Pro-inflammatory cytokines TNF-related weak inducer of apoptosis (TWEAK) and TNF alpha induce the mitogen-activated protein kinase (MAPK)-dependent expression of sclerostin in human osteoblasts

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dc.contributor.authorVincent, C.
dc.contributor.authorFindlay, D.
dc.contributor.authorWelldon, K.
dc.contributor.authorWijenayaka, A.
dc.contributor.authorZheng, T.
dc.contributor.authorHaynes, D.
dc.contributor.authorFazzalari, N.
dc.contributor.authorEvdokiou, A.
dc.contributor.authorAtkins, G.
dc.date.issued2009
dc.description.abstractWe have recently shown that TNF-related weak inducer of apoptosis (TWEAK) is a mediator of inflammatory bone remodeling. The aim of this study was to investigate the role of TWEAK in modulating human osteoblast activity, and how TWEAK and TNFalpha might interact in this context. Recombinant TWEAK and TNF were both mitogenic for human primary osteoblasts (NHBC). TWEAK dose- and time-dependently regulated the expression of the osteoblast transcription factors RUNX2 and osterix. TWEAK inhibited in vitro mineralization and downregulated the expression of osteogenesis-associated genes. Significantly, TWEAK and TWEAK/TNF induced the expression of the osteoblast differentiation inhibitor and SOST gene product, sclerostin. Sclerostin induction was mitogen-activated protein kinase (MAPK) dependent. The SOST mRNA levels induced by TWEAK were equivalent to or exceeded those seen in steady-state human bone, and the TWEAK/TNF induction of SOST mRNA was recapitulated in fresh cancellous bone explants. TWEAK-induced sclerostin expression was observed in immature osteoblastic cells, both in cycling (Ki67(+)) primary NHBC and in the cell lines MC3T3-E1 and MG-63, as well as in human osteocyte-like cells and in the osteocyte cell line, MLO-Y4. Treatment of NHBC with recombinant human sclerostin mimicked the effects of TWEAK to suppress RUNX2 and osteocalcin (OCN). TWEAK, TNF, and sclerostin treatment of NHBC similarly altered levels of phosphorylated and total GSK3beta and active and total levels of beta-catenin, implying that the Wnt signaling pathway was affected by all three stimuli. Sclerostin also rapidly activated ERK-1/2 MAPK signaling, indicating the involvement of additional signaling pathways. Together, our findings suggest that TWEAK, alone and with TNF, can regulate osteoblast function, at least in part by inducing sclerostin expression. Our results also suggest new roles and modes of action for sclerostin.
dc.description.statementofresponsibilityCristina Vincent, David M Findlay, Katie J Welldon, Asiri R Wijenayaka, Timothy S Zheng, David R Haynes, Nicola L Fazzalari, Andreas Evdokiou, Gerald J Atkins
dc.identifier.citationJournal of Bone and Mineral Research, 2009; 24(8):1434-1449
dc.identifier.doi10.1359/JBMR.090305
dc.identifier.issn0884-0431
dc.identifier.issn1523-4681
dc.identifier.orcidEvdokiou, A. [0000-0001-8321-9806]
dc.identifier.orcidAtkins, G. [0000-0002-3123-9861]
dc.identifier.urihttp://hdl.handle.net/2440/51367
dc.language.isoen
dc.publisherAmer Soc Bone & Mineral Res
dc.source.urihttps://doi.org/10.1359/jbmr.090305
dc.subject3T3 Cells
dc.subjectOsteoblasts
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectMitogen-Activated Protein Kinases
dc.subjectTumor Necrosis Factors
dc.subjectTumor Necrosis Factor-alpha
dc.subjectAdaptor Proteins, Signal Transducing
dc.subjectBone Morphogenetic Proteins
dc.subjectRecombinant Proteins
dc.subjectDNA Primers
dc.subjectInflammation Mediators
dc.subjectGenetic Markers
dc.subjectFluorescent Antibody Technique
dc.subjectBlotting, Western
dc.subjectFlow Cytometry
dc.subjectReverse Transcriptase Polymerase Chain Reaction
dc.subjectCell Proliferation
dc.subjectTranscription, Genetic
dc.subjectBase Sequence
dc.subjectCytokine TWEAK
dc.titlePro-inflammatory cytokines TNF-related weak inducer of apoptosis (TWEAK) and TNF alpha induce the mitogen-activated protein kinase (MAPK)-dependent expression of sclerostin in human osteoblasts
dc.typeJournal article
pubs.publication-statusPublished

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