Genistein induces adipogenesis but inhibits leptin induction in human synovial fibroblasts

[en] It was shown recently that synovial fibroblast transformation into adipocytes reduced the expression of interleukin-6 (IL-6) and IL-8. However, the synovial fibroblast adipogenesis was inhibited in inflammatory conditions induced by the tumor necrosis factor-alpha (TNF-alpha). Furthermore, adipogenesis is often accompanied by leptin production, a proinflammatory adipokine in rheumatic diseases. In this study, we tested the phytohormone genistein for adipogenic and anti-inflammatory properties on human synovial fibroblasts. Results showed that genistein was able to transform synovial fibroblasts into adipocytes that expressed perilipin-A and produced adiponectin, but not leptin. Furthermore, genistein enhanced glucocorticoid-mediated synovial fibroblast adipogenesis and, in parallel, downregulated glucocorticoid-induced leptin and leptin receptor. Endogenous and TNF-alpha-induced expressions of IL-6, IL-8, p38, p65 and C/EBP-beta were also downregulated by genistein, showing its anti-inflammatory properties. Peroxisome proliferator- activated receptor-gamma (PPAR-gamma) agonist, rosiglitazone, had a synergic effect on genistein-induced whereas the non-active tyrosine kinase inhibitor, daidzein, had a significantly inferior adipogenic activity than genistein. The Janus kinase-2 tyrosine kinase inhibitor, AG 490, mimicked the anti-leptin effect of genistein. These results showed that genistein-induced adipogenesis involves PPAR-gamma induction and tyrosine kinase inhibition. In conclusion, genistein, alone or coupled with glucocorticoids, have both adipogenic and anti-inflammatory effects on synovial fibroblasts.

Disciplines :

Hematology

Author, co-author :

Relic, Biserka ; Université de Liège - ULiège > Rhumatologie

Zeddou, Mustapha ; Université de Liège - ULiège > Département des sciences cliniques > Rhumatologie

Desoroux, Aline ; Université de Liège - ULiège > Rhumatologie

Beguin, Yves ; Université de Liège - ULiège > Département des sciences cliniques > Hématologie - Oncologie médicale

De Seny, Dominique ; Université de Liège - ULiège > Rhumatologie

Malaise, Michel ; Université de Liège - ULiège > Département des sciences cliniques > Rhumatologie

Language :

English

Title :

Genistein induces adipogenesis but inhibits leptin induction in human synovial fibroblasts

Publication date :

2009

Journal title :

Laboratory Investigation

ISSN :

0023-6837

eISSN :

1530-0307

Publisher :

Lippincott Williams & Wilkins, Hagerstown, United States - Maryland

Volume :

Issue :

Pages :

811-822

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 26 April 2011

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Bibliography

van den Berg WB, van Lent PL, Joosten LA, et al. Amplifying elements of arthritis and joint destruction. Ann Rheum Dis 2007;66(Suppl 3):iii45-iii48.
Lee DM, Kiener HP, Agarwal SK, et al. Cadherin-11 in synovial lining formation and pathology in arthritis. Science 2007;315: 1006-1010.
Jones S, Horwood N, Cope A, et al. The antiproliferative effect of mesenchymal stem cells is a fundamental property shared by all stromal cells. J Immunol 2007;179:2824-2831.
Yamasaki S, Nakashima T, Kawakami A, et al. Functional changes in rheumatoid fibroblast-like synovial cells through activation of peroxisome proliferator-activated receptor gamma-mediated signalling pathway. Clin Exp Immunol 2002;129:379-384.
De Bari C, Dell'Accio F, Tylzanowski P, et al. Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis Rheum 2001;44:1928-1942.
Yamasaki S, Nakashima T, Kawakami A, et al. Cytokines regulate fibroblast-like synovial cell differentiation to adipocyte-like cells. Rheumatology (Oxford) 2004;43:448-452.
Fiorito S, Magrini L, Adrey J, et al. Inflammatory status and cartilage regenerative potential of synovial fibroblasts from patients with osteoarthritis and chondropathy. Rheumatology (Oxford) 2005;44: 164-171.
Sakaguchi Y, Sekiya I, Yagishita K, et al. Comparison of human stem cells derived from various mesenchymal tissues: superiority of synovium as a cell source. Arthritis Rheum 2005;52:2521-2529.
Koga H, Muneta T, Ju YJ, et al. Synovial stem cells are regionally specified according to local microenvironments after implantation for cartilage regeneration. Stem Cells 2007;25:689-696.
Busso N, So A, Chobaz-Peclat V, et al. Leptin signaling deficiency impairs humoral and cellular immune responses and attenuates experimental arthritis. J Immunol 2002;168:875-882.
Dumond H, Presle N, Terlain B, et al. Evidence for a key role of leptin in osteoarthritis. Arthritis Rheum 2003;48:3118-3129.
Otero M, Lago R, Gomez R, et al. Phosphatidylinositol 3-kinase, MEK-1 and p38 mediate leptin/interferon-gamma synergistic NOS type II induction in chondrocytes. Life Sci 2007;81:1452-1460.
Tong KM, Shieh DC, Chen CP, et al. Leptin induces IL-8 expression via leptin receptor, IRS-1, PI3K, Akt cascade and promotion of NF-kappaB/ p300 binding in human synovial fibroblasts. Cell Signal 2008;20: 1478-1488.
Dang ZC, Audinot V, Papapoulos SE, et al. Peroxisome proliferatoractivated receptor gamma (PPARgamma) as a molecular target for the soy phytoestrogen genistein. J Biol Chem 2003;278:962-967.
Dixon RA, Ferreira D. Genistein. Phytochemistry 2002;60:205-211.
Relic B, Benoit V, Franchimont N, et al. Peroxisome proliferatoractivated receptor-gamma1 is dephosphorylated and degraded during BAY 11-7085-induced synovial fibroblast apoptosis. J Biol Chem 2006;281:22597-22604.
Dahl JA, Collas P. MicroChIP-a rapid micro chromatin immunoprecipitation assay for small cell samples and biopsies. Nucleic Acids Res 2008;36:e15.
Isshiki H, Akira S, Tanabe O, et al. Constitutive and interleukin-1 (IL-1)- inducible factors interact with the IL-1-responsive element in the IL-6 gene. Mol Cell Biol 1990;10:2757-2764.
Mastronarde JG, He B, Monick MM, et al. Induction of interleukin (IL)-8 gene expression by respiratory syncytial virus involves activation of nuclear factor (NF)-kappa B and NF-IL-6. J Infect Dis 1996;174:262-267.
Vanden Berghe W, Dijsselbloem N, Vermeulen L, et al. Attenuation of mitogen- and stress-activated protein kinase-1-driven nuclear factorkappaB gene expression by soy isoflavones does not require estrogenic activity. Cancer Res 2006;66:4852-4862.
Akiyama T, Ishida J, Nakagawa S, et al. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem 1987;262:5592-5595.
Nolte RT, Wisely GB, Westin S, et al. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature 1998;395:137-143.
Rahman SM, Schroeder-Gloeckler JM, Janssen RC, et al. CCAAT/ enhancing binding protein beta deletion in mice attenuates inflammation, endoplasmic reticulum stress, and lipid accumulation in diet-induced nonalcoholic steatohepatitis. Hepatology 2007;45: 1108-1117.
Zuo Y, Qiang L, Farmer SR. Activation of CCAAT/enhancer-binding protein (C/EBP) alpha expression by C/EBP beta during adipogenesis requires a peroxisome proliferator-activated receptor-gamma- associated repression of HDAC1 at the C/ebp alpha gene promoter. J Biol Chem 2006;281:7960-7967.
Stein B, Cogswell PC, Baldwin Jr AS. Functional and physical associations between NF-kappa B and C/EBP family members: a Rel domain-bZIP interaction. Mol Cell Biol 1993;13:3964-3974.
Kehlen A, Thiele K, Riemann D, et al. Expression, modulation and signalling of IL-17 receptor in fibroblast-like synoviocytes of patients with rheumatoid arthritis. Clin Exp Immunol 2002;127: 539-546.
Khanna D, Sethi G, Ahn KS, et al. Natural products as a gold mine for arthritis treatment. Curr Opin Pharmacol 2007;7:344-351.
Lecka-Czernik B, Moerman EJ, Grant DF, et al. Divergent effects of selective peroxisome proliferator-activated receptor-gamma 2 ligands on adipocyte versus osteoblast differentiation. Endocrinology 2002;143:2376-2384.
Hwang JT, Park IJ, Shin JI, et al. Genistein, EGCG, and capsaicin inhibit adipocyte differentiation process via activating AMP-activated protein kinase. Biochem Biophys Res Commun 2005;338:694-699.
Harmon AW, Patel YM, Harp JB. Genistein inhibits CCAAT/enhancerbinding protein beta (C/EBPbeta) activity and 3T3-L1 adipogenesis by increasing C/EBP homologous protein expression. Biochem J 2002;367(Pt 1):203-208.
Park HJ, Della-Fera MA, Hausman DB, et al. Genistein inhibits differentiation of primary human adipocytes. J Nutr Biochem 2009;20:140-148.
Heim M, Frank O, Kampmann G, et al. The phytoestrogen genistein enhances osteogenesis and represses adipogenic differentiation of human primary bone marrow stromal cells. Endocrinology 2004;145:848-859.
Hu E, Kim JB, Sarraf P, et al. Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPAR-g. Science 1996;274:2100-2103.
McLaughlin F, Mackintosh J, Hayes BP, et al. Glucocorticoid- induced osteopenia in the mouse as assessed by histomorphometry, microcomputed tomography, and biochemical markers. Bone 2002;30:924-930.
Fairbrother UL, Tanko LB, Walley AJ, et al. Leptin receptor genotype at Gln223Arg is associated with body composition, BMD, and vertebral fracture in postmenopausal Danish women. J Bone Miner Res 2007;22:544-550.
Matarese G, Leiter EH, La Cava A. Leptin in autoimmunity: many questions, some answers. Tissue Antigens 2007;70:87-95.
Matarese G, La Cava A, Sanna V, et al. Balancing susceptibility to infection and autoimmunity: a role for leptin? Trends Immunol 2002;23:182-187.
Chen TH, Chen L, Hsieh MS, et al. Evidence for a protective role for adiponectin in osteoarthritis. Biochim Biophys Acta 2006;1762: 711-718.
Tang CH, Chiu YC, Tan TW, et al. Adiponectin enhances IL-6 production in human synovial fibroblast via an AdipoR1 receptor, AMPK, p38, and NF-kappa B pathway. J Immunol 2007;179:5483-5492.
Straus DS, Glass CK. Anti-inflammatory actions of PPAR ligands: new insights on cellular and molecular mechanisms. Trends Immunol 2007;28:551-558.
Cuzzocrea S, Mazzon E, Dugo L, et al. Reduction in the evolution of murine type II collagen-induced arthritis by treatment with rosiglitazone, a ligand of the peroxisome proliferator-activated receptor gamma. Arthritis Rheum 2003;48:3544-3556.
Shiojiri T, Wada K, Nakajima A, et al. PPAR gamma ligands inhibit nitrotyrosine formation and inflammatory mediator expressions in adjuvant-induced rheumatoid arthritis mice. Eur J Pharmacol 2002;448:231-238.
Verdrengh M, Jonsson IM, Holmdahl R, et al. Genistein as an antiinflammatory agent. Inflamm Res 2003;52:341-346.