Interleukin-1β Increases Angptl4 (FIAF) Expression via the JNK Signaling Pathway in Osteoblastic MC3T3-E1 Cells

Abstract

Angiopoietin-like protein 4 (Angptl4), also known as fasting-induced adiopogenic factor (FIAF), has recently been reported to influence bone metabolism. However, there have been few studies on regulatory factors other than hypoxia for Angptl4 in bone, and particularly in osteoblasts. Expression of interleukin-1β (IL-1β), a proinflammatory cytokine, is increased in serum or bone microenvironments in inflammatory bone diseases or estrogen deficient-conditions. The present study was conducted to determine whether Angptl4 expression in osteoblasts is affected by IL-1β and investigate its involvement in MAP kinase signaling pathways. Angptl4 RNA levels were increased by IL-1β treatment in murine MC3T3-E1 osteoblastic cells. Western blotting and immunofluorescent staining showed a corresponding increase in Angptl4 protein. IL-1β treatment of osteoblasts induced phosphorylation of mitogen-activated protein kinases (MAPKs) including extracellular regulated kinases (ERKs), p38, and c-Jun N-terminal kinase (JNK). Furthermore, SP600125, an inhibitor of JNK, significantly blocked the upregulation of Angptl4 by IL-1β. In contrast, treatment with an inhibitor of p38 MAP kinase (SB203580) or an ERK inhibitor (PD98059) produced responses similar to those seen with the DMSO control. Taken together, these results suggest that IL-1β increases Angptl4 expression through a mechanism dependent on the JNK-MAPK signaling pathway in MC3T3-E1 cells.

Key words

angptl4 - osteoblast - interleukin-1beta - MAP kinase signaling system - JNK mitogen-activated protein kinase

^* These authors equally contributed to this work.

• References

• 1 Zhu P, Goh YY, Chin HF et al. Angiopoietin-like 4: a decade of research. Biosci Rep 2012; 32: 211-219
• 2 Lin JM, Naot D, Watson M et al. Skeletal actions of fasting induced adipose factor (FIAF). Endocrinology 2013; 154: 4685-4694
• 3 Ge H, Yang G, Huang L et al. Oligomerization and regulated proteolytic processing of angiopoietin-like protein 4. J Biol Chem 2004; 279: 2038-2045
• 4 Grootaert C, Van de Wiele T, Verstraete W et al. Angiopoietin-like protein 4: health effects, modulating agents and structure-function relationships. Expert Rev Proteomics 2012; 9: 181-199
• 5 Goh YY, Pal M, Chong HC et al. Angiopoietin-like 4 interacts with matrix proteins to modulate wound healing. J Biol Chem 2010; 285: 32999-33009
• 6 Murata M, Yudo K, Nakamura H et al. Hypoxia upregulates the expression of angiopoietin-like-4 in human articular chondrocytes: role of angiopoietin-like-4 in the expression of matrix metalloproteinases and cartilage degradation. J Orthop Res 2009; 27: 50-57
• 7 Chong HC, Chan JS, Goh CQ et al. Angiopoietin-like 4 stimulates STAT3-mediated iNOS expression and enhances angiogenesis to accelerate wound healing in diabetic mice. Mol Ther 2014; 22: 1593-1604
• 8 Padua D, Zhang XH, Wang Q et al. TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 2008; 133: 66-77
• 9 Xu A, Lam MC, Chan KW et al. Angiopoietin-like protein 4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice. Proc Natl Acad Sci USA 2005; 102: 6086-6091
• 10 Kim HK, Youn BS, Shin MS et al. Hypothalamic Angptl4/Fiaf is a novel regulator of food intake and body weight. Diabetes 2010; 59: 2772-2780
• 11 Clement LC, Mace C, Avila-Casado C et al. Circulating angiopoietin-like 4 links proteinuria with hypertriglyceridemia in nephrotic syndrome. Nat Med 2014; 20: 37-46
• 12 Knowles HJ, Cleton-Jansen AM, Korsching E et al. Hypoxia-inducible factor regulates osteoclast-mediated bone resorption: role of angiopoietin-like 4. FASEB J 2010; 24: 4648-4659
• 13 Li L, Fei Z, Ren J et al. Functional imaging of interleukin 1 beta expression in inflammatory process using bioluminescence imaging in transgenic mice. BMC Immunol 2008; 9: 49
• 14 Abrahamsen B, Shalhoub V, Larson EK et al. Cytokine RNA levels in transiliac bone biopsies from healthy early postmenopausal women. Bone 2000; 26: 137-145
• 15 Rooney M, Symons JA, Duff GW. Interleukin 1 beta in synovial fluid is related to local disease activity in rheumatoid arthritis. Rheumatol Int 1990; 10: 217-219
• 16 Broom OJ, Widjaya B, Troelsen J et al. Mitogen activated protein kinases: a role in inflammatory bowel disease?. Clin Exp Immunol 2009; 158: 272-280
• 17 Greenblatt MB, Shim JH, Glimcher LH. Mitogen-activated protein kinase pathways in osteoblasts. Annu Rev Cell Dev Biol 2013; 29: 63-79
• 18 Lee YA, Ji HI, Lee SH et al. The role of adiponectin in the production of IL-6, IL-8, VEGF and MMPs in human endothelial cells and osteoblasts: implications for arthritic joints. Exp Mol Med 2014; 46: e72
• 19 Hengartner NE, Fiedler J, Ignatius A et al. IL-1beta inhibits human osteoblast migration. Mol Med 2013; 19: 36-42
• 20 Mandard S, Zandbergen F, van Straten E et al. The fasting-induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity. J Biol Chem 2006; 281: 934-944
• 21 Muendlein A, Saely CH, Leiherer A et al. Angiopoietin-like protein 4 significantly predicts future cardiovascular events in coronary patients. Atherosclerosis 2014; 237: 632-638
• 22 Kon T, Cho TJ, Aizawa T et al. Expression of osteoprotegerin, receptor activator of NF-kappaB ligand (osteoprotegerin ligand) and related proinflammatory cytokines during fracture healing. J Bone Miner Res 2001; 16: 1004-1014
• 23 Pacifici R, Rifas L, Teitelbaum S et al. Spontaneous release of interleukin 1 from human blood monocytes reflects bone formation in idiopathic osteoporosis. Proc Natl Acad Sci USA 1987; 84: 4616-4620
• 24 Hu Y, Chan E, Wang SX et al. Activation of p38 mitogen-activated protein kinase is required for osteoblast differentiation. Endocrinology 2003; 144: 2068-2074
• 25 Kholodenko BN. Cell-signalling dynamics in time and space. Nat Rev Mol Cell Biol 2006; 7: 165-176
• 26 Marshall CJ. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 1995; 80: 179-185
• 27 Murphy LO, Smith S, Chen RH et al. Molecular interpretation of ERK signal duration by immediate early gene products. Nat Cell Biol 2002; 4: 556-564
• 28 Chang J, Wang Z, Tang E et al. Inhibition of osteoblastic bone formation by nuclear factor-kappaB. Nat Med 2009; 15: 682-689
• 29 Yamashita M, Ying SX, Zhang GM et al. Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation. Cell 2005; 121: 101-113