Dataset Information

The Sirt1 Activators SRT2183 and SRT3025 Inhibit RANKL-Induced Osteoclastogenesis in Bone Marrow-Derived Macrophages and Down-Regulate Sirt3 in Sirt1 Null Cells.

ABSTRACT: Increased osteoclast-mediated bone resorption is characteristic of osteoporosis, malignant bone disease and inflammatory arthritis. Targeted deletion of Sirtuin1 (Sirt1), a key player in aging and metabolism, in osteoclasts results in increased osteoclast-mediated bone resorption in vivo, making it a potential novel therapeutic target to block bone resorption. Sirt1 activating compounds (STACs) were generated and were investigated in animal disease models and in humans however their mechanism of action was a source of controversy. We studied the effect of SRT2183 and SRT3025 on osteoclastogenesis in bone-marrow derived macrophages (BMMs) in vitro, and discovered that these STACs inhibit RANKL-induced osteoclast differentiation, fusion and resorptive capacity without affecting osteoclast survival. SRT2183 and SRT3025 activated AMPK, increased Sirt1 expression and decreased RelA/p65 lysine310 acetylation, critical for NF-?B activation, and an established Sirt1 target. However, inhibition of osteoclastogenesis by these STACs was also observed in BMMs derived from sirt1 knock out (sirt1-/-) mice lacking the Sirt1 protein, in which neither AMPK nor RelA/p65 lysine 310 acetylation was affected, confirming that these effects require Sirt1, but suggesting that Sirt1 is not essential for inhibition of osteoclastogenesis by these STACs under these conditions. In sirt1 null osteoclasts treated with SRT2183 or SRT3025 Sirt3 was found to be down-regulated. Our findings suggest that SRT2183 and SRT3025 activate Sirt1 and inhibit RANKL-induced osteoclastogenesis in vitro however under conditions of Sirt1 deficiency can affect Sirt3. As aging is associated with reduced Sirt1 level and activity, the influence of STACs on Sirt3 needs to be investigated in vivo in animal and human disease models of aging and osteoporosis.

SUBMITTER: Gurt I

PROVIDER: S-EPMC4520518 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Publications

The Sirt1 Activators SRT2183 and SRT3025 Inhibit RANKL-Induced Osteoclastogenesis in Bone Marrow-Derived Macrophages and Down-Regulate Sirt3 in Sirt1 Null Cells.

Gurt Irina I Artsi Hanna H Cohen-Kfir Einav E Hamdani Gilad G Ben-Shalom Gal G Feinstein Ben B El-Haj Madi M Dresner-Pollak Rivka R

PloS one 20150730 7

Increased osteoclast-mediated bone resorption is characteristic of osteoporosis, malignant bone disease and inflammatory arthritis. Targeted deletion of Sirtuin1 (Sirt1), a key player in aging and metabolism, in osteoclasts results in increased osteoclast-mediated bone resorption in vivo, making it a potential novel therapeutic target to block bone resorption. Sirt1 activating compounds (STACs) were generated and were investigated in animal disease models and in humans however their mechanism of ...[more]

PMID: 26226624

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Project description:BackgroundSkeletal unloading usually induces severe disuse osteoporosis (DOP), which often occurs in patients subjected to prolonged immobility or in spaceflight astronauts. Increasing evidence suggests that exosomes are important mediators in maintaining the balance between bone formation and resorption. We hypothesized that exosomes play an important role in the maintenance of bone homeostasis through intercellular communication between bone marrow mesenchymal stem cells (BMSCs) and osteoclasts under mechanical loading.MethodsCells were divided into cyclic mechanical stretch (CMS)-treated BMSCs and normal static-cultured BMSCs, and exosomes were extracted by ultracentrifugation. After incubation with CMS-treated BMSC-derived exosomes (CMS_Exos) or static-cultured BMSC-derived exosomes (static_Exos), the apoptosis rates of bone marrow macrophages (BMMs) were determined by flow cytometry, and cell viability was detected with a Cell Counting Kit-8 (CCK-8) assay. Osteoclast differentiation was determined with an in vitro osteoclastogenesis assay. Signaling pathway activation was evaluated by western blotting and immunofluorescence staining. Hindlimb unloading (HU)-induced DOP mouse models were prepared to evaluate the function of exosomes in DOP.ResultsBoth CMS_Exos and static_Exos could be internalized by BMMs, and CMS_Exos did not affect BMM viability or increase apoptosis. The CMS_Exos effectively suppressed receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated osteoclastogenesis and F-actin ring formation. Further molecular investigation demonstrated that CMS_Exos impaired osteoclast differentiation via inhibition of the RANKL-induced nuclear factor kappa-B (NF-κB) signaling pathway. Both CMS_Exos and static_Exos partly rescued the osteoporosis caused by mechanical unloading; however, the CMS_Exo group showed more obvious rescue. Treatment with CMS_Exos significantly decreased the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts. Exosomes derived from CMS-treated BMSCs strongly inhibited osteoclast differentiation by attenuating the NF-κB signaling pathway in vitro and rescued osteoporosis caused by mechanical unloading in an HU mouse model in vivo.ConclusionsIn this research, we demonstrated that Exosomes derived from CMS-treated BMSCs inhibited osteoclastogenesis by attenuating NF-κB signaling pathway activity in vitro and ameliorated bone loss caused by mechanical unloading in an HU mouse model, providing new insights into intercellular communication between osteoblasts and osteoclasts under mechanical loading.

Dataset Information

The Sirt1 Activators SRT2183 and SRT3025 Inhibit RANKL-Induced Osteoclastogenesis in Bone Marrow-Derived Macrophages and Down-Regulate Sirt3 in Sirt1 Null Cells.

Publications

The Sirt1 Activators SRT2183 and SRT3025 Inhibit RANKL-Induced Osteoclastogenesis in Bone Marrow-Derived Macrophages and Down-Regulate Sirt3 in Sirt1 Null Cells.

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