scholarly journals Loss of phosphatase and tensin homolog (PTEN) in myeloid cells controls inflammatory bone destruction by regulating the osteoclastogenic potential of myeloid cells

2013 ◽  
Vol 74 (1) ◽  
pp. 227-233 ◽  
Author(s):  
Stephan Blüml ◽  
Martin Friedrich ◽  
Tobias Lohmeyer ◽  
Emine Sahin ◽  
Victoria Saferding ◽  
...  
Keyword(s):  
Myeloid Cells ◽  
Bone Destruction ◽  
Precursor Cells ◽  
Nuclear Factor ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Inflammatory Conditions ◽  
Local Bone

ObjectiveLocal bone destruction in rheumatic diseases, which often leads to disability and severely reduced quality of life, is almost exclusively mediated by osteoclasts. Therefore, it is important to understand pathways regulating the generation of osteoclasts. Here, we analysed the impact of the Phosphoinositide-3-Kinase (PI3K)/Phosphatase and tensin homolog (PTEN) axis on osteoclast generation and bone biology under basal and inflammatory conditions.MethodsWe analysed osteoclastogenesis of wildtype (wt) and PTEN−/− cells in vitro and in vivo, pit resorption and qPCR of osteoclasts in vitro. Mice with a myeloid cell-specific deletion of PTEN and wt littermate mice were investigated by bone histomorphometry and clinical and histological assessment in the human tumour necrosis factor (TNF)-transgenic (hTNFtg) arthritis model.ResultsWe show that myeloid-specific PTEN−/− mice display increased osteoclastogenesis in vitro and in vivo compared to wt mice. Loss of PTEN did not affect the generation or survival of osteoclast precursor cells. However, PTEN deficiency greatly enhanced receptor activator of nuclear factor κ-B ligand (RANKL)-induced expression of the master transcription factor of osteoclastogenesis, nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), resulting in markedly increased terminal differentiation of osteoclasts in vitro. We also observed increased osteoclastogenesis under inflammatory conditions in the hTNFtg mouse model of arthritis, where hTNFtg/myeloid-specific PTEN−/− mice displayed enhanced local bone destruction as well as osteoclast formation in the inflamed joints. The extent of synovial inflammation, however, as well as recruitment of osteoclast precursor cells was not different between wt and myeloid-specific PTEN−/− mice.ConclusionsThese data demonstrate that loss of PTEN and, therefore, sustained PI3-Kinase signalling in myeloid cells especially, elevates the osteoclastogenic potential of myeloid cells, leading to enhanced inflammatory local bone destruction. Therefore, although our study allows no direct translational conclusion since we used a conditional knockout approach, the therapeutic targeting of the PI3-Kinase pathway may be of benefit in preventing structural joint damage.

scholarly journals BMI1 promotes cardiac fibrosis in ischemia-induced heart failure via the PTEN-PI3K/Akt-mTOR signaling pathway

2019 ◽  
Vol 316 (1) ◽  
pp. H61-H69 ◽  
Author(s):  
Wenbo Yang ◽  
Zhijun Wu ◽  
Ke Yang ◽  
Yanxin Han ◽  
Yanjia Chen ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Mammalian Target Of Rapamycin ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatase And Tensin Homolog ◽  
B Lymphoma ◽  
Tensin Homolog ◽  
And Migration ◽  
Proliferation And Migration

Cardiac fibrosis has been known to play an important role in the etiology of heart failure after myocardial infarction (MI). B lymphoma Mo-MLV insertion region 1 homolog (BMI1), a transcriptional repressor, is important for fibrogenesis in the kidneys. However, the effect of BMI1 on ischemia-induced cardiac fibrosis remains unclear. BMI1 was strongly expressed in the infarct region 1 wk post-MI in mice and was detected by Western blot and histological analyses. Lentivirus-mediated overexpression of BMI1 significantly promoted cardiac fibrosis, worsened cardiac function 4 wk after the intervention in vivo, and enhanced the proliferation and migration capabilities of fibroblasts in vitro , whereas downregulation of BMI1 decreased cardiac fibrosis and prevented cardiac dysfunction in mice 4 wk post-MI in vivo. Furthermore, upregulated BMI1 inhibited phosphatase and tensin homolog (PTEN) expression, enhanced phosphatidylinositol 3-kinase (PI3K) expression, and increased the phosphorylation level of Akt and mammalian target of rapamycin (mTOR) in mice 4 wk after lentiviral infection, which was in accordance with the changes seen in their infarcted myocardial tissues. At the same time, the effects of BMI1 on cardiac fibroblasts were reversed in vitro when these cells were exposed to NVP-BEZ235, a dual-kinase (PI3K/mTOR) inhibitor. In conclusion, BMI1 is associated with cardiac fibrosis and dysfunction after MI by regulating cardiac fibroblast proliferation and migration, and these effects could be partially explained by the regulation of the PTEN-PI3K/Akt-mTOR pathway. NEW & NOTEWORTHY Ischemia-induced B lymphoma Mo-MLV insertion region 1 homolog (BMI1) significantly promoted cardiac fibrosis and worsened cardiac function in vivo, whereas downregulation of BMI1 decreased cardiac fibrosis and prevented cardiac dysfunction in myocardial infarcted mice. BMI1 also enhanced proliferation and migration capabilities of fibroblasts in vitro; these effects were reversed by NVP-BEZ235. Effects of BMI1 on cardiac fibrosis could be partially explained by regulation of the phosphatase and tensin homolog-phosphatidylinositol 3-kinase/Akt-mammalian target of rapamycin pathway.

scholarly journals Podocyte-specific knockin of PTEN protects kidney from hyperglycemia

2018 ◽  
Vol 314 (6) ◽  
pp. F1096-F1107 ◽  
Author(s):  
Huizhen Wang ◽  
Ziwei Feng ◽  
Jianteng Xie ◽  
Feng Wen ◽  
Menglei Jv ◽  
...  
Keyword(s):  
Diabetic Kidney Disease ◽  
Therapeutic Strategy ◽  
Renal Protection ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Matrix Expansion ◽  
Interfering Rna

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) has proven to be downregulated in podocytes challenged with high glucose (HG), and knockout of PTEN in podocytes aggravated the progression of diabetic kidney disease (DKD). However, whether podocyte-specific knockin of PTEN protects the kidney against hyperglycemia in vivo remains unknown. The inducible podocyte-specific PTEN knockin (PPKI) mice were generated by crossing newly created transgenic loxP-stop- loxP-PTEN mice with podocin-iCreERT2 mice. Diabetes mellitus was induced in mice by intraperitoneal injection of streptozotocin at a dose of 150 mg/kg. In vitro, small interfering RNA and adenovirus interference were used to observe the role of PTEN in HG-treated podocytes. Our data demonstrated that PTEN was markedly reduced in the podocytes of patients with DKD and focal segmental glomerulosclerosis, as well as in those of db/db mice. Interestingly, podocyte-specific knockin of PTEN significantly alleviated albuminuria, mesangial matrix expansion, effacement of podocyte foot processes, and incrassation of glomerular basement membrane in diabetic PPKI mice compared with wild-type diabetic mice, whereas no alteration was observed in the level of blood glucose. The potential renal protection of overexpressed PTEN in podocytes was partly attributed with an improvement in autophagy and motility and the inhibition of apoptosis. Our results showed that podocyte-specific knockin of PTEN protected the kidney against hyperglycemia in vivo , suggesting that targeting PTEN might be a novel and promising therapeutic strategy against DKD.

scholarly journals The Antioxidant from Ethanolic Extract of Rosa cymosa Fruits Activates Phosphatase and Tensin Homolog In Vitro and In Vivo: A New Insight on Its Antileukemic Effect

2019 ◽  
Vol 20 (8) ◽  
pp. 1935 ◽  
Author(s):  
Kuan-Chih Wang ◽  
Yi-Chang Liu ◽  
Mohamed El-Shazly ◽  
Shou-Ping Shih ◽  
Ying-Chi Du ◽  
...  
Keyword(s):  
Calcium Release ◽  
Herbal Remedy ◽  
Lymphoblastic Leukemia ◽  
Ethanolic Extract ◽  
Control Group ◽  
Ros Generation ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog

Rosa cymosa Tratt is a Chinese herbal remedy that is used in the treatment of diarrhea, burns, rheumatoid arthritis, and hemorrhage. Despite its use in Asian folk medicine, there are limited reports on the biological activity of R. cymosa fruits. This study focused on the investigation of the antitumor effect of the antioxidative ethanolic extract of R. cymosa fruits (RCE) along with its underlying mechanism of action. RCE showed a potent cytotoxic effect against Sup-T1 and Molt-4 lymphoblastic leukemia cells. In the xenograft animal model, the tumor size was significantly reduced to about 59.42% in the RCE-treated group in comparison with the control group. The use of RCE (37.5, 75, or 150 μg/mL) triggered apoptosis by 26.52–83.49%, disrupted mitochondrial membrane potential (MMP) by 10.44–58.60%, and promoted calcium release by 1.29-, 1.44-, and 1.71-fold compared with the control group. The extract induced redox oxygen species (ROS) generation through the elimination of Nrf2/Keap1/P62-mediated oxidative stress response. The loss of phosphatase and tensin homolog (PTEN) activation by RCE impaired PI3K/Akt/Foxo and Jak/Stat activation pathways, which contributed to tumorigenesis. These multiple targets of R. cymosa against hematologic cancer cells suggested its potential application as an antileukemic dietary supplement.

scholarly journals Levosimendan Protects against Doxorubicin-Induced Cardiotoxicity by Regulating the PTEN/Akt Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Ling-Li Li ◽  
Li Wei ◽  
Ning Zhang ◽  
Wen-Ying Wei ◽  
Can Hu ◽  
...  
Keyword(s):  
Critical Role ◽  
Cardiac Injury ◽  
Protective Role ◽  
Akt Inhibitor ◽  
Morphological Examination ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Myocardial Apoptosis

Background and Aims. Myocyte apoptosis plays a critical role in the development of doxorubicin- (DOX-) induced cardiotoxicity. In addition to its cardiotonic effect, laboratory evidence indicates that levosimendan can inhibit apoptosis, but its role in DOX-induced cardiac injury remains unclear. Therefore, the present study is aimed at exploring whether levosimendan could attenuate DOX-induced cardiotoxicity. Methods. Levosimendan (1 mg/kg) was administered to mice through oral gavage once daily for 4 weeks, and the mice were also subjected to an intraperitoneal injection of DOX (5 mg/kg) or saline, once a week for 4 weeks, to create a chronic model of DOX-induced cardiotoxicity. A morphological examination and biochemical analysis were used to evaluate the effects of levosimendan. H9C2 cells were used to verify the protective role of levosimendan in vitro. And an Akt inhibitor was utilized to verify the cardioprotection of levosimendan. Results. Levosimendan reduced the cardiac dysfunction and attenuated the myocardial apoptosis induced by DOX in vivo and in vitro. Levosimendan also inhibited the activation of phosphatase and tensin homolog (PTEN) and upregulated P-Akt expression both in vivo and in vitro. And inhibition of Akt abolished the cardioprotection of levosimendan in vitro. Conclusion. Levosimendan may protect against DOX-induced cardiotoxicity via modulation of the PTEN/Akt signaling pathway.

Production of the plasma-cell survival factor a proliferation-inducing ligand (APRIL) peaks in myeloid precursor cells from human bone marrow

Blood ◽  
2011 ◽  
Vol 118 (7) ◽  
pp. 1838-1844 ◽  
Author(s):  
Thomas Matthes ◽  
Isabelle Dunand-Sauthier ◽  
Marie-Laure Santiago-Raber ◽  
Karl-Heinz Krause ◽  
Olivier Donze ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Plasma Cells ◽  
Myeloid Cells ◽  
Precursor Cells ◽  
Dependent Manner ◽  
Term Survival ◽  
Cell Survival Factor

AbstractThe bone marrow (BM) is an organ extremely efficient in mediating long-term survival of plasma cells (PCs), ensuring an immune humoral memory. This implies that the BM must provide continuously key PC survival factors. Our results show that the BM is an organ constitutively rich in a proliferation-inducing ligand (APRIL), a member of the tumor necrosis factor superfamily implicated in PC survival. APRIL production is induced during hematopoiesis in myeloid cells by non–lineage-committing factors such as stem cell factor, thrombopoietin, IL-3, and FMS-like tyrosine kinase 3 ligand. Notably, APRIL production, both in the human and mouse systems, peaks in myeloid precursor cells, before dropping in fully mature granulocytes. Myeloid cells secrete APRIL that circulates freely in BM plasma to act on PCs, usually at distance from APRIL production sites. Selective APRIL in vivo antagonism and in vitro coculture experiments further demonstrated that myeloid precursor cells mediates PC survival in an APRIL-dependent manner Thus, APRIL production by myeloid precursor cells shows that the 2 main BM functions, hematopoiesis and long-term PC survival, are linked. Such constitutive and high APRIL production may explain why BM mediates long-term PC survival.

scholarly journals 3-Hydroxyolean-12-en-27-oic Acids Inhibit RANKL-Induced Osteoclastogenesis in Vitro and Inflammation-Induced Bone Loss in Vivo

2020 ◽  
Vol 21 (15) ◽  
pp. 5240
Author(s):  
Wonyoung Seo ◽  
Suhyun Lee ◽  
Phuong Thao Tran ◽  
Thi Quynh-Mai Ngo ◽  
Okwha Kim ◽  
...  
Keyword(s):  
Bone Destruction ◽  
Osteoclast Formation ◽  
Bone Diseases ◽  
Marker Genes ◽  
Tartrate Resistant Acid Phosphatase ◽  
Specific Marker ◽  
Nuclear Factor ◽  
Activated T Cells

Olean-12-en-27-oic acids possess a variety of pharmacological effects. However, their effects and underlying mechanisms on osteoclastogenesis remain unclear. This study aimed to investigate the anti-osteoclastogenic effects of five olean-12-en-27-oic acid derivatives including 3α,23-isopropylidenedioxyolean-12-en-27-oic acid (AR-1), 3-oxoolean-12-en-27-oic acid (AR-2), 3α-hydroxyolean-12-en-27-oic acid (AR-3), 23-hydroxy-3-oxoolean-12-en-27-oic acid (AR-4), and aceriphyllic acid A (AR-5). Among the five olean-12-en-27-oic acid derivatives, 3-hydroxyolean-12-en-27-oic acid derivatives, AR-3 and AR-5, significantly inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced mature osteoclast formation by reducing the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts, F–actin ring formation, and mineral resorption activity. AR-3 and AR-5 decreased RANKL-induced expression levels of osteoclast-specific marker genes such as c-Src, TRAP, and cathepsin K (CtsK) as well as c-Fos and nuclear factor of activated T cells cytoplasmic 1 (NFATc1). Mice treated with either AR-3 or AR-5 showed significant protection of the mice from lipopolysaccharide (LPS)-induced bone destruction and osteoclast formation. In particular, AR-5 suppressed RANKL-induced phosphorylation of JNK and ERK mitogen-activated protein kinases (MAPKs). The results suggest that AR-3 and AR-5 attenuate osteoclast formation in vitro and in vivo by suppressing RANKL-mediated MAPKs and NFATc1 signaling pathways and could potentially be lead compounds for the prevention or treatment of osteolytic bone diseases.

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