Sirt1 Promotes Osteogenic Differentiation and Increases Alveolar Bone Mass via Bmi1 Activation in Mice

Abstract

Sirtuin 1 (Sirt1), a protein deacetylase, is a novel target for bone metabolism. To investigate whether overexpression of Sirt1 in mandibular mesenchymal stem cells (M-MSCs) increased alveolar bone mass in vivo, we generated Sirt1 transgenic mice (Sirt1 TG ), with Sirt1 gene expression driven by the Prx1 gene, which represents the mesenchymal lineage. Our results demonstrated that overexpression of Sirt1 in M-MSCs increased the alveolar bone volume in 1-month-old, 9-month-old, and 18-month-old Sirt1 TG mice compared with age-matched wild-type (WT) mice, and in ovariectomized Sirt1 TG mice compared with ovariectomized WT mice by stimulating M-MSC differentiation into osteoblasts. Treatment with resveratrol, a Sirt1 activator, increased Sirt1 binding with Bmi1 and reduced Bmi1 acetylation in a dose-dependent manner demonstrated in M-MSC cultures. Both treatment with resveratrol in M-MSC cultures and overexpressed Sirt1 in M-MSCs ex vivo cultures increased nuclear translocation of Bmi1. Furthermore, we demonstrated that deletion of Bmi1 blocked the increased alveolar bone volume in Sirt1 TG mice. The Sirt1 activator resveratrol inhibited human MSC senescence and promoted their differentiation into osteoblasts, which were associated with upregulating the expression levels of Sirt1 and nuclear translocation of Bmi1. The present results suggested that Sirt1 promotes MSC proliferation and osteogenic differentiation, inhibits MSC senescence to increase alveolar bone volume by promoting the deacetylation and nuclear translocation of Bmi1. Thus, our study elucidated the mechanism by which Sirt1 increases alveolar bone mass, and these findings are important for the clinical application of the Sirt1 activator resveratrol for the promotion of alveolar bone formation and prevention of alveolar bone loss.

The role of sirtuin 1 and its activator, resveratrol in osteoarthritis

“…Other factors were also involved in the process of SIRT1 regulation of MSC, such as the activation of the adenosine monophosphate-activated protein kinase (AMPK)-SIRT1 signaling pathway as well as beneficial mechanical stretch to induce antioxidant responses, attenuate intracellular reactive oxygen species (ROS), and improve osteogenesis of human BM-MSCs [52]. In mice, Sirt1 promotes MSC proliferation and osteogenic differentiation and inhibits MSC senescence via Bmi1 activation; therefore, treatment with resveratrol could promote bone formation and prevent bone loss [53]. SIRT1 was also directly involved in the regulation of beige adipocyte differentiation.…”

Melatonin Reverses the Loss of Stemness Induced by TNF-α in Human Bone Marrow Mesenchymal Stem Cells through Upregulation of YAP Expression

“…For in vitro generation and origination, the stemness of MSCs can be maintained in the early and middle generations of in vitro growth. However, stemness can experience a significant reduction once a critical time is exceeded [36,37]. Meanwhile, stem cells from different tissue sources have significant differences in their abilities to maintain stemness during in vitro culture.…”

Nicotinamide mononucleotide attenuates glucocorticoid‑induced osteogenic inhibition by regulating the SIRT1/PGC‑1α signaling pathway

“…Qu et al (43) revealed that SIRT1 was involved in osteogenic proliferation and differentiation by regulating miR-132-3p. Furthermore, Wang et al (44) demonstrated that SIRT1 promotes osteogenic differentiation and increases alveolar bone mass via B cell-specific Moloney murine leukemia virus integration site 1. in the present study, the expression of SIRT1 and its downstream target PGc-1α was discovered to be decreased in osteoblasts exposed to Dex. Therefore, it was speculated that the SIRT1/PGC-1α signaling pathway played an important role in the protective effects of NMN in Dex-treated BMSCs.…”