Activation of peroxisome proliferator-activated receptor-γ (PPARγ) induces cell death through MAPK-dependent mechanism in osteoblastic cells

Kim, Sung Hun; Yoo, Chong Il; Kim, Hui Taek; Park, Ji Yeon; Kwon, Chae Hwa; Kim, Yong Keun

doi:10.1016/j.taap.2006.03.001

Cited by 44 publications

(31 citation statements)

References 63 publications

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“…Thus, oxidized PUFAs stimulate apoptosis of osteoblastic OB-6 cells via a PPAR␥-dependent mechanism, consistent with previous evidence for a negative impact of RGL on osteoblast survival in vitro (55) and in vivo (51). We found that the proapoptotic effect of 4-HNE is mediated by increased oxidative stress; however, other mechanisms, for example activation of p53 (56), could also be involved.…”

Section: Discussionsupporting

confidence: 91%

Increased Lipid Oxidation Causes Oxidative Stress, Increased Peroxisome Proliferator-activated Receptor-γ Expression, and Diminished Pro-osteogenic Wnt Signaling in the Skeleton

Almeida

Ambrogini

Han

et al. 2009

Journal of Biological Chemistry

238

189

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Loss of bone mass with advancing age in mice is because of decreased osteoblast number and is associated with increased oxidative stress and decreased canonical Wnt signaling. However, the underlying mechanisms are poorly understood. We report an age-related increase in the lipid oxidation product 4-hydroxynonenal (4-HNE) as well as increased expression of lipoxygenase and peroxisome proliferator-activated receptor-␥ (PPAR␥) in the murine skeleton. These changes together with decreased Wnt signaling are reproduced in 4-month-old mice bearing a high expressing allele of the lipoxygenase Alox15. The addition of 4-HNE to cultured osteoblastic cells increases oxidative stress, which in turn diverts ␤-catenin from T-cell-specific transcription factors to Forkhead box O (FoxO) transcription factors, thereby attenuating the suppressive effect of ␤-catenin on PPAR␥ gene expression. Oxidized lipids, acting as ligands of PPAR␥, promote binding of PPAR␥2 to ␤-catenin and reduce the levels of the latter, and they attenuate Wnt3a-stimulated proliferation and osteoblast differentiation. Furthermore, oxidized lipids and 4-HNE stimulate apoptosis of osteoblastic cells. In view of the role of oxidized lipids in atherogenesis, the adverse effects of lipoxygenase-mediated lipid oxidation on the differentiation and survival of osteoblasts may provide a mechanistic explanation for the link between atherosclerosis and osteoporosis.Age-related bone loss is primarily because of an insufficient number of osteoblasts (1, 2) attributed to exhaustion of multipotential mesenchymal stem cell progenitors (3, 4) and the diversion of these progenitors toward the adipocyte lineage (5-11). Increased osteoblast apoptosis may also be involved as we recently demonstrated that loss of bone mass and strength in C57BL/6 (B6) 3 mice with advancing age is associated with an increase in the prevalence of apoptotic osteoblasts and a corresponding decrease in osteoblast number and bone formation rate (12). Moreover, these changes are accompanied by increased oxidative stress and diminished canonical Wnt signaling, a critical regulator of bone formation. Wnts are secreted proteins that bind to a Frizzled receptor and a low density lipoprotein receptor-related protein 5 (LRP5) or LRP6 co-receptor, resulting in a rise in the level of ␤-catenin by preventing its degradation by the proteasome. Binding of ␤-catenin to members of TCF family converts them from repressors to activators of a variety of genes, including those involved in the differentiation and survival of osteoblasts (13-16). Importantly, however, ␤-catenin is also an essential partner of the FoxO family of transcription factors, which defend against oxidative stress by stimulating the transcription of oxidant scavenging enzymes such as manganese superoxide dismutase and catalase (17). In fact, we have elucidated that oxidative stress compromises ␤-catenin/TCF-mediated transcription and osteoblastogenesis because of competition between FoxO and TCF for a limited pool of ␤-catenin (18). Such competiti...

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Section: Discussionsupporting

confidence: 91%

Increased Lipid Oxidation Causes Oxidative Stress, Increased Peroxisome Proliferator-activated Receptor-γ Expression, and Diminished Pro-osteogenic Wnt Signaling in the Skeleton

Almeida

Ambrogini

Han

et al. 2009

Journal of Biological Chemistry

238

189

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“…Several antineoplastic effects, such as induction of apoptosis and differentiation, have been described as a result of PPARc-mediated action both in vitro and in vivo [4][5][6][7][8][9][10], although the molecular mechanisms by which PPARc causes these effects remain to be fully elucidated. PPARc is able to be activated by ligands of physiological or pharmacological origin [11].…”

Section: Introductionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor gamma activates fas ligand gene promoter inducing apoptosis in human breast cancer cells

Bonofiglio

Gabriele

Aquila

et al. 2008

Breast Cancer Res Treat

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“…Indomethacin, SC-236, MG-132, and cell-permeable caspase 3 inhibitor, ac-DVED aldehyde (DEVD-CHO), were from Calbiochem (San Diego, CA). We used 10 Amol/L of MG-132 and 50 Amol/L of DEVD-CHO, which were reported to block proteasome and caspase 3 activities, respectively (22,23).…”

Section: Methodsmentioning

confidence: 99%

Nonsteroidal Anti-inflammatory Drugs Induce Colorectal Cancer Cell Apoptosis by Suppressing 14-3-3ε

et al. 2007

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Activation of peroxisome proliferator-activated receptor-γ (PPARγ) induces cell death through MAPK-dependent mechanism in osteoblastic cells

Cited by 44 publications

References 63 publications

Increased Lipid Oxidation Causes Oxidative Stress, Increased Peroxisome Proliferator-activated Receptor-γ Expression, and Diminished Pro-osteogenic Wnt Signaling in the Skeleton

Increased Lipid Oxidation Causes Oxidative Stress, Increased Peroxisome Proliferator-activated Receptor-γ Expression, and Diminished Pro-osteogenic Wnt Signaling in the Skeleton

Peroxisome proliferator-activated receptor gamma activates fas ligand gene promoter inducing apoptosis in human breast cancer cells

Nonsteroidal Anti-inflammatory Drugs Induce Colorectal Cancer Cell Apoptosis by Suppressing 14-3-3ε

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