SIRT6-PAI-1 axis is a promising therapeutic target in aging-related bone metabolic disruption
説明
<jats:title>Abstract</jats:title><jats:p>The mechanistic regulation of bone mass in aged animals is poorly understood. In this study, we examined the role of SIRT6, a longevity-associated factor, in osteocytes, using mice lacking <jats:italic>Sirt6</jats:italic> in <jats:italic>Dmp-1</jats:italic>-expressing cells (cKO mice) and the MLO-Y4 osteocyte-like cell line. cKO mice exhibited increased osteocytic expression of <jats:italic>Sost, Fgf23</jats:italic> and senescence inducing gene <jats:italic>Pai-1</jats:italic> and the senescence markers <jats:italic>p16</jats:italic> and <jats:italic>Il-6</jats:italic>, decreased serum phosphate levels, and low-turnover osteopenia. The cKO phenotype was reversed in mice that were a cross of PAI-1-null mice with cKO mice. Furthermore, senescence induction in MLO-Y4 cells increased the <jats:italic>Fgf23</jats:italic> and <jats:italic>Sost</jats:italic> mRNA expression. <jats:italic>Sirt6</jats:italic> knockout and senescence induction increased HIF-1α binding to the <jats:italic>Fgf23</jats:italic> enhancer sequence. Bone mass and serum phosphate levels were higher in PAI-1-null aged mice than in wild-type mice. Therefore, SIRT6 agonists or PAI-1 inhibitors may be promising therapeutic options for aging-related bone metabolism disruptions.</jats:p>
収録刊行物
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- Scientific Reports
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Scientific Reports 13 (1), 2023-05-17
Springer Science and Business Media LLC