SAPK/JNK Plays a Role in Transforming Growth Factor-β-induced VEGF Synthesis in Osteoblasts

Y. Kanno; A. Ishisaki; M. Yoshida; H. Tokuda; O. Numata; O. Kozawa

doi:10.1055/s-2005-861291

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2005; 37(3): 140-145
DOI: 10.1055/s-2005-861291

Original Basic

SAPK/JNK Plays a Role in Transforming Growth Factor-β-induced VEGF Synthesis in Osteoblasts

Y. Kanno^1, ² , A. Ishisaki¹ , M. Yoshida¹ , H. Tokuda^2, ³ , O. Numata² , O. Kozawa¹

¹Department of Pharmacology, Gifu University School of Medicine, Japan
²Institute of Biological Science, University of Tsukuba, Ibaraki, Japan
³Department of Internal Medicine, Chubu National Hospital, National Institute for Longevity Sciences, Obu, Aichi, Japan

Abstract

We previously reported that transforming growth factor-β (TGF-β) activates p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase, resulting in the stimulation of vascular endothelial growth factor (VEGF) synthesis in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the involvement of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), another member of the MAP kinase superfamily, in TGF-β-induced VEGF synthesis in these cells. TGF-β markedly induced SAPK/JNK phosphorylation. SP600125, a specific inhibitor of SAPK/JNK, markedly reduced TGF-β-induced VEGF synthesis. SP600125 suppressed TGF-β-induced SAPK/JNK phosphorylation. PD98059, an inhibitor of upstream kinase of p44/p42 MAP kinase and SB203580, an inhibitor of p38 MAP kinase, each failed to reduce TGF-β-induced SAPK/JNK phosphorylation. A combination of SP600125 and PD98059 or SP600125 and SB203580 suppressed TGF-β-stimulated VEGF synthesis in an additive manner. These results strongly suggest that TGF-β activates SAPK/JNK in osteoblasts, and that SAPK/JNK plays a role in addition to p42/p44 MAP kinase and p38 MAP kinase in TGF-β-induced VEGF synthesis.

Key words

TGF-β - VEGF - SAPK/JNK - Osteoblast

Full Text

References

1 Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 1997; 18 4-25
2 Gerber H-P, Vu T H, Ryan A M, Kowalski J, Werb Z, Ferrara N. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med. 1999; 5 623-628
3 Goad D L, Rubin J, Wang H, Tashijian A H Jr, Patterson C. Enhanced expression of vascular endothelial growth factor in human SaOS-2 osteoblast-like cells and murine osteoblasts induced by insulin-like growth factor I. Endocrinology. 1996; 137 2262-2268
4 Wang D S, Yamazaki K, Nohtomi K, Shizume K, Ohsumi K, Shibuya M, Demura H, Sato K. Increase of vascular endothelial growth factor mRNA expression by 1,25-dihydroxyvitamin D₃ in human osteoblast-like cells. J Bone Miner Res. 1996; 11 472-479
5 Schalaeppi J M, Gutzwiller S, Finlenzeller G, Fournier B. 1,25-dihydroxyvitamin D₃ induces the expression of vascular endothelial growth factor in osteoblastic cells. Endocr Res. 1997; 23 213-229
6 Nijweide P J, Burger E H, Feyen J HM. Cells of bone: proliferation, differentiation, and humoral regulation. Physiol Rev. 1986; 66 855-886
7 Erlebacher A, Filvaroff E H, Girelman S E, Derynck R. Toward a molecular understanding of skeletal development. Cell. 1995; 80 371-378
8 Saadeh P B, Mehrara B J, Steinbrech D S, Dudziak M E, Greenwald J A, Luchs J S, Spector J A, Ueno H, Gittes G K, Longaker M T. Transforming growth factor-β1 modulates the expression of vascular endothelial growth factor by osteoblasts. American J Physiol. 1999; 277 C628-C637
9 Chua C C, Hamdy R C, Chua B H. Mechanism of transforming growth factor-β-induced expression of vascular endothelial growth factor in murine osteoblastic MC3T3-E1 cells. Biochim Biophys Acta. 2000; 1497 69-76
10 Massague J, Blain S W, Lo R S. TGF-β signaling in growth control, cancer, and heritable disorders. Cell. 2000; 103 295-309
11 Bonewald L F. Transforming growth factor-beta. In: Bilezikian JP, Raisz LG, Rodan GA (eds) Principles of Bone Biology, 2nd ed. San Diego; Academic Press 2002: 903-918
12 Heldin C H, Miyazono K, ten Dijke P. TGF-β signalling from cell membrane to nucleus through SMAD proteins. Nature. 1997; 390 465-471
13 Massague J. TGF-β signal transduction. Ann Rev Biochem. 1998; 67 753-791
14 Miyazono K, Kusanagi K, Inoue H. Divergence and convergence of TGF-β/BMP signaling. J Cell Physiol. 2001; 187 265-276
15 Widmann C, Gibson S, Jarpe M B, Johnson G L. Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol Rev. 1999; 79 143-180
16 Yamaguchi K, Shirakabe K, Shibuya H, Irie K, Oishi I, Ueno N, Taniguchi T, Nishida E, Matsumoto K. Identification of a member of the MAPKKK family as a potential mediator of TGF-β signal transduction. Science. 1995; 270 2008-2011
17 Palcy S, Goltzman D. Protein kinase signalling pathways involved in the up-regulation of the rat alpha1(I) collagen gene by transforming growth factor β1 and bone morphogenetic protein 2 in osteoblastic cells. Biochem J. 1999; 343 21-27
18 Hatakeyama D, Kozawa O, Niwa M, Matsuno H, Ito H, Kato K, Tatematsu N, Shibata T, Uematsu T. Upregulation by retinoic acid of transforming growth factor-β-stimulated heat shock protein 27 induction in osteoblasts: involvement of mitogen-activated protein kinases. Biochim Biophys Acta. 2002; 1589 15-30
19 Tokuda H, Hatakeyama D, Akamatsu S, Tanabe K, Yoshida M, Shibata T, Kozawa O. Involvement of MAP kinases in TGF-β-stimulated vascular endothelial growth factor synthesis in osteoblasts. Arch Biochem Biophys. 2003; 415 117-125
20 Sudo H, Kodama H, Amagai Y, Yamamoto S, Kasai S. In vivo differentiation and calcification in a new clonal osteogenic cell line derived from newborn mouse calvaria. J Cell Biol. 1983; 96 191-198
21 Kozawa O, Tokuda H, Miwa M, Kotoyori J, Oiso Y. Cross-talk regulation between cyclic AMP production and phosphoinositide hydrolysis induced by prostaglandin E₂ in osteoblast-like cells. Exp Cell Res. 1992; 198 130-134
22 Laemmli U K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970; 227 680-685
23 Kato K, Ito H, Hasegawa K, Inaguma Y, Kozawa O, Asano T. Modulation of the stress-induced synthesis of hsp27 and αB-crystallin by cyclic AMP in C6 glioma cells. J Neurochem. 1996; 66 946-950
24 Bennett B L, Sasaki D T, Murray B W, O’Leary E C, Sakata S T, Xu W, Leisten J C, Motiwala A, Pierce S, Satoh Y, Bhagwat S S, Manning A M, Anderson D W. SP600125, an anthrapyrazolone inhibitor of Jun N-terminal Kinase. Proc Natl Acad Sci USA. 2001; 98 13 681-13 686
25 Alessi D R, Cuenda A, Cohen P, Dudley D T, Saltiel A R. PD98059 is a specific inhibitor of the activation of mitogen-activated protein kinase in vitro and in vivo. J Biol Chem. 1995; 270 27 489-27 494
26 Cuenda A, Rouse J, Doza Y N, Meier R, Cohen P, Gallagher T F, Young P R, Lee J C. SB203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. FEBS Lett. 1995; 364 229-233
27 Raingeaud J, Gupta S, Rogers J S, Dickens M, Han J, Ulevitch R J, David R J. Pro-inflammatory cytokines and enviromental stress cause p38 MAP kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem. 1995; 270 7420-7426
28 Kanno Y, Tokuda H, Nakajima K, Ishisaki A, Shibata T, Numata O, Kozawa O. Involvement of SAPK/JNK in prostaglandin E(1)-induced VEGF synthesis in osteoblast-like cells. Mol Cell Endocrinol.. 2004; 220 89-95
29 Tokuda H, Kozawa O, Miwa M, Uematsu T. p38 mitogen-activated protein (MAP) kinase but not p44/p42 MAP kinase is involved in prostaglandin E1-induced vascular endothelial growth factor synthesis in osteoblasts. J Endocrinol.. 2001; 170 629-638
30 Sowa H, Kaji H, Yamaguchi T, Sugimoto T, Chihara K. Activations of ERK1/2 and JNK by transforming growth factor beta negatively regulate Smad3-induced alkaline phosphatase activity and mineralization in mouse osteoblastic cells. J Biol Chem.. 2002; 277 36 024-36 031
31 Yamamoto T, Kozawa O, Tanabe K, Akamatsu S, Matsuno H, Dohi S, Uematsu T. Involvement of p38 MAP kinase in TGF-beta-stimulated VEGF synthesis in aortic smooth muscle cells. J Cell Biochem.. 2001; 82 591-598
32 Sawano A, Iwai S, Sakurai Y, Ito M, Shitara K, Nakahata T, Shibuya M. Flt-1, vascular endothelial growth factor receptor 1, is a novel cell surface marker for the lineage of monocyte-macrophages in humans. Blood. 2001; 97 785-791
33 Henriksen K, Karsdal M A, Delaissé J M, Engsig M T. RANKL and VEGF induce osteoclast chemotaxis through an ERK1/2 dependent mechanism. J Biol Chem. 2003; 278 48 745-48 753
34 Strammiello R, Benini S, Manara M C, Perdichizzi S, Serra M, Spisni E, Picci P, Scotlandi K. Impact of IGF-I/IGF-IR circuit on the angiogenetic properties of Ewing’s sarcoma cells. Horm Metab Res.. 2003; 35 675-684

Dr. Osamu Kozawa

Department of Pharmacology · Gifu University Graduate School of Medicine ·

Gifu 501-1194 · Japan

Phone: + 81 (58) 230-6214 ·

Fax: + 81 (58) 230-6218 ·

Email: okozawa@cc.gifu-u.ac.jp