Effect of estrogens on bone marrow adipogenesis and Sirt1 in aging C57BL/6J mice

Lady Davis Institute for Medical Research, McGill University, Montreal, QC H3T 1E2, Canada.
Biogerontology (Impact Factor: 3.29). 04/2009; 10(6):747-55. DOI: 10.1007/s10522-009-9221-7
Source: PubMed


Age-related bone loss has been associated with high levels of marrow adipogenesis. Estrogens (E2) are known to regulate the differentiation of marrow precursors into osteoblasts, however, their role in bone marrow adipogenesis remain unknown. E2 regulate adipocyte differentiation in subcutaneous and visceral fat through interaction with other nuclear receptors. This interaction has not been assessed in bone marrow adipocytes in vivo. In this study, we compared two groups of animals, young and old, after either oophorectomy (OVX) or oophorectomy plus E2 (OVX + E2) replacement. We found that absence of E2 was associated with higher levels of PPARc and lower levels of Sirt1 most significantly in the old group. In addition, old mice responded better to E2 replacement in terms of reducing adipogenesis and PPARc expression as well as increasing levels of Sirt1 expression. Our findings represent a new understanding of the role of E2 in age-related bone loss, which could be mediated through the regulation of Sirt1 expression within the bone marrow. In addition, this evidence suggests that old individuals may show a better response to E2 administration in terms of reverting the high levels of marrow fat seen in age-related bone loss.

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    • "In culture experiments , serum from postmenopausal women induced greater adipogenic differentiation of stromal precursors, however hormone replacement did not reverse the adipogenic differentiation observed in vitro [60]. In addition, OVX mice have been illustrated to have an increased adipogenic marrow, accompanied by a reduction in Sirt1 protein expression and an increase in PPAR-γ protein, which were reversed by estrodial administration [59]. The above investigations illustrate an overall disruption to steady-state functioning of the bone marrow microenvironment both independent and dependent on estrogen in ageing and menopause. "
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    ABSTRACT: The bone marrow is a complex environment that houses haematopoietic and mesenchymal cell populations and regulates bone turnover throughout life. The high proliferative capacity of these cell populations however, makes them susceptible to damage and injury, altering the steady-state of the bone marrow environment. Following cancer chemotherapy, irradiation and long-term glucocorticoid use, reduced bone and increased fat formation of marrow stromal progenitor cells results in a fatty marrow cavity, reduced bone mass and increased fracture risk. These bone and marrow defects are also observed in age-related complications such as estrogen deficiency and increased oxidative stress. Although the underlying mechanisms are yet to be clarified, recent investigations have suggested a switch in lineage commitment of bone marrow mesenchymal stem cells down the adipogenic lineage at the expense of osteogenic differentiation following such stress or injury. The Wnt/β-catenin signalling pathway is however has been recognized the key mechanism regulating stromal commitment, and its involvement in the osteogenic and adipogenic lineage commitment switch under the damaging conditions has been of great interest. This article reviews the effects of various types of stress or injury on the commitment to the adipogenic and osteogenic lineages of bone marrow stromal progenitor cells, and summarizes the roles of the Wnt/β-catenin and associated signalling pathways in the lineage commitment, switch, and recovery after damage, and as a therapeutic target.
    Full-text · Article · Jan 2012 · American Journal of Stem Cells
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    • "Thus, Sirt1 appears to regulate the preferred differentiation pathway of mesenchymal progenitor cells. Estrogen depletion (via ovariectomy) depletes Sirt1 protein levels in vivo, which may contribute to the increase in marrow adiposity and bone loss observed during normal aging and in animal models of postmenopausal osteoporosis (Elbaz et al., 2009). Genetic deletion of Sirt1 causes axial and appendicular trabecular bone loss due to increased osteoclast number and osteoclast activity and decreased osteoblast number (Edwards et al., 2007). "
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    ABSTRACT: The skeleton is a multifunctional and regenerative organ. Dynamic activities within the bone microenvironment necessitate and instigate rapid and temporal changes in gene expression within the cells (osteoclasts, osteoblasts, and osteocytes) responsible for skeletal maintenance. Regulation of gene expression is controlled, in part, by histone deacetylases (Hdacs), which are intracellular enzymes that directly affect chromatin structure and transcription factor activity. Key roles for several Hdacs in bone development and biology have been elucidated though in vitro and in vivo models. Recent findings suggest that clinical usage of small molecule Hdac inhibitors for conditions like epilepsy, bipolar disorder, cancer, and a multitude of other ailments may have unintended effects on bone cell populations. Here we review the progress that has been made in the last decade in understanding how Hdacs contribute to bone development and maintenance.
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    ABSTRACT: Obesity and osteoporosis are common and complex disorders with important consequences for human health and for society. The two conditions are intimately linked, as evidenced by epidemiological studies showing that obesity protects from osteoporosis while low body weight poses a strong risk factor 1, 2. Obesity, defined as a body mass index (BMI) of 30 kg/m2 and over, has become a global epidemic and represents an important risk factor for type 2 diabetes mellitus, hypertension, cardiovascular disease, stroke, some types of cancer and disability. Osteoporosis, a skeletal disorder characterized by loss of bone strength and proneness to fractures, is a major health threat to hundreds of millions of elderly individuals worldwide and prevalence will continue to rise as populations age. Osteoporosis and obesity result from an interaction between genetic factors and environment. Although the growing prevalence of obesity is most likely driven by changing lifestyles encompassing increased caloric intake and decreased energy expenditure through physical activity, individual susceptibility varies widely and is strongly influenced by genetic factors. Heritability estimates for BMI, the most widely used parameter of obesity, range from 30 to 70% in family- and twin studies 3. There are also genetic influences on obesity-related traits like total body fat mass, lean mass and measures of fat distribution 4-8, but the heritability of these parameters is less clear than that of BMI. A large contribution of genes has also been documented for the susceptibly to develop osteoporosis. Heritability estimates for bone mineral density (BMD), the most widely used parameter for osteoporosis, range between 50 and 85% 9. The age-adjusted heritability of osteoporotic fractures is smaller (between 25 and 50%) and may be independent to that of BMD 10, possibly due to other important factors associated with fractures such as falls.
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