Pharmacological repression of PPARγ promotes osteogenesis

被引：115

作者：

Marciano, David P. ^{[1
]}

Kuruvilla, Dana S. ^{[1
]}

Boregowda, Siddaraju V. ^{[1
]}

Asteian, Alice ^{[1
]}

Hughes, Travis S. ^{[1
]}

Garcia-Ordonez, Ruben ^{[1
]}

Corzo, Cesar A. ^{[1
]}

Khan, Tanya M. ^{[1
]}

Novick, Scott J. ^{[1
]}

Park, HaJeung ^{[1
]}

Kojetin, Douglas J. ^{[1
]}

Phinney, Donald G. ^{[1
]}

Bruning, John B. ^{[2
]}

Kamenecka, Theodore M. ^{[1
]}

Griffin, Patrick R. ^{[1
]}

机构：

[1] Scripps Florida, Scripps Res Inst, Dept Mol Therapeut, Jupiter, FL 33458 USA

[2] Univ Adelaide, Sch Mol & Biomed Sci, Adelaide, SA 5005, Australia

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

关键词：

STRUCTURAL BASIS; BINDING-SITE; LIGAND; ROSIGLITAZONE; ANTAGONISM; MODULATOR; CELLS;

D O I：

10.1038/ncomms8443

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) is the master regulator of adipogenesis and the pharmacological target of the thiazolidinedione (TZD) class of insulin sensitizers. Activation of PPAR gamma by TZDs promotes adipogenesis at the expense of osteoblast formation, contributing to their associated adverse effects on bone. Recently, we reported the development of PPAR gamma antagonist SR1664, designed to block the obesity-induced phosphorylation of serine 273 (S273) in the absence of classical agonism, to derive insulin-sensitizing efficacy with improved therapeutic index. Here we identify the structural mechanism by which SR1664 actively antagonizes PPAR gamma, and extend these findings to develop the inverse agonist SR2595. Treatment of isolated bone marrow-derived mesenchymal stem cells with SR2595 promotes induction of osteogenic differentiation. Together these results identify the structural determinants of ligand-mediated PPAR gamma repression, and suggest a therapeutic approach to promote bone formation.

引用

页数：7

共 32 条

[1]

PPARγ insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors [J].

Akune, T ;

Ohba, S ;

Kamekura, S ;

Yamaguchi, M ;

Chung, UI ;

Kubota, N ;

Terauchi, Y ;

Harada, Y ;

Azuma, Y ;

Nakamura, K ;

Kadowaki, T ;

Kawaguchi, H .

JOURNAL OF CLINICAL INVESTIGATION, 2004, 113 (06) :846-855

[2]

Rosiglitazone and pioglitazone increase fracture risk in women and men with type 2 diabetes [J].

Aubert, R. E. ;

Herrera, V. ;

Chen, W. ;

Haffner, S. M. ;

Pendergrass, M. .

DIABETES OBESITY & METABOLISM, 2010, 12 (08) :716-721

[3]

Partial agonists activate PPARγ using a helix 12 independent mechanism [J].

Bruning, John B. ;

Chalmers, Michael J. ;

Prasad, Swati ;

Busby, Scott A. ;

Karnenecka, Theodore M. ;

He, Yuanjun ;

Nettles, Kendall W. ;

Griffin, Patrick R. .

STRUCTURE, 2007, 15 (10) :1258-1271

[4]

Potential of Peroxisome Proliferator-Activated Receptor Gamma Antagonist Compounds as Therapeutic Agents for a Wide Range of Cancer Types [J].

Burton, Jack D. ;

Goldenberg, David M. ;

Blumenthal, Rosalyn D. .

PPAR RESEARCH, 2008, 2008

[5]

S 26948:: A new specific peroxisome proliferator-activated receptor γ modulator with potent antidiabetes and antiatherogenic effects [J].

Carmona, Maria Carmen ;

Louche, Katie ;

Lefebvre, Bruno ;

Pilon, Antoine ;

Hennuyer, Nathalie ;

Audinot-Bouchez, Veronique ;

Fievet, Catherine ;

Torpier, Gerard ;

Formstecher, Pierre ;

Renard, Pierre ;

Lefebvre, Philippe ;

Dacquet, Catherine ;

Staels, Bart ;

Casteilla, Louis ;

Penicaud, Luc .

DIABETES, 2007, 56 (11) :2797-2808

[6]

Chalmers Michael J, 2007, J Biomol Tech, V18, P194

[7]

Probing protein ligand interactions by automated hydrogen/deuterium exchange mass spectrometry [J].

Chalmers, MJ ;

Busby, SA ;

Pascal, BD ;

He, YJ ;

Hendrickson, CL ;

Marshall, AG ;

Griffin, PR .

ANALYTICAL CHEMISTRY, 2006, 78 (04) :1005-1014

[8]

Lysophosphatidic acid-induced arterial wall remodeling: Requirement of PPARγ but not LPA1 or LPA2 GPCR [J].

Cheng, Yunhui ;

Makarova, Natalia ;

Tsukahara, Ryoko ;

Guo, Huazhang ;

Shuyu, E. ;

Farrar, Patricia ;

Balazs, Louisa ;

Zhang, Chunxiang ;

Tigyi, Gabor .

CELLULAR SIGNALLING, 2009, 21 (12) :1874-1884

[9]

Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation [J].

Choi, Jang Hyun ;

Banks, Alexander S. ;

Kamenecka, Theodore M. ;

Busby, Scott A. ;

Chalmers, Michael J. ;

Kumar, Naresh ;

Kuruvilla, Dana S. ;

Shin, Youseung ;

He, Yuanjun ;

Bruning, John B. ;

Marciano, David P. ;

Cameron, Michael D. ;

Laznik, Dina ;

Jurczak, Michael J. ;

Schuerer, Stephan C. ;

Vidovic, Dusica ;

Shulman, Gerald I. ;

Spiegelman, Bruce M. ;

Griffin, Patrick R. .

NATURE, 2011, 477 (7365) :477-U131

[10]

Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARγ by Cdk5 [J].

Choi, Jang Hyun ;

Banks, Alexander S. ;

Estall, Jennifer L. ;

Kajimura, Shingo ;

Bostroem, Pontus ;

Laznik, Dina ;

Ruas, Jorge L. ;

Chalmers, Michael J. ;

Kamenecka, Theodore M. ;

Blueher, Matthias ;

Griffin, Patrick R. ;

Spiegelman, Bruce M. .

NATURE, 2010, 466 (7305) :451-U1

← 1 2 3 4 →