SIRT1: A Therapeutic Target for Osteoporosis?

Many researchers have studied the sirtuin family of proteins and described them as NAD+ dependent enzymes that are evolutionarily conserved from yeast to humans. Previous research has shown that SIRT1 expression declines in certain tissues as organisms age. Additionally, research in mice has revealed that overexpression or pharmacological activation of SIRT1 increases the health span and lifespan of mice and delays the onset of many aging-related diseases.

New research now suggests that SIRT1 is a positive regulator of bone mass and that pharmacological activation of SIRT1 protects against osteoporosis. Kayvan Zainabadi, PhD, a postdoctoral fellow at MIT in Cambridge, Mass., and colleagues published their work in the Sept. 22 issue of Plos One. Their results reinforce the notion that SIRT1 regulates β-catenin and RUNX2 and promotes osteoblast commitment and differentiation.¹

The investigators used two independent models of osteoporosis (ovariectomized female mice and aged male mice) and found that pharmacological activation of SIRT1 with the SIRT1 agonist SRT1720 resulted in significant increases in bone mass. In other words, mice fed SRT1720 experienced significant improvements in bone mass relative to control animals.

The researchers then evaluated whole-body SIRT1 knockout mice and tissue-specific SIRT1 knockout mice using microcomputed tomography (µCT). Unlike the whole-body SIRT1 knockouts, the osteoblast knockout and osteoclast knockout mice were indistinguishable from wildtype littermates. The investigators then crossed the osteoblast knockout and osteoclast knockout mice to obtain double knockouts. Although SIRT1 whole-body knockout mice, as well as osteoblast and osteoclast specific knockouts, did have a low bone mass phenotype, double knockout mice did not show a more severe phenotype.

Next, the investigators examined calorie restriction, which had previously been shown to delay many diseases of aging. However, the role of calorie restriction in bone mass is less clear. The investigators found that calorie restriction resulted in a two fold upregulation in sirt1 mRNA expression in bone tissue. This upregulation was also associated with increased bone mass in calorie-restricted mice.

“Unlike a previous report, we did not find SIRT1 expression [decreased] with age in bone,” write the authors in their discussion. “We attribute this discrepancy to the following: 1) We used calvaria for our qRT-PCR analysis, whereas the aforementioned study used whole long bones [in which] the majority of RNA comes from hematopoietic and mesenchymal precursor cells in the marrow; 2) we used ribosomal gene rpl19 for normalization, whereas Edwards et al normalized with the metabolically relevant gapdh gene, the expression of which has previously been shown to change with age, nutritional status, and mechanical strain on bone. In contrast, expression of rpl19 has been shown to be more constant under a variety of conditions, including during normal aging.”