PDF herunterladen
Horm Metab Res 2022; 54(01): 42-49
DOI: 10.1055/a-1713-7967
Endocrine Research

Incretins Enhance PGF2α-Induced Synthesis of IL-6 and Osteoprotegerin in Osteoblasts

Tomoyuki Hioki
1   Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
2   Department of Dermatology, Kizawa Memorial Hospital, Minokamo, Japan
,
Gen Kuroyanagi 
1   Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
3   Department of Rehabilitation Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
4   Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
,
Kazuhiko Fujita
1   Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
4   Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
,
Go Sakai
1   Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
4   Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
,
Tetsu Kawabata
1   Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
4   Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
,
Woo Kim
1   Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
5   Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
,
Junko Tachi
1   Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
5   Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
,
Rie Matsushima-Nishiwaki
1   Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
,
Hiroki Iida
5   Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
,
Osamu Kozawa 
1   Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
,
Haruhiko Tokuda
1   Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
6   Department of Clinical Laboratory/Biobank of Medical Genome Center, National Center for Geriatrics and Gerontology, Obu, Japan
› Institutsangaben Funding Information Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan: 15K10487, 17K11002, 19K18471.
› Weitere Informationen
Auch verfügbar auf
    Lizenzen und Reprints

Abstract

Incretins including glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), which are secreted from the small intestine after oral food ingestion, are currently well-known to stimulate insulin secretion from pancreatic β-cells and used for the treatment of type 2 diabetes mellitus. We have previously reported that prostaglandin F2α (PGF2α) stimulates the synthesis of interleukin-6 (IL-6) and osteoprotegerin in osteoblast-like MC3T3-E1 cells, and that IL-6 and osteoprotegerin release are mediated through the p44/p42 mitogen-activated protein (MAP) kinase, p38 MAP kinase or stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) pathways. In the present study, we investigated the effects of incretins including GLP-1 and GIP, on the PGF2α-induced synthesis of IL-6 and osteoprotegerin and examined the detailed mechanism in osteoblast-like MC3T3-E1 cells. We found that GIP and GLP-1 significantly stimulated the PGF2α-induced synthesis of IL-6 in osteoblast-like MC3T3-E1 cells. In addition, GIP and GLP-1 significantly enhanced the PGF2α-induced mRNA expression levels of IL-6. On the other hand, GIP and GLP-1 markedly stimulated the PGF2α-induced synthesis of osteoprotegerin. However, the phosphorylation of p44/p42 MAP kinase, p38 MAP kinase, or JNK induced by PGF2α was not affected by GIP or GLP-1. Therefore, these results strongly suggest that incretins enhance the PGF2α-induced synthesis of IL-6 and osteoprotegerin in osteoblast-like MC3T3-E1 cells. However, these syntheses are not mediated through p44/p42 MAP kinase, p38 MAP kinase, or JNK pathways.

Key words

glucose-dependent insulinotropic peptide - glucagon-like peptide-1 - prostaglandin F2α - interleukin-6 - osteoprotegerin - osteoblast


Publikationsverlauf

Eingereicht: 21. Februar 2021

Angenommen nach Revision: 30. November 2021

Artikel online veröffentlicht:
05. Januar 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev 2007; 87: 1409-1439
    CrossrefPubMedGoogle Scholar
  • 2 Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007; 132: 2131-2157
    CrossrefPubMedGoogle Scholar
  • 3 Aoyama E, Watari I, Podyma-Inoue KA. et al. Expression of glucagon-like peptide-1 receptor and glucose dependent insulinotropic polypeptide receptor is regulated by the glucose concentration in mouse osteoblastic MC3T3-E1 cells. Int J Mol Med 2014; 34: 475-482
    CrossrefPubMedGoogle Scholar
  • 4 Kular J, Tickner J, Chim SM. et al. An overview of the regulation of bone remodeling at the cellular level. Clin Biochem 2012; 45: 863-873
    CrossrefPubMedGoogle Scholar
  • 5 Bollag RJ, Zhong Q, Phillips P. et al. Osteoblast-derived cells express functional glucose-dependent insulinotropic peptide receptors. Endocrinology 2000; 141: 1228-1235
    CrossrefPubMedGoogle Scholar
  • 6 Sanz C, Vázquez P, Blázquez C. et al. Signaling and biological effects of glucagon-like peptide 1 on the differentiation of mesenchymal stem cells from human bone marrow. Am J Physiol Endocrinol Metab 2010; 298: E634-E643
    CrossrefPubMedGoogle Scholar
  • 7 Hikiji H, Takato T, Shimizu T. et al. The roles of prostanoids, leukotrienes, and platelet-activating factor in bone metabolism and disease. Prog Lipid Res 2008; 47: 107-126
    CrossrefPubMedGoogle Scholar
  • 8 Agas D, Marchetti L, Hurley MM. et al. Prostaglandin F2α: a bone remodeling mediator. J Cell Physiol 2013; 228: 25-29
    CrossrefPubMedGoogle Scholar
  • 9 Raisz LG, Alander CB, Fall PM. et al. Effects of prostaglandin F2 alpha on bone formation and resorption in cultured neonatal mouse calvariae: role of prostaglandin E2 production. Endocrinology 1990; 126: 1076-1079
    CrossrefPubMedGoogle Scholar
  • 10 Akira S, Hirano T, Taga T. et al. Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF). FASEB J 1990; 4: 2860-2867
    CrossrefPubMedGoogle Scholar
  • 11 Heymann D, Rousselle AV. gp130 Cytokine family and bone cells. Cytokine 2000; 12: 1455-1468
    CrossrefPubMedGoogle Scholar
  • 12 Ishimi Y, Miyaura C, Jin CH. et al. IL-6 is produced by osteoblasts and induces bone resorption. J Immunol 1990; 145: 3297-3303
    CrossrefPubMedGoogle Scholar
  • 13 Tat SK, Pelletier JP, Lajeunesse D. et al. Differential modulation of RANKL isoforms by human osteoarthritic subchondral bone osteoblasts: influence of osteotropic factors. Bone 2008; 43: 284-291
    CrossrefPubMedGoogle Scholar
  • 14 Amarasekara DS, Yun H, Kim S. et al. Regulation of osteoclast differentiation by cytokine networks. Immune Netw 2018; 18: e8
    CrossrefPubMedGoogle Scholar
  • 15 Tokuda H, Kozawa O, Harada A. et al. p42/p44 mitogen-activated protein kinase activation is involved in prostaglandin F2α-induced interleukin-6 synthesis in osteoblasts. Cell Signal 1999; 11: 325-330
    CrossrefPubMedGoogle Scholar
  • 16 Minamitani C, Otsuka T, Takai S. et al. Involvement of rho-kinase in prostaglandin F2alpha-stimulated interleukin-6 synthesis via p38 mitogen-activated protein kinase in osteoblasts. Mol Cell Endocrinol 2008; 291: 27-32
    CrossrefPubMedGoogle Scholar
  • 17 Simonet WS, Lacey DL, Dunstan CR. et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997; 89: 309-319
    CrossrefPubMedGoogle Scholar
  • 18 Boyce BF, Xing L. The RANKL/RANK/OPG pathway. Curr Osteoporos Rep 2007; 5: 98-104
    CrossrefPubMedGoogle Scholar
  • 19 Kuroyanagi G, Tokuda H, Matsushima-Nishiwaki R. et al. Resveratrol suppresses prostaglandin F2α-induced osteoprotegerin synthesis in osteoblasts: inhibition of the MAP kinase signaling. Arch Biochem Biophys 2014; 542: 39-45
    CrossrefPubMedGoogle Scholar
  • 20 Kasperk C, Georgescu C, Nawroth P. Diabetes Mellitus and Bone Metabolism. Exp Clin Endocrinol Diabetes 2017; 125: 213-217
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 21 Calanna S, Christensen M, Holst JJ. et al. Secretion of glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes: Systematic review and meta-analysis of clinical studies. Diabetes Care 2013; 36: 3346-3352
    CrossrefPubMedGoogle Scholar
  • 22 Fujita K, Tokuda H, Yamamoto N. et al. Incretins amplify TNF-α-stimulated IL-6 synthesis in osteoblasts: Suppression of the IκB/NF-κB pathway. Int J Mol Med 2017; 39: 1053-1060
    CrossrefPubMedGoogle Scholar
  • 23 Kainuma S, Tokuda H, Fujita K. et al. Attenuation by incretins of thyroid hormone-stimulated osteocalcin synthesis in osteoblasts. Biomed Rep 2016; 5: 771-775
    CrossrefPubMedGoogle Scholar
  • 24 Sudo H, Kodama HA, Amagai Y. et al. In vitro differentiation and calcification in a new clonal osteogenic cell line derived from newborn mouse calvaria. J Cell Biol 1983; 96: 191-198
    CrossrefPubMedGoogle Scholar
  • 25 Kozawa O, Suzuki A, Tokuda H. et al. Prostaglandin F2alpha stimulates interleukin-6 synthesis via activation of PKC in osteoblast-like cells. Am J Physiol 1997; 272: E208-E211
    PubMedGoogle Scholar
  • 26 Simpson DA, Freeney S, Boyle C. et al. Retinal VEGF mRNA measured by SYBR green I fluorescence: a versatile approach to quantitative PCR. Mol Vis 2000; 6: 178-183
    PubMedGoogle Scholar
  • 27 Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970; 227: 680-685
    CrossrefPubMedGoogle Scholar
  • 28 Kato K, Ito H, Hasegawa K. et al. Modulation of the stress-induced synthesis of hsp27 and alpha B-crystallin by cyclic AMP in C6 rat glioma cells. J Neurochem 1996; 66: 946-950
    CrossrefPubMedGoogle Scholar
  • 29 Trujillo JM, Nuffer W. GLP-1 receptor agonists for type 2 diabetes mellitus: recent developments and emerging agents. Pharmacotherapy 2014; 34: 1174-1186
    CrossrefPubMedGoogle Scholar
  • 30 Widmann C, Gibson S, Jarpe MB. et al. Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol Rev 1999; 79: 143-180
    CrossrefPubMedGoogle Scholar
  • 31 Nuche-Berenguer B, Portal-Nuñez S, Moreno P. et al. Presence of a functional receptor for GLP-1 in osteoblastic cells, independent of the cAMP-linked GLP-1 receptor. J Cell Physiol 2010; 225: 585-592
    CrossrefPubMedGoogle Scholar
  • 32 Tamura T, Udagawa N, Takahashi N. et al. Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6. Proc Natl Acad Sci U S A 1993; 90: 11924-11928
    CrossrefPubMedGoogle Scholar
  • 33 Kaneshiro S, Ebina K, Shi K. et al. IL-6 negatively regulates osteoblast differentiation through the SHP2/MEK2 and SHP2/Akt2 pathways in vitro. J Bone Miner Metab 2014; 32: 378-392
    CrossrefPubMedGoogle Scholar
  • 34 Prystaz K, Kaiser K, Kovtun A. et al. Distinct effects of IL-6 classic and trans-signaling in bone fracture healing. Am J Pathol 2018; 188: 474-490
    CrossrefPubMedGoogle Scholar
  • 35 Iepsen EW, Lundgren JR, Hartmann B. et al. GLP-1 Receptor agonist treatment increases bone formation and prevents bone loss in weight-reduced obese women. J Clin Endocrinol Metab 2015; 100: 2909-2917
    CrossrefPubMedGoogle Scholar
  • 36 Hansen MSS, Tencerova M, Frølich FJ. et al. Effects of gastric inhibitory polypeptide, glucagon-like peptide-1 and glucagon-like peptide-1 receptor agonists on bone cell metabolism. Basic Clin Pharmacol Toxicol 2018; 122: 25-37
    CrossrefPubMedGoogle Scholar
  • 37 Oei L, Rivadeneira F, Zillikens MC. et al. Diabetes, diabetic complications, and fracture risk. Curr Osteoporos Rep 2015; 13: 106-115
    CrossrefPubMedGoogle Scholar