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SIRT6-PAI-1 axis is a promising therapeutic target in aging-related bone metabolic disruption

Alkebaier Aobulikasimu1, Tao Liu1, Jinying Piao1

  • 1Department of Orthopedics Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyo-Ku, Tokyo, 113-8519, Japan.

Scientific Reports
|May 17, 2023
PubMed

Insights

Sirtuin 6 (SIRT6) deficiency in osteocytes accelerates aging bone loss by promoting senescence and altering bone metabolism. Restoring PAI-1 levels reversed these effects, suggesting therapeutic potential.

Area of Science:

  • Gerontology and Bone Biology
  • Molecular Mechanisms of Aging
  • Skeletal Physiology

Background:

  • The regulation of bone mass in aging animals is not well understood.
  • Sirtuin 6 (SIRT6), a longevity-associated factor, plays a role in cellular regulation.
  • Osteocytes are key cells in maintaining bone homeostasis.

Purpose of the Study:

  • To investigate the role of SIRT6 in osteocytes concerning bone mass regulation in aged animals.
  • To elucidate the molecular mechanisms linking SIRT6 deficiency, senescence, and bone loss.

Main Methods:

  • Generated mice with Sirt6 specifically deleted in osteocytes (cKO mice) using Dmp-1-Cre.
  • Utilized the MLO-Y4 osteocyte-like cell line for in vitro experiments.
  • Analyzed gene expression (Sost, Fgf23, Pai-1, p16, Il-6), serum phosphate, bone mass, and senescence markers.
  • Investigated the effect of crossing cKO mice with PAI-1-null mice.
  • Examined HIF-1α binding to the Fgf23 enhancer sequence.

Main Results:

  • Sirt6 deletion in osteocytes led to increased expression of Sost, Fgf23, Pai-1, p16, and Il-6, indicating enhanced senescence.
  • cKO mice showed decreased serum phosphate levels and low-turnover osteopenia.
  • The cKO phenotype was ameliorated in mice lacking PAI-1, and aged PAI-1-null mice had higher bone mass.
  • Senescence induction in osteocyte-like cells increased Fgf23 and Sost mRNA.
  • Sirt6 knockout and senescence increased HIF-1α binding to the Fgf23 enhancer.

Conclusions:

  • SIRT6 deficiency in osteocytes promotes senescence and contributes to aging-related bone loss.
  • PAI-1 plays a critical role in the SIRT6-mediated regulation of bone metabolism and senescence.
  • SIRT6 agonists or PAI-1 inhibitors represent potential therapeutic strategies for age-related bone disorders.

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