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IL-6, leukemia inhibitory factor, and oncostatin M stimulate bone resorption and regulate the expression of receptor activator of NF-kB ligand, osteoprotegerin, and receptor activator of NF-kB in mouse calvariae
Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
2002 (English)In: Journal of Immunology, ISSN 0022-1767, Vol. 169, no 6, 3353-3362 p.Article in journal (Refereed) Published
Abstract [en]

IL-6, leukemia inhibitory factor (LIF), and oncostatin M (OSM) are IL-6-type cytokines that stimulate osteoclast formation and function. In the present study, the resorptive effects of these agents and their regulation of receptor activator of NF-kappaB ligand (RANKL), RANK, and osteoprotegerin (OPG) were studied in neonatal mouse calvaria. When tested separately, neither human (h) IL-6 nor the human soluble IL-6R (shIL-6R) stimulated bone resorption, but when hIL-6 and the shIL-6R were combined, significant stimulation of both mineral and matrix release from bone explants was noted. Semiquantitative RT-PCR showed that hIL-6 plus shIL-6R enhanced the expression of RANKL and OPG in calvarial bones, but decreased RANK expression. Human LIF, hOSM, and mouse OSM (mOSM) also stimulated 45Ca release and enhanced the mRNA expression of RANKL and OPG in mouse calvaria, but had no effect on the expression of RANK. In agreement with the RT-PCR analyses, ELISA measurements showed that both hIL-6 plus shIL-6R and mOSM increased RANKL and OPG proteins. 1,25-Dihydroxyvitamin D3 (D3) also increased the RANKL protein level, but decreased the protein level of OPG. OPG inhibited 45Ca release stimulated by RANKL, hIL-6 plus shIL-6R, hLIF, hOSM, mOSM, and D3. An Ab neutralizing mouse gp130 inhibited 45Ca release induced by hIL-6 plus shIL-6R. These experiments demonstrated stimulation of calvarial bone resorption and regulation of mRNA and protein expression of RANKL and OPG by D3 and IL-6 family cytokines as well as regulation of RANK expression in preosteoclasts/osteoclasts of mouse calvaria by D3 and hIL-6 plus shIL-6R.

Place, publisher, year, edition, pages
2002. Vol. 169, no 6, 3353-3362 p.
Identifiers
URN: urn:nbn:se:umu:diva-9427PubMedID: 12218157OAI: oai:DiVA.org:umu-9427DiVA: diva2:149098
Available from: 2008-04-02 Created: 2008-04-02 Last updated: 2009-10-28Bibliographically 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
2. Osteotropic cytokines: expression in human gingival fibroblasts and effects on bone
Open this publication in new window or tab >>Osteotropic cytokines: expression in human gingival fibroblasts and effects on bone
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Bone metabolism is regulated by endocrine and paracrine signalling molecules influencing bone cells in the continuously remodelling bone tissue. These molecules include a variety of osteotropic stimulatory and inhibitory cytokines. Degradation of alveolar bone in periodontal disease is believed to be a result of local release of such osteotropic cytokines, although the relative importance of particular cytokines and their cellular origin is currently unknown.

The aim of the present project was to study if, and how, pro-inflammatory cytokines in the interleukin-6 (IL-6) family of cytokines, and anti-inflammatory IL-4 and IL-13 type of cytokines, can affect osteoclast differentiation and bone resorption. Additionally, the objective was to study if gingival fibroblasts may influence alveolar bone resorption through secretion of IL-6 type cytokine release and if the secretion is regulated by pro-inflammatory as well as anti-inflammatory mediators such as IL-4 and IL-13.

IL-6 in combination with its soluble receptor (sIL-6R) was found to stimulate mouse calvarial bone resorption. Similarly, two other IL-6 family members, leukemia inhibitory factor (LIF) and oncostatin M (OSM) were found to stimulate bone resorption. The stimulatory effect on bone resorption induced by the three cytokines was associated with increased expression of receptor activator of NF- κB ligand (RANKL), a cytokine which is essential in osteoclast formation and activation through binding to receptor activator of NF- κB (RANK) on osteoclastic cells. The interaction between RANKL and RANK can be inhibited by binding of the decoy receptor osteoprotegerin (OPG) to RANKL, and the expression of OPG was also regulated by IL-6, LIF and OSM (Paper I). The two related cytokines IL-4 and IL-13 were found to inhibit osteoclastogenesis and mouse calvarial bone resorption by mechanisms involving a decreased RANKL/OPG ratio in osteoblasts and decreased RANK expression in

osteoclastic cells. The results further demonstrated that IL-4 and IL-13 exert their effects on both osteoblasts and osteoclasts by a mechanism involving the transcription factor signal transducer and activator of transcription 6 (STAT6) (Paper II). Constitutional expression of IL-6, LIF and another member of the IL-6 family of cytokines, IL-11, was demonstrated in human gingival fibroblasts. IL-6 type cytokine expression levels were found to be enhanced by IL-1β and tumour necrosis factor-α (TNF-α) (Paper III), whereas IL-4 and IL-13 inhibited IL 11 and LIF release from gingival fibroblasts (Paper IV).

In conclusion, IL 6 type cytokines were found to be stimulators and IL-4 and IL-13 inhibitors of bone resorption in vitro via mechanisms involving RANK/RANKL/OPG interactions. Additionally, gingival fibroblasts were able to secrete several cytokines in the IL-6 family. Secretion was further enhanced by pro-inflammatory mediators and inhibited by IL-4 and IL- 13. These findings support the view that resident cells may influence the pathogenesis of periodontal disease through osteotropic cytokine production.

Publisher
64 p.
Series
Umeå University odontological dissertations, ISSN 0345-7532 ; 96
Keyword
osteoblasts, osteoclasts, fibroblasts, cytokines, IL-6, LIF, OSM, IL-4, IL-3, bone resorption
Research subject
Odontology
Identifiers
urn:nbn:se:umu:diva-960 (URN)91-7264-194-0 (ISBN)
Public defence
2007-01-19, sal B, Tandläkarhögskolan 9 tr, Umeå, 09:00 (English)
Opponent
Available from: 2006-12-22 Created: 2006-12-22 Last updated: 2009-10-28Bibliographically approved

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Palmqvist, PyPersson, EmmaLerner, Ulf

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