Deletion of IGF-1 Receptors in Cardiomyocytes Attenuates Cardiac Aging in Male Mice

Abstract IGF-1 receptor (IGF-1R) signaling is implicated in cardiac hypertrophy and longevity. However, the role of IGF-1R in age-related cardiac remodeling is only partially understood. We therefore sought to determine whether the deletion of the IGF-1R in cardiomyocytes might delay the development of aging-associated myocardial pathologies by examining 2-year-old male cardiomyocyte-specific IGF-1R knockout (CIGF1RKO) mice. Aging was associated with the induction of IGF-1R expression in hearts. Cardiomyocytes hypertrophied with age in wild-type (WT) mice. In contrast, the cardiac hypertrophic response associated with aging was blunted in CIGF1RKO mice. Concomitantly, fibrosis was reduced in aged CIGF1RKO compared with aged WT hearts. Expression of proinflammatory cytokines such as IL-1α, IL-1β, IL-6, and receptor activator of nuclear factor-κB ligand was increased in aged WT hearts, but this increase was attenuated in aged CIGF1RKO hearts. Phosphorylation of Akt was increased in aged WT, but not in aged CIGF1RKO, hearts. In cultured cardiomyocytes, IGF-1 induced senescence as demonstrated by increased senescence-associated β-galactosidase staining, and a phosphoinositide 3-kinase inhibitor inhibited this effect. Furthermore, inhibition of phosphoinositide 3-kinase significantly prevented the increase in IL-1α, IL-1β, receptor activator of nuclear factor-κB ligand, and p21 protein expression by IGF-1. These data reveal an essential role for the IGF-1-IGF-1R-Akt pathway in mediating cardiomyocyte senescence.

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Akt isoforms differentially regulate neutrophil functions

Blood ◽

10.1182/blood-2009-11-255323 ◽

2010 ◽

Vol 115 (21) ◽

pp. 4237-4246 ◽

Cited By ~ 73

Author(s):

Jia Chen ◽

Haiyang Tang ◽

Nissim Hay ◽

Jingsong Xu ◽

Richard D. Ye

Keyword(s):

Kinase Inhibitor ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Leading Edge ◽

Neutrophil Activation ◽

Enzyme Release ◽

Wild Type ◽

Akt Isoforms ◽

Phosphoinositide 3 Kinase ◽

O2 Production

In neutrophils, the phosphoinositide 3-kinase/Akt signaling cascade is involved in migration, degranulation, and O2− production. However, it is unclear whether the Akt kinase isoforms have distinct functions in neutrophil activation. Here we report functional differences between the 2 major Akt isoforms in neutrophil activation on the basis of studies in which we used individual Akt1 and Akt2 knockout mice. Akt2−/− neutrophils exhibited decreased cell migration, granule enzyme release, and O2− production compared with wild-type and Akt1−/− neutrophils. Surprisingly, Akt2 deficiency and pharmacologic inhibition of Akt also abrogated phorbol ester-induced O2− production, which was unaffected by treatment with the phosphoinositide 3-kinase inhibitor LY294002. The decreased O2− production in Akt2−/− neutrophils was accompanied by reduced p47phox phosphorylation and its membrane translocation, suggesting that Akt2 is important for the assembly of phagocyte nicotinamide adenine dinucleotide phosphate oxidase. In wild-type neutrophils, Akt2 but not Akt1 translocated to plasma membrane upon chemoattractant stimulation and to the leading edge in polarized neutrophils. In the absence of Akt2, chemoattractant-induced Akt protein phosphorylation was significantly reduced. These results demonstrate a predominant role of Akt2 in regulating neutrophil functions and provide evidence for differential activation of the 2 Akt isoforms in neutrophils.

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Pyridone 6, A Pan-Janus-Activated Kinase Inhibitor, Suppresses Osteoclast Formation and Bone Resorption through Down-Regulation of Receptor Activator of Nuclear Factor-κB (NF-κB) Ligand (RANKL)-Induced c-Fos and Nuclear Factor of Activated T Cells (NFAT) c1 Expression

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.32.45 ◽

2009 ◽

Vol 32 (1) ◽

pp. 45-50 ◽

Cited By ~ 10

Author(s):

Han Bok Kwak ◽

Hun Soo Kim ◽

Myeung Su Lee ◽

Kwang-Jin Kim ◽

Eun-Yong Choi ◽

...

Keyword(s):

T Cells ◽

Bone Resorption ◽

Kinase Inhibitor ◽

Nuclear Factor Κb ◽

Osteoclast Formation ◽

Nuclear Factor ◽

Down Regulation ◽

Activated T Cells ◽

Receptor Activator

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The Role of miR-21 in Osteoblasts–Osteoclasts Coupling In Vitro

Cells ◽

10.3390/cells9020479 ◽

2020 ◽

Vol 9 (2) ◽

pp. 479 ◽

Cited By ~ 4

Author(s):

Agnieszka Smieszek ◽

Klaudia Marcinkowska ◽

Ariadna Pielok ◽

Mateusz Sikora ◽

Lukas Valihrach ◽

...

Keyword(s):

Cathepsin K ◽

Nuclear Factor Κb ◽

Tartrate Resistant Acid Phosphatase ◽

Type I ◽

Nuclear Factor ◽

Paracrine Signaling ◽

Receptor Activator ◽

The Impact

MiR-21 is being gradually more and more recognized as a molecule regulating bone tissue homeostasis. However, its function is not fully understood due to the dual role of miR-21 on bone-forming and bone-resorbing cells. In this study, we investigated the impact of miR-21 inhibition on pre-osteoblastic cells differentiation and paracrine signaling towards pre-osteoclasts using indirect co-culture model of mouse pre-osteoblast (MC3T3) and pre-osteoclast (4B12) cell lines. The inhibition of miR-21 in MC3T3 cells (MC3T3inh21) modulated expression of genes encoding osteogenic markers including collagen type I (Coll-1), osteocalcin (Ocl), osteopontin (Opn), and runt-related transcription factor 2 (Runx-2). Inhibition of miR-21 in osteogenic cultures of MC3T3 also inflected the synthesis of OPN protein which is essential for proper mineralization of extracellular matrix (ECM) and anchoring osteoclasts to the bones. Furthermore, it was shown that in osteoblasts miR-21 regulates expression of factors that are vital for survival of pre-osteoclast, such as receptor activator of nuclear factor κB ligand (RANKL). The pre-osteoclast cultured with MC3T3inh21 cells was characterized by lowered expression of several markers associated with osteoclasts’ differentiation, foremost tartrate-resistant acid phosphatase (Trap) but also receptor activator of nuclear factor-κB ligand (Rank), cathepsin K (Ctsk), carbonic anhydrase II (CaII), and matrix metalloproteinase (Mmp-9). Collectively, our data indicate that the inhibition of miR-21 in MC3T3 cells impairs the differentiation and ECM mineralization as well as influences paracrine signaling leading to decreased viability of pre-osteoclasts.

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Interleukin-6 Inhibits Receptor Activator of Nuclear Factor κB Ligand-Induced Osteoclastogenesis by Diverting Cells into the Macrophage Lineage: Key Role of Serine727 Phosphorylation of Signal Transducer and Activator of Transcription 3

Endocrinology ◽

10.1210/en.2007-1719 ◽

2008 ◽

Vol 149 (7) ◽

pp. 3688-3697 ◽

Cited By ~ 89

Author(s):

Laurence Duplomb ◽

Marc Baud’huin ◽

Céline Charrier ◽

Martine Berreur ◽

Valérie Trichet ◽

...

Keyword(s):

Osteoclast Differentiation ◽

Nuclear Factor Κb ◽

Mouse Bone Marrow ◽

Nuclear Factor ◽

Signal Transducer ◽

Blood Monocytes ◽

Receptor Activator ◽

Few Data ◽

Macrophage Lineage

Osteoclasts are bone-resorptive cells that differentiate from hematopoietic precursors upon receptor activator of nuclear factor κB ligand (RANKL) activation. Previous studies demonstrated that IL-6 indirectly stimulates osteoclastogenesis through the production of RANKL by osteoblasts. However, few data described the direct effect of IL-6 on osteoclasts. To investigate this effect, we used several models: murine RAW264.7 cells, mouse bone marrow, and human blood monocytes. In the three models used, the addition of IL-6 inhibited RANKL-induced osteoclastogenesis. Furthermore, IL-6 decreased the expression of osteoclast markers and up-modulated macrophage markers. To elucidate this inhibition, signal transducer and activator of transcription (STAT) 3, the main signaling molecule activated by IL-6, was analyzed. Addition of two STAT3 inhibitors completely abolished RANKL-induced osteoclastogenesis, revealing a key role of STAT3. We demonstrated that a basal level of phosphorylated-STAT3 on Serine727 associated with an absence of phosphorylation on Tyrosine705 is essential for osteoclastogenesis. Furthermore, a decrease of Serine727 phosphorylation led to an inhibition of osteoclast differentiation, whereas an increase of Tyrosine705 phosphorylation upon IL-6 stimulation led to the formation of macrophages instead of osteoclasts. In conclusion, we showed for the first time that IL-6 inhibits RANKL-induced osteoclastogenesis by diverting cells into the macrophage lineage, and demonstrated the functional role of activated-STAT3 and its form of phosphorylation in the control of osteoclastogenesis.

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Parathyroid Hormone-Related Protein (PTHrP) Accelerates Soluble RANKL Signals for Downregulation of Osteogenesis of Bone Mesenchymal Stem Cells

Journal of Clinical Medicine ◽

10.3390/jcm8060836 ◽

2019 ◽

Vol 8 (6) ◽

pp. 836 ◽

Cited By ~ 3

Author(s):

Jeevithan Elango ◽

Saeed Ur Rahman ◽

Yves Henrotin ◽

José Eduardo Maté Sánchez de Val ◽

Bin Bao ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Parathyroid Hormone ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Related Protein ◽

Bone Mesenchymal Stem Cells ◽

Parathyroid Hormone Related Protein ◽

Receptor Activator

A recent study reported the expression of receptor activator of nuclear factor-κB (RANK) in mesenchymal stem cells (MSCs) surface that negatively regulates osteogenesis of MSCs. Empirical evidence from the previous study confirmed the role of parathyroid hormone-related protein (PTHrP) in osteoblastogenesis. However, it is necessary to understand the paracrine role of PTHrP and RANKL for osteogenesis in order to explore the hidden secrets in bone biology. Considering the above concept, paracrine cues of soluble-receptor activator of nuclear factor-κB ligand (sRANKL) and PTHrP in osteogenic differentiation of MSCs were investigated. Our results confirmed that sRANKL increased the expression of surface-RANK in MSCs at the earlier stage of osteogenesis, which was downregulated later in differentiated MSCs. In contrast, RANKL expression was low at the earlier stage of MSCs proliferation and high at the differentiation stage of MSCs, which may play a fundamental role in osteoclast formation. sRANKL downregulated osteogenesis of MSCs by decreasing progressive ankylosis (ANK) protein expression while PTHrP upregulated the osteogenic exploitive effect of sRANKL. Interestingly, when they were co-cultured with MSCs, T-lymphocytes expressed high membrane-RANKL levels that contribute to osteogenesis inhibition during MSC differentiation. Thus, our results disclose that sRANKL treatment downregulates osteogenesis of MSCs by increasing RANK expression at the earlier stage of differentiation and by inhibiting ANK. Further, we demonstrated that PTHrP accelerated the downregulating osteogenic effect of sRANKL.

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Role of Osteoprotegerin and Receptor Activator of Nuclear Factor-κB Ligand in Bone Loss Related to Advanced Chronic Obstructive Pulmonary Disease

Chinese Medical Journal ◽

10.4103/0366-6999.185857 ◽

2016 ◽

Vol 129 (14) ◽

pp. 1696-1703 ◽

Cited By ~ 3

Author(s):

Ludmila Ugay ◽

Evgenia Kochetkova ◽

Vera Nevzorova ◽

Yuliya Maistrovskaia

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Bone Loss ◽

Pulmonary Disease ◽

Nuclear Factor Κb ◽

Chronic Obstructive ◽

Nuclear Factor ◽

Obstructive Pulmonary Disease ◽

Receptor Activator

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A Role for Site-Specific Phosphorylation of Mouse Progesterone Receptor at Serine 191 in Vivo

Molecular Endocrinology ◽

10.1210/me.2014-1206 ◽

2014 ◽

Vol 28 (12) ◽

pp. 2025-2037 ◽

Cited By ~ 3

Author(s):

Sandra L. Grimm ◽

Robert D. Ward ◽

Alison E. Obr ◽

Heather L. Franco ◽

Rodrigo Fernandez-Valdivia ◽

...

Keyword(s):

Mammary Epithelial Cells ◽

Phosphorylation Site ◽

Three Dimensional ◽

Progesterone Receptors ◽

Nuclear Factor Κb ◽

Mammary Epithelial ◽

Nuclear Factor ◽

Wild Type ◽

Receptor Activator

Progesterone receptors (PRs) are phosphorylated on multiple sites, and a variety of roles for phosphorylation have been suggested by cell-based studies. Previous studies using PR-null mice have shown that PR plays an important role in female fertility, regulation of uterine growth, the uterine decidualization response, and proliferation as well as ductal side-branching and alveologenesis in the mammary gland. To study the role of PR phosphorylation in vivo, a mouse was engineered with homozygous replacement of PR with a PR serine-to-alanine mutation at amino acid 191. No overt phenotypes were observed in the mammary glands or uteri of PR S191A treated with progesterone (P4). In contrast, although PR S191A mice were fertile, litters were 19% smaller than wild type and the estrous cycle was lengthened slightly. Moreover, P4-dependent gene regulation in primary mammary epithelial cells (MECs) was altered in a gene-selective manner. MECs derived from wild type and PR S191A mice were grown in a three-dimensional culture. Both formed acinar structures that were morphologically similar, and proliferation was stimulated equally by P4. However, P4 induction of receptor activator of nuclear factor-κB ligand and calcitonin was selectively reduced in S191A cultures. These differences were confirmed in freshly isolated MECs. Chromatin immunoprecipitation analysis showed that the binding of S191A PR to some of the receptor activator of nuclear factor-κB ligand enhancers and a calcitonin enhancer was substantially reduced. Thus, the elimination of a single phosphorylation site is sufficient to modulate PR activity in vivo. PR contains many phosphorylation sites, and the coordinate regulation of multiple sites is a potential mechanism for selective modulation of PR function.

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