Oncostatin M enhances osteoprotegerin synthesis but reduces macrophage colony‑stimulating factor synthesis in bFGF‑stimulated osteoblast‑like cells

Hioki,Tomoyuki; Tachi,Junko; Ueda,Kyohei; Matsushima‑Nishiwaki,Rie; Iida,Hiroki; Kozawa,Osamu; Tokuda,Haruhiko

doi:10.3892/etm.2023.12322

Oncostatin M enhances osteoprotegerin synthesis but reduces macrophage colony‑stimulating factor synthesis in bFGF‑stimulated osteoblast‑like cells

Authors:
- Tomoyuki Hioki
- Junko Tachi
- Kyohei Ueda
- Rie Matsushima‑Nishiwaki
- Hiroki Iida
- Osamu Kozawa
- Haruhiko Tokuda
View Affiliations

Affiliations: Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501‑1194, Japan, Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine, Gifu 501‑1194, Japan
Published online on: November 24, 2023 https://doi.org/10.3892/etm.2023.12322
Article Number: 34

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Bone remodeling is tightly controlled by various factors, including hormones, autacoids and cytokines. Among them, oncostatin M (OSM) is a multifunctional cytokine produced by osteal macrophages, which serves as an essential modulator of bone remodeling. Macrophage colony‑stimulating factor (M‑CSF) and osteoprotegerin are secreted by osteoblasts, and also have pivotal roles in the regulation of the bone remodeling process. The binding of basic fibroblast growth factor (bFGF), a key regulator of bone remodeling, to the corresponding receptor [fibroblast growth factor receptor (FGFR)] triggers the dimerization and activation of FGFRs, which causes the phosphorylation of FGFR substrates and subsequent activation of downstream effectors, including mitogen‑activated protein kinases (MAPKs), via Grb2. bFGF can activate MAPKs, resulting in the synthesis of osteoprotegerin and vascular endothelial growth factor in osteoblast‑like MC3T3‑E1 cells. In the present study, the effects of OSM on bFGF‑induced osteoblast activation were investigated in the synthesis of osteoprotegerin and M‑CSF in osteoblasts. The release of osteoprotegerin and M‑CSF were analyzed using ELISA. The mRNA expression levels of osteoprotegerin and M‑CSF were analyzed using reverse transcription‑quantitative PCR. Phosphorylation of p38 MAPK, stress‑activated protein kinase/c‑Jun N‑terminal kinase (SAPK/JNK) and p44/p42 MAPK was assessed using western blotting. OSM enhanced bFGF‑induced osteoprotegerin release and bFGF‑stimulated mRNA expression of osteoprotegerin. By contrast, OSM suppressed the bFGF‑induced release of M‑CSF and bFGF‑stimulated mRNA expression of M‑CSF. SB203580, a p38 MAPK inhibitor, and SP600125, a SAPK/JNK inhibitor, suppressed the bFGF‑stimulated M‑CSF release, whereas PD98059, an upstream kinase inhibitor of p44/p42 MAPK, failed to suppress the M‑CSF release stimulated by bFGF. Furthermore, OSM enhanced the bFGF‑induced phosphorylation of p38 MAPK, but attenuated the bFGF‑stimulated phosphorylation of SAPK/JNK. By contrast, OSM had little effect on the bFGF‑induced phosphorylation of p44/p42 MAPK. SB203580 markedly reduced the amplification of bFGF‑stimulated osteoprotegerin release enhanced by OSM. These results strongly suggested that OSM may possess divergent effects on bFGF‑induced osteoblast activation, upregulation of p38 MAPK and downregulation of SAPK/JNK, leading to the amplification of osteoprotegerin synthesis and the attenuation of M‑CSF synthesis.

View Figures

View References

1	Kular J, Tickner J, Chim SM and Xu J: An overview of the regulation of bone remodeling at the cellular level. Clin Biochem. 45:863–873. 2012.PubMed/NCBI View Article : Google Scholar
2	Kim JM, Lin C, Stavre Z, Greenblatt MB and Shim JH: Osteoblast-osteoclast communication and bone homeostasis. Cells. 9(2073)2020.PubMed/NCBI View Article : Google Scholar
3	Fuller K, Owens JM, Jagger CJ, Wilson A, Moss R and Chambers TJ: Macrophage colony-stimulating factor stimulates survival and chemotactic behavior in isolated osteoclasts. J Exp Med. 178:1733–1744. 1993.PubMed/NCBI View Article : Google Scholar
4	Fixe P and Praloran V: M-CSF: Haematopoietic growth factor or inflammatory cytokine? Cytokine. 10:32–37. 1998.PubMed/NCBI View Article : Google Scholar
5	Walsh MC, Kim N, Kadono Y, Rho J, Lee SY, Lorenzo J and Choi Y: Osteoimmunology: Interplay between the immune system and bone metabolism. Annu Rev Immunol. 24:33–63. 2006.PubMed/NCBI View Article : Google Scholar
6	Amarasekara DS, Yun H, Kim S, Lee N, Kim H and Rho J: Regulation of osteoclast differentiation by cytokine networks. Immune Netw. 18(e8)2018.PubMed/NCBI View Article : Google Scholar
7	Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Lüthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, et al: Osteoprotegerin: A novel secreted protein involved in the regulation of bone density. Cell. 89:309–319. 1997.PubMed/NCBI View Article : Google Scholar
8	Theoleyre S, Wittrant Y, Tat SK, Fortun Y, Redini F and Heymann D: The molecular triad OPG/RANK/RANKL: Involvement in the orchestration of pathophysiological bone remodeling. Cytokine Growth Factor Rev. 15:457–475. 2004.PubMed/NCBI View Article : Google Scholar
9	Sinder BP, Pettit AR and McCauley LK: Macrophages: Their emerging roles in bone. J Bone Miner Res. 30:2140–2149. 2015.PubMed/NCBI View Article : Google Scholar
10	Zarling JM, Shoyab M, Marquardt H, Hanson MB, Lioubin MN and Todaro GJ: Oncostatin M: A growth regulator produced by differentiated histiocytic lymphoma cells. Proc Natl Acad Sci USA. 83:9739–9743. 1986.PubMed/NCBI View Article : Google Scholar
11	Sims NA and Quinn JMW: Osteoimmunology: Oncostatin M as a pleiotropic regulator of bone formation and resorption in health and disease. Bonekey Rep. 3(527)2014.PubMed/NCBI View Article : Google Scholar
12	Bellido T, Stahl N, Farruggella TJ, Borba V, Yancopoulos GD and Manolagas SC: Detection of receptors for interleukin-6, interleukin-11, leukemia inhibitory factor, oncostatin M, and ciliary neurotrophic factor in bone marrow stromal/osteoblastic cells. J Clin Invest. 97:431–437. 1996.PubMed/NCBI View Article : Google Scholar
13	Walker EC, McGregor NE, Poulton IJ, Solano M, Pompolo S, Fernandes TJ, Constable MJ, Nicholson GC, Zhang JG, Nicola NA, et al: Oncostatin M promotes bone formation independently of resorption when signaling through leukemia inhibitory factor receptor in mice. J Clin Invest. 120:582–592. 2010.PubMed/NCBI View Article : Google Scholar
14	Guihard P, Boutet MA, Brounais-Le Royer B, Gamblin AL, Amiaud J, Renaud A, Berreur M, Rédini F, Heymann D, Layrolle P and Blanchard F: Oncostatin m, an inflammatory cytokine produced by macrophages, supports intramembranous bone healing in a mouse model of tibia injury. Am J Pathol. 185:765–775. 2015.PubMed/NCBI View Article : Google Scholar
15	Aguirre JI, Leal ME, Rivera MF, Vanegas SM, Jorgensen M and Wronski TJ: Effects of basic fibroblast growth factor and a prostaglandin E2 receptor subtype 4 agonist on osteoblastogenesis and adipogenesis in aged ovariectomized rats. J Bone Miner Res. 22:877–888. 2007.PubMed/NCBI View Article : Google Scholar
16	Charoenlarp P, Rajendran AK and Iseki S: Role of fibroblast growth factors in bone regeneration. Inflamm Regen. 37(10)2017.PubMed/NCBI View Article : Google Scholar
17	Abboud SL and Pinzani M: Peptide growth factors stimulate macrophage colony-stimulating factor in murine stromal cells. Blood. 78:103–109. 1991.PubMed/NCBI
18	Xie Y, Su N, Yang J, Tan Q, Huang S, Jin M, Ni Z, Zhang B, Zhang D, Luo F, et al: FGF/FGFR signaling in health and disease. Signal Transduct Target Ther. 5(181)2020.PubMed/NCBI View Article : Google Scholar
19	Suzuki A, Shinoda J, Kanda S, Oiso Y and Kozawa O: Basic fibroblast growth factor stimulates phosphatidylcholine-hydrolyzing phospholipase D in osteoblast-like cells. J Cell Biochem. 63:491–499. 1996.PubMed/NCBI View Article : Google Scholar
20	Kuroyanagi G, Otsuka T, Yamamoto N, Matsushima-Nishiwaki R, Nakakami A, Mizutani J, Kozawa O and Tokuda H: Down-regulation by resveratrol of basic fibroblast growth factor-stimulated osteoprotegerin synthesis through suppression of Akt in osteoblasts. Int J Mol Sci. 15:17886–17900. 2014.PubMed/NCBI View Article : Google Scholar
21	Tokuda H, Kozawa O and Uematsu T: Basic fibroblast growth factor stimulates vascular endothelial growth factor release in osteoblasts: Divergent regulation by p42/p44 mitogen-activated protein kinase and p38 mitogen-activated protein kinase. J Bone Miner Res. 15:2371–2379. 2000.PubMed/NCBI View Article : Google Scholar
22	Tokuda H, Hirade K, Wang X, Oiso Y and Kozawa O: Involvement of SAPK/JNK in basic fibroblast growth factor-induced vascular endothelial growth factor release in osteoblasts. J Endocrinol. 177:101–107. 2003.PubMed/NCBI View Article : Google Scholar
23	Doi T, Hioki T, Tachi J, Ueda K, Matsushima-Nishiwaki R, Iida H, Ogura S, Kozawa O and Tokuda H: Oncostatin M reduces the synthesis of macrophage-colony stimulating factor stimulated by TGF-β via suppression of p44/p42 MAP kinase and JNK in osteoblasts. Biomed Res. 43:41–51. 2022.PubMed/NCBI View Article : Google Scholar
24	Sudo H, Kodama HA, Amagai Y, Yamamoto S and Kasai S: In vitro differentiation and calcification in a new clonal osteogenic cell line derived from newborn mouse calvaria. J Cell Biol. 96:191–198. 1983.PubMed/NCBI View Article : Google Scholar
25	Zambelli A, Mongiardini E, Villegas SN, Carri NG, Boot-Handford RP and Wallis GA: Transcription factor XBP-1 is expressed during osteoblast differentiation and is transcriptionally regulated by parathyroid hormone (PTH). Cell Biol Int. 29:647–653. 2005.PubMed/NCBI View Article : Google Scholar
26	Simpson DA, Feeney S, Boyle C and Stitt AW: Retinal VEGF mRNA measured by SYBR green I fluorescence: A versatile approach to quantitative PCR. Mol Vis. 6:178–183. 2000.PubMed/NCBI
27	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
28	Laemmli UK: Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 227:680–685. 1970.PubMed/NCBI View Article : Google Scholar
29	Alessi DR, Cuenda A, Cohen P, Dudley DT and Saltiel AR: PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem. 270:27489–27494. 1995.PubMed/NCBI View Article : Google Scholar
30	Cuenda A, Rouse J, Doza YN, Meier R, Cohen P, Gallagher TF, Young PR and Lee JC: SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. FEBS Lett. 364:229–233. 1995.PubMed/NCBI View Article : Google Scholar
31	Bennett BL, Sasaki DT, Murray BW, O'Leary EC, Sakata ST, Xu W, Leisten JC, Motiwala A, Pierce S, Satoh Y, et al: SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci USA. 98:13681–13686. 2001.PubMed/NCBI View Article : Google Scholar
32	Cuenda A and Rousseau S: p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta. 1773:1358–1375. 2007.PubMed/NCBI View Article : Google Scholar
33	Rodríguez-Carballo E, Gámez B and Ventura F: p38 MAPK signaling in osteoblast differentiation. Front Cell Dev Biol. 4(40)2016.PubMed/NCBI View Article : Google Scholar
34	Han Y, You X, Xing W, Zhang Z and Zou W: Paracrine and endocrine actions of bone-the functions of secretory proteins from osteoblasts, osteocytes, and osteoclasts. Bone Res. 6(16)2018.PubMed/NCBI View Article : Google Scholar