SIRT1 is a positive regulator of in vivo bone mass and a therapeutic target for osteoporosis

Kayvan Zainabadi; Cassie J Liu; Alison L M Caldwell; Leonard Guarente

doi:10.1371/journal.pone.0185236

SIRT1 is a positive regulator of in vivo bone mass and a therapeutic target for osteoporosis

PLoS One. 2017 Sep 22;12(9):e0185236. doi: 10.1371/journal.pone.0185236. eCollection 2017.

Authors

Kayvan Zainabadi¹, Cassie J Liu¹, Alison L M Caldwell¹, Leonard Guarente¹

Affiliation

¹ Glenn Center for the Science of Aging, Department of Biology, Koch Institute, MIT, Cambridge, Massachusetts, United States of America.

Abstract

Overexpression or pharmacological activation of SIRT1 has been shown to extend the lifespan of mice and protect against aging-related diseases. Here we show that pharmacological activation of SIRT1 protects in two models of osteoporosis. Ovariectomized female mice and aged male mice, models for post-menopausal and aging-related osteoporosis, respectively, show significant improvements in bone mass upon treatment with SIRT1 agonist, SRT1720. Further, we find that calorie restriction (CR) results in a two-fold upregulation of sirt1 mRNA expression in bone tissue that is associated with increased bone mass in CR mice. Reciprocally, SIRT1 whole-body knockout (KO) mice, as well as osteoblast and osteoclast specific KOs, show a low bone mass phenotype; though double knockout mice (containing SIRT1 deleted in both osteoblasts and osteoclasts) do not show a more severe phenotype. Altogether, these findings provide strong evidence that SIRT1 is a positive regulator of bone mass and a promising target for the development of novel therapeutics for osteoporosis.

MeSH terms

Aging / drug effects
Aging / metabolism
Animals
Bone Density / drug effects*
Bone Density / physiology
Bone Density Conservation Agents / pharmacology*
Bone and Bones / diagnostic imaging
Bone and Bones / drug effects*
Bone and Bones / metabolism
Caloric Restriction
Disease Models, Animal
Female
Heterocyclic Compounds, 4 or More Rings / pharmacology*
Male
Mice, 129 Strain
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Transgenic
Osteoblasts / drug effects
Osteoblasts / metabolism
Osteoclasts / drug effects
Osteoclasts / metabolism
Osteoporosis / diagnostic imaging
Osteoporosis / drug therapy*
Osteoporosis / metabolism
Ovariectomy
Phenotype
RNA, Messenger / metabolism
Sirtuin 1 / genetics
Sirtuin 1 / metabolism*

Substances

Bone Density Conservation Agents
Heterocyclic Compounds, 4 or More Rings
RNA, Messenger
SRT1720
Sirt1 protein, mouse
Sirtuin 1

Grants and funding

This work was supported by grants from the NIH and The Glenn Foundation for Medical Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.