Silent information regulator (Sir)T1 inhibits NF-κB signaling to maintain normal skeletal remodeling

Authors

  • James R Edwards,

    Corresponding author
    1. Vanderbilt Center for Bone Biology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
    2. Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
    • Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK OX3 7LD.
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  • Daniel S Perrien,

    1. Vanderbilt Center for Bone Biology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
    2. Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, Nashville, TN, USA
    3. Vanderbilt University Institute of Imaging Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
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  • Nicole Fleming,

    1. Vanderbilt Center for Bone Biology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
    2. Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, Nashville, TN, USA
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  • Jeffry S Nyman,

    1. Vanderbilt Center for Bone Biology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
    2. Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, Nashville, TN, USA
    3. Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA
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  • Koichiro Ono,

    1. Vanderbilt Center for Bone Biology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
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  • Linda Connelly,

    1. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA
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  • Megan M Moore,

    1. Vanderbilt Center for Bone Biology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
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  • Seint T Lwin,

    1. Vanderbilt Center for Bone Biology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
    2. Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
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  • Fiona E Yull,

    1. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA
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  • Gregory R Mundy,

    1. Vanderbilt Center for Bone Biology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
    2. Vanderbilt University Institute of Imaging Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
    3. Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA
    4. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA
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  • Florent Elefteriou

    Corresponding author
    1. Vanderbilt Center for Bone Biology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
    • Vanderbilt Center for Bone Biology, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
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Abstract

Silent information regulator T1 (SirT1) is linked to longevity and negatively controls NF-κB signaling, a crucial mediator of survival and regulator of both osteoclasts and osteoblasts. Here we show that NF-κB repression by SirT1 in both osteoclasts and osteoblasts is necessary for proper bone remodeling and may contribute to the mechanisms linking aging and bone loss. Osteoclast- or osteoblast-specific SirT1 deletion using the Sirtflox/flox mice crossed to lysozyme M-cre and the 2.3 kb col1a1-cre transgenic mice, respectively, resulted in decreased bone mass caused by increased resorption and reduced bone formation. In osteoclasts, lack of SirT1 promoted osteoclastogenesis in vitro and activated NF-κB by increasing acetylation of Lysine 310. Importantly, this increase in osteoclastogenesis was blocked by pharmacological inhibition of NF-κB. In osteoblasts, decreased SirT1 reduced osteoblast differentiation, which could also be rescued by inhibition of NF-κB. In further support of the critical role of NF-κB signaling in bone remodeling, elevated NF-κB activity in IκBα+/− mice uncoupled bone resorption and formation, leading to reduced bone mass. These findings support the notion that SirT1 is a genetic determinant of bone mass, acting in a cell-autonomous manner in both osteoblasts and osteoclasts, through control of NF-κB and bone cell differentiation. © 2013 American Society for Bone and Mineral Research.

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