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Osteotropic cytokines: expression in human gingival fibroblasts and effects on bone
Umeå University, Faculty of Medicine, Odontology.
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.

Place, publisher, year, edition, pages
2006. , 64 p.
Series
Umeå University odontological dissertations, ISSN 0345-7532 ; 96
Keyword [en]
osteoblasts, osteoclasts, fibroblasts, cytokines, IL-6, LIF, OSM, IL-4, IL-3, bone resorption
Research subject
Odontology
Identifiers
URN: urn:nbn:se:umu:diva-960ISBN: 91-7264-194-0 (print)OAI: oai:DiVA.org:umu-960DiVA: diva2:145200
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
List of papers
1. 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
Open this publication in new window or tab >>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
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.

Identifiers
urn:nbn:se:umu:diva-9427 (URN)12218157 (PubMedID)
Available from: 2008-04-02 Created: 2008-04-02 Last updated: 2009-10-28Bibliographically approved
2. Inhibition of hormone and cytokine-stimulated osteoclastogenesis and bone resorption by interleukin-4 and interleukin-13 is associated with increased osteoprotegerin and decreased RANKL and RANK in a STAT6-dependent pathway
Open this publication in new window or tab >>Inhibition of hormone and cytokine-stimulated osteoclastogenesis and bone resorption by interleukin-4 and interleukin-13 is associated with increased osteoprotegerin and decreased RANKL and RANK in a STAT6-dependent pathway
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2006 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, Vol. 281, no 5, 2414-2429 p.Article in journal (Refereed) Published
Abstract [en]

Interleukin (IL)-4 and IL-13 are cytokines that inhibit bone resorption. Data showing an inhibitory effect of IL-4 and IL-13 on RANK mRNA in mouse calvariae were first reported at the 22nd American Society for Bone and Mineral Research Meeting (Lerner, U.H., and Conaway, H. H. 2000) J. Bone Min. Res. 15, Suppl. 1, Abstr. SU 230). In the present study, release of 45Ca from cultured mouse calvarial bones stimulated by different cytokines, peptides, and steroid hormones was inhibited by IL-4 and IL-13. IL-4 and IL-13 decreased receptor activator of nuclear factor-kappaB ligand (RANKL) and RANK mRNA and increased osteoprotegerin (OPG) mRNA in calvariae. Additionally, the cytokines decreased RANKL protein and increased OPG protein in calvarial bones. In osteoblasts isolated from calvariae, both an increase in RANKL mRNA and a decrease in OPG mRNA and protein elicited by vitamin D3 were reversed by IL-4 and IL-13. IL-4 and IL-13 decreased the number of tartrate-resistant acid phosphatase positive multinucleated cells and the mRNA expression of calcitonin receptor, tartrate-resistant acid phosphatase, and cathepsin K in mouse spleen cells and bone marrow macrophages (BMM) treated with macrophage colony-stimulating factor and RANKL. Inhibition of mRNA for RANK and the transcription factor NFAT2 was also noted in spleen cell and BMM cultures treated with IL-4 and IL-13. In addition, RANK mRNA and RANK protein were decreased by IL-4 and IL-13 in RAW 264.7 cells. Osteoblasts, spleen cells, and BMM expressed mRNA for the four proteins making up the IL-4 and IL-13 receptors. No effects by IL-4 on bone resorption and osteoclast formation or on RANKL and RANK mRNA expression were seen in Stat6-/- mice. The data indicate that IL-4 and IL-13, via a STAT6-dependent pathway, inhibit osteoclast differentiation and bone resorption by activating receptors on osteoblasts and osteoclasts that affect the RANKL/RANK/OPG system.

Identifiers
urn:nbn:se:umu:diva-17885 (URN)10.1074/jbc.M510160200 (DOI)16251181 (PubMedID)
Available from: 2008-03-04 Created: 2008-03-04 Last updated: 2009-09-10Bibliographically approved
3. IL-1beta and TNF-alpha regulate IL-6-type cytokines in gingival fibroblasts.
Open this publication in new window or tab >>IL-1beta and TNF-alpha regulate IL-6-type cytokines in gingival fibroblasts.
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2008 (English)In: Journal of Dental Research, ISSN 0022-0345, Vol. 87, no 6, 558-563 p.Article in journal (Refereed) Published
Abstract [en]

Interleukin-6 (IL-6)-type cytokines are pleiotropic molecules capable of stimulating bone resorption and expressed by numerous cell types. In the present study, we tested the hypothesis that gingival fibroblasts may exert local osteotropic effects through production of IL-6 and related cytokines. IL-6-type cytokine expression and regulation by IL-1beta and tumor necrosis factor-alpha (TNF-alpha) were studied in fibroblasts from the non-inflamed gingiva of healthy individuals. Constitutive mRNA expression of IL-6, IL-11, and leukemia inhibitory factor (LIF), but not of oncostatin M (OSM), was demonstrated, as was concentration-dependent stimulation of IL-6 and LIF mRNA and of protein by IL-1beta and TNF-alpha. IL-11 mRNA and protein were concentration-dependently stimulated by IL-1beta. The signaling pathway involved in IL-6 and LIF mRNA stimulation involved MAP kinases, but not NF-kappaB. The findings support the view that resident cells may influence the pathogenesis of periodontal disease through osteotropic IL-6-type cytokine production mediated by activation of MAP kinases. Abbreviations: IL-1alpha (interleukin-1alpha); IL-1beta (interleukin-1beta); IL-6 (interleukin-6); IL-11 (interleukin-11); LIF (leukemia inhibitory factor); OSM (oncostatin M); alpha(1)-coll. I (alpha(1)-collagen I); ALP (alkaline phosphatase); BMP-2 (bone morphogenetic protein-2); OC (osteocalcin); BSP (bone sialoprotein); TNFR I (tumor necrosis factor receptor I); TNFR II (tumor necrosis factor receptor II); IL-1R1 (interleukin-1 receptor 1); GAPDH (glyceraldehyde-3-phosphate dehydrogenase); RPL13A (ribosomal protein L13A); mRNA (messenger ribonucleic acid); cDNA (complementary deoxyribonucleic acid); PCR (polymerase chain-reaction); BCA (bicinchoninic acid); ELISA (enzyme-linked immunosorbent assay); alpha-MEM (alpha modification of Minimum Essential Medium); and FCS (fetal calf serum).

Keyword
fibroblasts, IL-6type cytokines, periodontitis
National Category
Cell and Molecular Biology
Research subject
Odontology
Identifiers
urn:nbn:se:umu:diva-20364 (URN)10.1177/154405910808700614 (DOI)18502965 (PubMedID)
Available from: 2009-03-18 Created: 2009-03-18 Last updated: 2009-12-03
4. Regulation of IL-6 type cytokines in human gingival fibroblasts by interleukin-4 and interleukin-13
Open this publication in new window or tab >>Regulation of IL-6 type cytokines in human gingival fibroblasts by interleukin-4 and interleukin-13
Show others...
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-5622 (URN)
Available from: 2006-12-22 Created: 2006-12-22 Last updated: 2010-01-13Bibliographically approved

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