Sirtuin 1 deficiency decreases bone mass and increases bone marrow adiposity in a mouse model of chronic energy deficiency

Abstract

Sirtuin of type 1 (Sirt1), a class III HDAC, is known to be involved in the regulation of differentiation of skeletal stem cells (SSCs) into osteoblasts and adipocytes. In caloric restriction, it has been shown that the expression and activity of Sirt1 is a tissue-dependent regulation. However, at present, no study has focused on the link between Sirt1, bone marrow adiposity (BMA) and osteoporosis related to anorexia nervosa (AN). Thus, the aims of this work were to (i) determine BMA and bone changes in a mouse model replicating the phenotypes of AN (separation-based anorexia model (SBA)); (ii) determine the expression of Sirt1 in bone marrow stromal cells (BMSCs) extracted from these mice and identify their differentiation capacities; (iii) study the effects of pharmacological activation and inhibition of Sirt1 on the osteoblastogenesis and adipogenesis of these cells and (iiii) delineate the molecular mechanism by which Sirt1 could regulate osteogenesis in an SBA model. Our results demonstrated that SBA protocol induces an increase in BMA and alteration of bone architecture. In addition, BMSCs from restricted mice present a down-regulation of Sirt1 which is accompanied by an increase in adipogenesis at expense of osteogenesis. After a 10-day organotypic culture, tibias from SBA mice displayed low levels of Sirt1 mRNA which are restored by resveratrol treatment. Interestingly, this recovery of Sirt1 levels also returned the BMA, BV/TV and Tb.Th in cultured tibias from SBA mice to normal levels. In contrast of down-regulation of Sirt1 expression induced by sirtinol treatment, stimulation of Sirt1 expression by resveratrol lead to a decrease in adipogenesis and increase in osteogenesis. Finally, to investigate the molecular mechanisms by which Sirt1 could regulate osteogenesis in the SBA model, the acetylation levels of Runx2 and Foxo1 transcription factors were determined. Our data show that this chronic energy deficiency in female mice causes a decrease in BMSC activity, resulting in critical changes to Runx2 and Foxo1 acetylation levels and thus to their activity. Altogether, these data suggest that Sirt1 could be considered as a potential therapeutic target in osteoporosis related to AN.

Keywords: Anorexia nervosa; Bone marrow adiposity; Bone marrow stromal cells; Osteoblast; Separation-based anorexia; Sirtuin of type 1.