Sirt1 Is a Regulator of Bone Mass and a Repressor of Sost Encoding for Sclerostin, a Bone Formation Inhibitor

Abstract

Sirt1, the mammalian ortholog of the yeast Sir2 (silent information regulator 2), was shown to play an important role in metabolism and in age-associated diseases, but its role in skeletal homeostasis and osteoporosis has yet not been studied. Using 129/Sv mice with a germline mutation in the Sirt1 gene, we demonstrate that Sirt1 haplo-insufficient (Sirt1(+/-)) female mice exhibit a significant reduction in bone mass characterized by decreased bone formation and increased marrow adipogenesis. Importantly, we identify Sost, encoding for sclerostin, a critical inhibitor of bone formation, as a novel target of Sirt1. Using chromatin immunoprecipitation analysis, we reveal that Sirt1 directly and negatively regulates Sost gene expression by deacetylating histone 3 at lysine 9 at the Sost promoter. Sost down-regulation by small interfering RNA and the administration of a sclerostin-neutralizing antibody restore gene expression of osteocalcin and bone sialoprotein as well as mineralized nodule formation in Sirt1(+/-) marrow-derived mesenchymal stem cells induced to osteogenesis. These findings reveal a novel role for Sirt1 in bone as a regulator of bone mass and a repressor of sclerostin, and have potential implications suggesting that Sirt1 is a target for promoting bone formation as an anabolic approach for treatment of osteoporosis.

Sirtuin1 (Sirt1) Promotes Cortical Bone Formation by Preventing β-Catenin Sequestration by FoxO Transcription Factors in Osteoblast Progenitors

“…The effects of Sirt1 deletion were readily seen in females but not in males. Similar female-specific effects of Sirt1 in the skeleton have been reported by others (8). A potential explanation for these findings could be cross-talk between Sirt1 and estrogen receptor ␣ (ER␣), documented in other cell types (33).…”

“…Attenuation of ␤-catenin/TCF transcription by FoxOs in osteoblast progeni- tors restrains their proliferation and decreases bone formation and mass (7). Germline deletion or overexpression of Sirt1 decreases or increases bone mass, respectively (8,9). In line with this evidence, Sirt1 stimulators, such as resveratrol or SRT2140, prevent the loss of bone mass caused by unloading (10,11), ovariectomy (12), or aging (11,13).…”

“…Cohen-Kfir et al (8) have previously suggested that Sirt1-mediated repression of Sost expression, one of the secreted inhibitors of the Wnt pathway, contributes to the stimulatory actions of Sirt1 on bone formation. To examine whether this was the case in our model, we quantified the mRNA levels of Sost in vertebral bone lysates from Sirt1 ⌬Osx1 mice.…”

The Wnt Inhibitor Sclerostin Is Up-regulated by Mechanical Unloading in Osteocytes in Vitro

“…Notably, no changes in mRNA of transcripts responsible for PGE 2 production, PGE 2 degradation, or PGE 2 receptors were observed between static and unloaded cultures, implying that the increases of SOST/ sclerostin in mechanical unloading are presumably not arising from changes in the PGE 2 pathway. Several transcription factors have also been reported to suppress the SOST promoter (like SIRT1 and osterix) (58,59) or act at the distal enhancer (ECR5) (like TGF␤ 1-3 ) (47). However, in the context of mechanical unloading, we observed no change in SIRT1, osterix, or TGF␤ 1-3 mRNAs (Table 2).…”

Sirtuin 1 Is a Negative Regulator of Parathyroid Hormone Stimulation of Matrix Metalloproteinase 13 Expression in Osteoblastic Cells

“…SIRT1 is involved in a variety of human diseases (33,36,37), including bone diseases. SIRT1 has many functions in bone; global Sirt1 deletion (19,38,39) and osteoblast-specific Sirt1 deletion (18,20,38) lead to reduced bone formation. Potentially, SIRT1 regulates osteoblast differentiation and bone formation through regulation of the transcription factor Runx2 (40,41).…”