newly discovered pharmaceutical properties of NMP as it enhances bone regeneration in a rabbit calvarial defect model in vivo. At the cellular level, the pharmaceutical effect of NMP was confirmed, in particular, in combination with BMP-2, as NMP increased early and late markers for maturation of preosteoblasts and human bone marrow derived stem cells in vitro. When we used the multipotent cell line C2C12 lacking autologous BMP expression, NMP alone had no effect on alkaline phosphatase activity, a marker for osteogenic transdifferentiation. Nevertheless, in combination with low BMP-2-doses alkaline phosphatase activity was increased more than 8 fold. Thus, the pharmaceutical NMP mode of action is that of an enhancer of BMP activity. The dependency of the effects of NMP on BMP was confirmed in preosteoblasts as noggin, an extracellular BMP-inhibitor, suppressed NMP-induced increase in early markers for osteoblast maturation in vitro. At the molecular level, NMP was shown to have no effect on the binding of BMP-2 to the ectodomain of the high affinity BMP receptor IA. However, NMP further increased the phosphorylation of p38 and Smad1,5,8 induced by BMP-2. Thus, the small chemical NMP enhances BMP activity by increasing the kinase activity of the BMP receptor complex for Smad1,5,8 and p38 and could be employed as a potent drug for bone tissue regeneration and engineering.

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19 citations in Web of Science®
24 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Dental Medicine > Clinic for Cranio-Maxillofacial Surgery
04 Faculty of Medicine > University Hospital Zurich > Clinic for Obstetrics
04 Faculty of Medicine > Center for Dental Medicine > Clinic for Fixed and Removable Prosthodontics
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:7 October 2009
Deposited On:30 Apr 2009 13:48
Last Modified:05 Apr 2016 13:13
Publisher:Mary Ann Liebert
ISSN:1937-3341
Publisher DOI:10.1089/ten.TEA.2009.0009
Official URL:http://www.liebertonline.com/doi/abs/10.1089/ten.TEA.2009.0009
PubMed ID:19320543
Permanent URL: http://doi.org/10.5167/uzh-18430

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