Interleukin-18 is regulated by parathyroid hormone and is required for its bone anabolic actions

Liza J. Raggatt, Ling Qin, Joseph Tamasi, Stephen C. Jefcoat, Emi Shimizu, Nagarajan Selvamurugan, Foo Y. Liew, Laura Bevelock, Jean H M Feyen, Nicola Partridge

Research output: Contribution to journalArticle

Abstract

Interleukin-18 (IL-18) can regulate osteoblast and osteoclast function. We have identified, using cDNA microarray technology, that IL-18 expression is increased in UMR106-01 rat osteoblastic cells in response to parathyroid hormone (PTH) treatment. Confirmation of these data using real-time reverse transcription-PCR showed that steady-state levels of IL-18 mRNA increased by 2 h (3-fold), peaked by 4 h (10-fold), and had diminished after 12 h (4.4-fold) and that this regulation was via the protein kinase A signaling pathway and did not involve activation of the PKC signal cascade. PTH regulation of IL-18 was confirmed at the protein level, and analysis of differentiating primary rat calvarial osteoblasts verified that both IL-18 mRNA and protein are regulated by PTH in primary rat osteoblasts. Promoter reporter assays revealed that PTH regulated the upstream IL-18 promoter and induced the exon 1 containing 1.1-kb IL-18 mRNA transcript in primary osteoblast cells. The in vivo physiological role of IL-18 in the anabolic actions of PTH on bone was then assessed using IL-18 knock-out mice. Female IL-18 null mice and wild-type littermate controls were injected with vehicle or 8 μg/100 g of human 1-38 PTH for 4 weeks. In IL-18 knock-out animals the anabolic effect of PTH (determined by bone mineral density changes in the proximal tibia) was abolished in trabecular bone but not in the cortical component. These data characterize the PTH regulation of IL-18 expression in osteoblastic cells and suggest that this cytokine is involved in the anabolic actions of PTH.

Original languageEnglish (US)
Pages (from-to)6790-6798
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number11
DOIs
StatePublished - Mar 14 2008

Fingerprint

Interleukin-18
Parathyroid Hormone
Bone
Bone and Bones
Osteoblasts
Rats
Messenger RNA
Anabolic Agents
Osteoclasts
Transcription
Microarrays
Cyclic AMP-Dependent Protein Kinases
Oligonucleotide Array Sequence Analysis
Tibia
Knockout Mice
Bone Density
Reverse Transcription
Minerals
Exons
Assays

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Interleukin-18 is regulated by parathyroid hormone and is required for its bone anabolic actions. / Raggatt, Liza J.; Qin, Ling; Tamasi, Joseph; Jefcoat, Stephen C.; Shimizu, Emi; Selvamurugan, Nagarajan; Liew, Foo Y.; Bevelock, Laura; Feyen, Jean H M; Partridge, Nicola.

In: Journal of Biological Chemistry, Vol. 283, No. 11, 14.03.2008, p. 6790-6798.

Research output: Contribution to journalArticle

Raggatt, LJ, Qin, L, Tamasi, J, Jefcoat, SC, Shimizu, E, Selvamurugan, N, Liew, FY, Bevelock, L, Feyen, JHM & Partridge, N 2008, 'Interleukin-18 is regulated by parathyroid hormone and is required for its bone anabolic actions', Journal of Biological Chemistry, vol. 283, no. 11, pp. 6790-6798. https://doi.org/10.1074/jbc.M709909200
Raggatt, Liza J. ; Qin, Ling ; Tamasi, Joseph ; Jefcoat, Stephen C. ; Shimizu, Emi ; Selvamurugan, Nagarajan ; Liew, Foo Y. ; Bevelock, Laura ; Feyen, Jean H M ; Partridge, Nicola. / Interleukin-18 is regulated by parathyroid hormone and is required for its bone anabolic actions. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 11. pp. 6790-6798.
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abstract = "Interleukin-18 (IL-18) can regulate osteoblast and osteoclast function. We have identified, using cDNA microarray technology, that IL-18 expression is increased in UMR106-01 rat osteoblastic cells in response to parathyroid hormone (PTH) treatment. Confirmation of these data using real-time reverse transcription-PCR showed that steady-state levels of IL-18 mRNA increased by 2 h (3-fold), peaked by 4 h (10-fold), and had diminished after 12 h (4.4-fold) and that this regulation was via the protein kinase A signaling pathway and did not involve activation of the PKC signal cascade. PTH regulation of IL-18 was confirmed at the protein level, and analysis of differentiating primary rat calvarial osteoblasts verified that both IL-18 mRNA and protein are regulated by PTH in primary rat osteoblasts. Promoter reporter assays revealed that PTH regulated the upstream IL-18 promoter and induced the exon 1 containing 1.1-kb IL-18 mRNA transcript in primary osteoblast cells. The in vivo physiological role of IL-18 in the anabolic actions of PTH on bone was then assessed using IL-18 knock-out mice. Female IL-18 null mice and wild-type littermate controls were injected with vehicle or 8 μg/100 g of human 1-38 PTH for 4 weeks. In IL-18 knock-out animals the anabolic effect of PTH (determined by bone mineral density changes in the proximal tibia) was abolished in trabecular bone but not in the cortical component. These data characterize the PTH regulation of IL-18 expression in osteoblastic cells and suggest that this cytokine is involved in the anabolic actions of PTH.",
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AU - Shimizu, Emi

AU - Selvamurugan, Nagarajan

AU - Liew, Foo Y.

AU - Bevelock, Laura

AU - Feyen, Jean H M

AU - Partridge, Nicola

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N2 - Interleukin-18 (IL-18) can regulate osteoblast and osteoclast function. We have identified, using cDNA microarray technology, that IL-18 expression is increased in UMR106-01 rat osteoblastic cells in response to parathyroid hormone (PTH) treatment. Confirmation of these data using real-time reverse transcription-PCR showed that steady-state levels of IL-18 mRNA increased by 2 h (3-fold), peaked by 4 h (10-fold), and had diminished after 12 h (4.4-fold) and that this regulation was via the protein kinase A signaling pathway and did not involve activation of the PKC signal cascade. PTH regulation of IL-18 was confirmed at the protein level, and analysis of differentiating primary rat calvarial osteoblasts verified that both IL-18 mRNA and protein are regulated by PTH in primary rat osteoblasts. Promoter reporter assays revealed that PTH regulated the upstream IL-18 promoter and induced the exon 1 containing 1.1-kb IL-18 mRNA transcript in primary osteoblast cells. The in vivo physiological role of IL-18 in the anabolic actions of PTH on bone was then assessed using IL-18 knock-out mice. Female IL-18 null mice and wild-type littermate controls were injected with vehicle or 8 μg/100 g of human 1-38 PTH for 4 weeks. In IL-18 knock-out animals the anabolic effect of PTH (determined by bone mineral density changes in the proximal tibia) was abolished in trabecular bone but not in the cortical component. These data characterize the PTH regulation of IL-18 expression in osteoblastic cells and suggest that this cytokine is involved in the anabolic actions of PTH.

AB - Interleukin-18 (IL-18) can regulate osteoblast and osteoclast function. We have identified, using cDNA microarray technology, that IL-18 expression is increased in UMR106-01 rat osteoblastic cells in response to parathyroid hormone (PTH) treatment. Confirmation of these data using real-time reverse transcription-PCR showed that steady-state levels of IL-18 mRNA increased by 2 h (3-fold), peaked by 4 h (10-fold), and had diminished after 12 h (4.4-fold) and that this regulation was via the protein kinase A signaling pathway and did not involve activation of the PKC signal cascade. PTH regulation of IL-18 was confirmed at the protein level, and analysis of differentiating primary rat calvarial osteoblasts verified that both IL-18 mRNA and protein are regulated by PTH in primary rat osteoblasts. Promoter reporter assays revealed that PTH regulated the upstream IL-18 promoter and induced the exon 1 containing 1.1-kb IL-18 mRNA transcript in primary osteoblast cells. The in vivo physiological role of IL-18 in the anabolic actions of PTH on bone was then assessed using IL-18 knock-out mice. Female IL-18 null mice and wild-type littermate controls were injected with vehicle or 8 μg/100 g of human 1-38 PTH for 4 weeks. In IL-18 knock-out animals the anabolic effect of PTH (determined by bone mineral density changes in the proximal tibia) was abolished in trabecular bone but not in the cortical component. These data characterize the PTH regulation of IL-18 expression in osteoblastic cells and suggest that this cytokine is involved in the anabolic actions of PTH.

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