The sirtuin1 activator SRT3025 down-regulates sclerostin and rescues ovariectomy-induced bone loss and biomechanical deterioration in female mice

Hanna Artsi, Einav Cohen-Kfir, Irina Gurt, Ron Shahar, Alon Bajayo, Noga Kalish, Teresita Bellido, Yankel Gabet, Rivka Dresner-Pollak

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Estrogen deficiency leads to rapid bone loss and skeletal fragility. Sclerostin, encoded by the sost gene, and a product of the osteocyte, is a negative regulator of bone formation. Blocking sclerostin increases bone mass and strength in animals and humans. Sirtuin1 (Sirt1), a player in aging and metabolism, regulates bone mass and inhibits sost expression by deacetylating histone 3 at its promoter.Weasked whether a Sirt1-activating compound could rescue ovariectomy (OVX)-induced bone loss and biomechanical deterioration in 9-week-old C57BL/6 mice. OVX resulted in a substantial decrease in skeletal Sirt1 expression accompanied by an increase in sclerostin. Oral administration of SRT3025, a Sirt1 activator, at 50 and 100 mg/kg.d for 6 weeks starting 6 weeks after OVX fully reversed the deleterious effects of OVX on vertebral bone mass, microarchitecture, and femoral biomechanical properties. Treatment with SRT3025 decreased bone sclerostin expression and increased cortical periosteal mineralizing surface and serum propeptide of type I procollagen, a bone formation marker. In vitro, in the murinelongboneosteocyte-Y4 osteocyte-like cell lineSRT3025down-regulated sclerostinandinactive β-catenin, whereas a reciprocal effect was observed with EX-527, a Sirt1 inhibitor. Sirt1 activation by Sirt1-activating compounds is a potential novel pathway to down-regulate sclerostin and design anabolic therapies for osteoporosis concurrently ameliorating other metabolic and age-associated conditions. Copyright

Original languageEnglish
Pages (from-to)3508-3515
Number of pages8
JournalEndocrinology
Volume155
Issue number9
DOIs
StatePublished - Sep 1 2014

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Ovariectomy
Down-Regulation
Bone and Bones
Osteocytes
Osteogenesis
Catenins
Collagen Type I
Thigh
Inbred C57BL Mouse
Histones
Osteoporosis
Oral Administration
SRT3025
Estrogens
Therapeutics
Serum
Genes

ASJC Scopus subject areas

  • Endocrinology

Cite this

The sirtuin1 activator SRT3025 down-regulates sclerostin and rescues ovariectomy-induced bone loss and biomechanical deterioration in female mice. / Artsi, Hanna; Cohen-Kfir, Einav; Gurt, Irina; Shahar, Ron; Bajayo, Alon; Kalish, Noga; Bellido, Teresita; Gabet, Yankel; Dresner-Pollak, Rivka.

In: Endocrinology, Vol. 155, No. 9, 01.09.2014, p. 3508-3515.

Research output: Contribution to journalArticle

Artsi, H, Cohen-Kfir, E, Gurt, I, Shahar, R, Bajayo, A, Kalish, N, Bellido, T, Gabet, Y & Dresner-Pollak, R 2014, 'The sirtuin1 activator SRT3025 down-regulates sclerostin and rescues ovariectomy-induced bone loss and biomechanical deterioration in female mice', Endocrinology, vol. 155, no. 9, pp. 3508-3515. https://doi.org/10.1210/en.2014-1334
Artsi, Hanna ; Cohen-Kfir, Einav ; Gurt, Irina ; Shahar, Ron ; Bajayo, Alon ; Kalish, Noga ; Bellido, Teresita ; Gabet, Yankel ; Dresner-Pollak, Rivka. / The sirtuin1 activator SRT3025 down-regulates sclerostin and rescues ovariectomy-induced bone loss and biomechanical deterioration in female mice. In: Endocrinology. 2014 ; Vol. 155, No. 9. pp. 3508-3515.
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