title: O-Phenanthroline as modulator of the hypoxic and catabolic response in cartilage tissue-engineering models.
abstract: Hypoxia has been shown to be important for maintaining cartilage homeostasis as well as for inducing chondrogenic differentiation. Ensuring low oxygen levels during in vitro culture is difficult, therefore we assessed the chondro-inductive capabilities of the hypoxia-mimicking agent O-phenanthroline, which is also known as a non-specific matrix metalloproteinase (MMP) inhibitor. We found that O-phenanthroline reduced the expression of MMP3 and MMP13 mRNA levels during chondrogenic differentiation of human chondrocytes (hChs), as well as after TNFα/IL-1β exposure in an explant model. Interestingly, O-phenanthroline significantly inhibited matrix degradation in a TNFα/IL-1β-dependent model of cartilage degeneration when compared to control and natural hypoxia (2.5% O2). O-Phenanthroline had limited ability to improve the chondrogenic differentiation or matrix deposition in the chondrogenic pellet model. Additionally, O-phenanthroline alleviated MMP-induced cartilage degradation without affecting chondrogenesis in the explant culture. The data presented in this study indicate that the inhibitory effect of O-phenanthroline on MMP expression is dominant over the hypoxia-mimicking effect. Copyright © 2014 John Wiley & Sons, Ltd.
authors.affiliation: Department of Developmental BioEngineering, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.
authors.forename: Nicole
authors.initials: N
authors.lastname: Georgi
authors.affiliation: Department of Developmental BioEngineering, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.
authors.forename: Ellie B M
authors.initials: EB
authors.lastname: Landman
authors.affiliation: Cartilage Regeneration Laboratory, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Australia.
authors.forename: Travis J
authors.initials: TJ
authors.lastname: Klein
authors.affiliation: Department of Tissue Regeneration, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.
authors.forename: Clemens A
authors.initials: CA
authors.lastname: van Blitterswijk
authors.affiliation: Department of Developmental BioEngineering, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: Karperien
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000473:pathology*; D002452:Cell Count; D015687:Cell Hypoxia / Q000187:drug effects; D020219:Chondrogenesis / Q000187:drug effects / Q000235:genetics; D003035:Cobalt / Q000494:pharmacology; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005121:Extremities / Q000196:embryology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D051379:Mice; D008875:Middle Aged; D008954:Models, Biological; D010618:Phenanthrolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D023822:Tissue Engineering / Q000379:methods*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D010618:Phenanthrolines; D012333:RNA, Messenger; D055758:SOX9 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D003035:Cobalt; C018021:cobaltous chloride; C025205:1,10-phenanthroline
keywords: cartilage; chondrogenesis; degradation; differentiation; phenanthroline