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

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

doi:10.1371/journal.pone.0185236

Cited by 95 publications

(76 citation statements)

References 60 publications

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“…In mammalian cells, SIRT1 is found predominantly in the nucleus to remove acyl groups from histones and a number of cellular targets (316). The action of SIRT1 is protective against osteoporosis, acting as a positive regulator of bone mass in mice (317,318). This may be mediated by forkhead transcription factors of class O (FoxO) proteins (319) or under inflammatory conditions, through negative regulation of NF-B signaling (320,321).…”

Section: Parp Nad ؉ Metabolism and Inflammationmentioning

confidence: 99%

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

Brady

Goel

Johnson

2019

Microbiol Mol Biol Rev

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SUMMARYThe literature review presented here details recent research involving members of the poly(ADP-ribose) polymerase (PARP) family of proteins. Among the 17 recognized members of the family, the human enzyme PARP1 is the most extensively studied, resulting in a number of known biological and metabolic roles. This review is focused on the roles played by PARP enzymes in host-pathogen interactions and in diseases with an associated inflammatory response. In mammalian cells, several PARPs have specific roles in the antiviral response; this is perhaps best illustrated by PARP13, also termed the zinc finger antiviral protein (ZAP). Plant stress responses and immunity are also regulated by poly(ADP-ribosyl)ation. PARPs promote inflammatory responses by stimulating proinflammatory signal transduction pathways that lead to the expression of cytokines and cell adhesion molecules. Hence, PARP inhibitors show promise in the treatment of inflammatory disorders and conditions with an inflammatory component, such as diabetes, arthritis, and stroke. These functions are correlated with the biophysical characteristics of PARP family enzymes. This work is important in providing a comprehensive understanding of the molecular basis of pathogenesis and host responses, as well as in the identification of inhibitors. This is important because the identification of inhibitors has been shown to be effective in arresting the progression of disease.

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Section: Parp Nad ؉ Metabolism and Inflammationmentioning

confidence: 99%

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

Brady

Goel

Johnson

2019

Microbiol Mol Biol Rev

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“…Caloric restriction from adulthood to old age in rodents attenuates skeletal aging . In addition, a recent study in which calorie restriction was initiated during adulthood (at 4 months of age) in C57BL/6J male mice, and maintained for 4 or 8 months, show a marked increase in bone mass . The beneficial effects of caloric restriction on bone mass are associated with a twofold induction of Sirt1 expression in bone, as seen in other tissues .…”

Section: Deregulated Nutrient Sensingmentioning

confidence: 99%

“…The stimulatory actions of Sirt1 on osteoblastogenesis might also be mediated by direct effects on β‐catenin and Runx2 . On the other hand, Sirt1 in osteoclasts inhibits bone resorption …”

Section: Deregulated Nutrient Sensingmentioning

confidence: 99%

“…The beneficial effects of caloric restriction on bone mass are associated with a twofold induction of Sirt1 expression in bone, as seen in other tissues . Importantly, long‐term administration of Sirt1 activators or overexpression of Sirt1 attenuates the loss of bone mass with aging . Sirt1 stimulators also cause significant increases in bone mass in the ovariectomy or hind limb unloading models of osteoporosis .…”

Section: Deregulated Nutrient Sensingmentioning

confidence: 99%

“…(106,108) On the other hand, Sirt1 in osteoclasts inhibits bone resorption. (109,110) Dietary restriction upregulates Sirt1 and increases lifespan or healthspan in all investigated species, including lower organisms, mice, and nonhuman primates, (62,111,112) underlying the relevance of deregulated nutrient-sensing as a hallmark of aging. Caloric restriction from adulthood to old age in rodents attenuates skeletal aging.…”

Section: Sirtuinsmentioning

confidence: 99%

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The Spectrum of Fundamental Basic Science Discoveries Contributing to Organismal Aging

Farr

Almeida

2018

Journal of Bone and Mineral Research

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Aging research has undergone unprecedented advances at an accelerating rate in recent years, leading to excitement in the field as well as opportunities for imagination and innovation. Novel insights indicate that, rather than resulting from a preprogrammed series of events, the aging process is predominantly driven by fundamental non-adaptive mechanisms that are interconnected, linked, and overlap. To varying degrees, these mechanisms also manifest with aging in bone where they cause skeletal fragility. Because these mechanisms of aging can be manipulated, it might be possible to slow, delay, or alleviate multiple age-related diseases and their complications by targeting conserved genetic signaling pathways, controlled functional networks, and basic biochemical processes. Indeed, findings in various mammalian species suggest that targeting fundamental aging mechanisms (eg, via either loss-of-function or gain-of-function mutations or administration of pharmacological therapies) can extend healthspan; ie, the healthy period of life free of chronic diseases. In this review, we summarize the evidence supporting the role of the spectrum of fundamental basic science discoveries contributing to organismal aging, with emphasis on mammalian studies and in particular aging mechanisms in bone that drive skeletal fragility. These mechanisms or aging hallmarks include: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Because these mechanisms are linked, interventions that ameliorate one hallmark can in theory ameliorate others. In the field of bone and mineral research, current challenges include defining the relative contributions of each aging hallmark to the natural skeletal aging process, better understanding the complex interconnections among the hallmarks, and identifying the most effective therapeutic strategies to safely target multiple hallmarks. Based on their interconnections, it may be feasible to simultaneously interfere with several fundamental aging mechanisms to alleviate a wide spectrum of age-related chronic diseases, including osteoporosis. © 2018 American Society for Bone and Mineral Research.

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SIRT1/Notch1 signal axis involves in the promoting effect of Segetalin B on bone formation

Lan

Cheng

et al. 2022

Drug Development Research

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Phytoestrogens are a class of potential natural medicines for treating postmenopausal osteoporosis (PMOP). Segetalin B (SB) is a cyclic peptide compound showing estrogenic activity. This study reports the effect of SB on bone formation among ovariectomized (OVX) rats. The bone marrow mesenchymal stem cells (BMSCs) from OVX rats were cultured in vitro. Alizarin Red staining was utilized to observe the effect of SB on the mineralization of BMSCs. The levels of alkaline phosphatase (ALP), osteocalcin, bone morphogenetic protein (BMP‐2), and Sirtuin 1 (SIRT1) activities were detected. The OVX rats were treated with SB in vivo. Micro‐CT was utilized for imaging analysis. Urine calcium and phosphorus, and ALP activity in bone marrow were assayed. Western blot analysis and immunofluorescence were incorporated to detect protein expressions in vitro and in vivo. The results showed that SB dose‐dependently promoted mineralization of OVX rat‐derived BMSCs in vitro increased the level of Osteocalcin, BMP‐2, ALP, and SIRT1 activity. Moreover, it upregulated expressions of Runx2, Osterix, and SIRT1, downregulated expressions of Notch intracellular domain (NICD), acetyl‐NICD, and hairy and enhancer of split 1 (Hes1). In addition, SB treatment significantly decreased bone loss, inhibited calcium and phosphorus loss, elevated ALP activity, upregulated Runx2, Osterix, and SIRT1, and downregulated NICD and Hes1 in OVX rats in vivo. However, EX527, a SIRT1‐selective inhibitor, could reverse the above effects of SB in vitro or in vivo. These results indicate that SB is a potential natural medicine to improve PMOP. Thus, its mechanism of promoting bone formation involves the SIRT1/Notch1 signaling axis.

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

Cited by 95 publications

References 60 publications

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

The Spectrum of Fundamental Basic Science Discoveries Contributing to Organismal Aging

SIRT1/Notch1 signal axis involves in the promoting effect of Segetalin B on bone formation

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