umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
The neuropeptide VIP potentiates IL-6 production induced by proinflammatory osteotropic cytokines in calvarial osteoblasts and the osteoblastic cell line MC3T3-E1.
Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
2005 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, Vol. 335, no 3, 705-711 p.Article in journal (Refereed) Published
Abstract [en]

Skeletal turnover is orchestrated by a complex network of regulatory factors. Lately, regulation of bone metabolism through neuro-osteological interactions has been proposed. Here, we address the question whether IL-6 production can be affected by interactions between the neuropeptide VIP and proinflammatory, bone-resorbing cytokines. By using calvarial osteoblasts, we showed that IL-1beta increased IL-6 production time- and concentration-dependently, and that these effects were potentiated by VIP. Furthermore, IL-1beta stimulated IL-6 promoter activity in the osteoblastic cell line MC3T3-E1 stably transfected with a human IL-6 promoter/luciferase construct, and both VIP, and the related neuropeptide PACAP-38, increased the effect of IL-1beta in a synergistic manner. The IL-6 protein release from calvarial osteoblasts was also stimulated by the osteoclastogenic, proinflammatory cytokines IL-11, LIF, OSM, IL-17, TGF-beta, and TNF-alpha. All effects, except for that of TNF-alpha, were synergistically potentiated by VIP. These findings further support the role of neuropeptides, and the presence of neuro-immunological interactions, in bone metabolism.

Place, publisher, year, edition, pages
2005. Vol. 335, no 3, 705-711 p.
Identifiers
URN: urn:nbn:se:umu:diva-18080DOI: 10.1016/j.bbrc.2005.07.135PubMedID: 16095565OAI: oai:DiVA.org:umu-18080DiVA: diva2:157753
Available from: 2008-03-04 Created: 2008-03-04 Last updated: 2009-10-07Bibliographically approved
In thesis
1. The neuropeptide VIP and the IL-6 family of cytokines in bone: effects on bone resorption, cytokine expression and receptor signalling in osteoblasts and bone marrow stromal cells
Open this publication in new window or tab >>The neuropeptide VIP and the IL-6 family of cytokines in bone: effects on bone resorption, cytokine expression and receptor signalling in osteoblasts and bone marrow stromal cells
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Bone tissue is continuously degraded and rebuilt to respond to the needs of the body. Cells of the osteoblast lineage are responsible for the formation of bone, whereas the resorption of bone tissue is carried out by osteoclasts. To prevent imbalance between bone formation and resorption, these processes are delicately regulated by a complex network of both systemic factors and factors produced locally in the bone microenvironment, including members of the IL-6 family of cytokines. During the last decades, the presence of nerve fibers in skeletal tissue and presence of receptors for several neurotransmitters on both osteoblasts and osteoclasts, have suggested a possible role for neuropeptides in the regulation of skeletal metabolism.

The overall aim of this study was to investigate the roles of cytokines in the IL-6 family and the neuropeptide VIP in regulation of osteotropic cytokine expression and bone metabolism in vitro.

In Paper I, stimulation of bone resorption by the cytokine IL-6, in the presence of its soluble receptor sIL-6R, was demonstrated in mouse calvarial bones. OSM and LIF, other members of the IL-6 family of cytokines, were also shown to increase bone resorption. Furthermore, IL-6+sIL-6R, LIF, and OSM increased the expression of RANKL, which by binding to its receptor RANK functions as a crucial inducer of osteoclast formation and activation.

In Paper II-IV, the effects of the neuropeptide VIP and related peptides on expression of osteotropic cytokines by osteoblasts and bone resorption in vitro have been studied. VIP and PACAP-38 both increased IL-6 production in osteoblasts in a time- and concentration-dependent manner. In contrast, no effect was seen with the related peptide secretin, indicating that the effects were mediated by the VPAC2 receptor. VIP and PACAP, in contrast to secretin, also induced IL-6 promoter activity in osteoblastic MC3T3-E1 cells transfected with an IL-6 promoter/luciferase construct. The effects of VIP on IL-6 were shown to be mediated by several intracellular pathways, including cAMP/PKA/CREB, AP-1, and C/EBP, but not NF-kB or the cAMP-activated Epac pathway. The release of IL-6 from osteoblasts was increased by several pro-inflammatory osteotropic cytokines, including interleukin-1b, an effect that was further potentiated by VIP, indicating a possible neuro-immunomodulatory interaction in the regulation of bone metabolism. VIP and PACAP-38 also increased the osteoblastic expression of RANKL and decreased the expression of OPG and M-CSF, factors crucial in regulation of differentiation and activation of osteoclasts. Although this indicated a possible bone resorptive effect, VIP was found to decrease osteoclast formation and bone resorption by directly targeting osteoclast progenitor cells through an inhibitory mechanism.

In conclusion, the results in this thesis indicate that several cytokines in the IL-6 family stimulate bone resorption in calvarial bones in vitro, most likely through the RANKL-RANK interaction. Furthermore, expression of the osteotropic cytokine IL-6 in osteoblasts is stimulated by the neuropeptide VIP through VPAC2 receptors via several intracellular pathways, further strengthening the role of neuropeptides as local regulators of bone metabolism.

Place, publisher, year, edition, pages
Umeå: Odontologi, 2005. 161 p.
Series
Umeå University odontological dissertations, ISSN 0345-7532 ; 91
Keyword
osteoblast, bone resorption, cytokines, IL-6, neuropeptides, VIP, transcription factor
National Category
Cell Biology
Identifiers
urn:nbn:se:umu:diva-606 (URN)91-7305-939-0 (ISBN)
Public defence
2005-10-14, Sal B, Tandläkarhögskolan, Tandläkarhögskolan, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2005-10-10 Created: 2005-10-10 Last updated: 2009-11-26Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Authority records BETA

Persson, EmmaLerner, Ulf

Search in DiVA

By author/editor
Persson, EmmaLerner, Ulf
By organisation
Oral Cell Biology
In the same journal
Biochemical and Biophysical Research Communications - BBRC

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 69 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf