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Farr J.N.,Endocrine Research Unit and Kogod Center on Aging | Khosla S.,Endocrine Research Unit and Kogod Center on Aging
Bone | Year: 2016

There is growing evidence that the higher fracture rate observed in patients with type 2 diabetes mellitus (T2DM) is associated with normal, or even increased, areal bone mineral density (aBMD) by DXA. This has led to the hypothesis that patients with T2DM may have abnormalities in bone microarchitecture and/or material composition - i.e., key determinants of bone "quality." Consistent with this hypothesis, several studies using high-resolution peripheral quantitative computed tomography (HRpQCT) have demonstrated preserved indices of trabecular microarchitecture but increased cortical porosity in T2DM patients. In addition, a recent study using a novel in vivo microindentation device found an impairment in a measure of bone material properties (bone material strength index, BMSi) in postmenopausal women with longstanding T2DM; notably, the reduction in BMSi was associated with chronic glycemic control, suggesting that the skeleton should be included as another target organ subject to diabetic complications. The underlying pathogenesis of skeletal fragility in T2DM remains to be defined, although high levels of advanced glycation endproducts (AGEs) may play a role. In addition, T2DM is associated with reduced bone turnover, perhaps with an imbalance between bone resorption and bone formation. Although several studies have found increased serum sclerostin levels in patients with T2DM, the role of these increased levels in mediating the observed increases in cortical porosity or reduction in BMSi remains to be defined. Thus, although bone quality appears to be impaired in T2DM, the pathogenesis of these abnormalities and their relationship to the increased fracture risk observed in these patients needs further study. © 2015 Elsevier Inc. Source


Khosla S.,Endocrine Research Unit and Kogod Center on Aging | Oursler M.J.,Endocrine Research Unit and Kogod Center on Aging | Monroe D.G.,Endocrine Research Unit and Kogod Center on Aging
Trends in Endocrinology and Metabolism | Year: 2012

Estrogen is the major hormonal regulator of bone metabolism in women and men. Therefore, there is considerable interest in unraveling the pathways by which estrogen exerts its protective effects on bone. Although the major consequence of the loss of estrogen is an increase in bone resorption, estrogen deficiency is associated with a gap between bone resorption and formation, indicating that estrogen is also important for maintaining bone formation at the cellular level. Direct estrogen effects on osteocytes, osteoclasts, and osteoblasts lead to inhibition of bone remodeling, decreased bone resorption, and maintenance of bone formation, respectively. Estrogen also modulates osteoblast/osteocyte and T-cell regulation of osteoclasts. Unraveling these pleiotropic effects of estrogen may lead to new approaches to prevent and treat osteoporosis. © 2012 Elsevier Ltd. Source


Roforth M.M.,Endocrine Research Unit and Kogod Center on Aging | Farr J.N.,Endocrine Research Unit and Kogod Center on Aging | Fujita K.,Endocrine Research Unit and Kogod Center on Aging | McCready L.K.,Endocrine Research Unit and Kogod Center on Aging | And 6 more authors.
Bone | Year: 2015

Age-related bone loss in humans is associated with a decrease in bone formation relative to bone resorption, although the mechanisms for this impairment in bone formation with aging are not well understood. It is known that the precursors for the bone-forming osteoblasts reside in the mesenchymal cell population in bone marrow. Thus, in an effort to identify relevant genetic pathways that are altered with aging, we examined the gene expression and DNA methylation patterns from a highly enriched bone marrow mesenchymal cell population from young (mean age, 28.7. years) versus old (mean age, 73.3. years) women. Bone marrow mononuclear cells from these women were depleted of hematopoietic lineage (lin) and endothelial cells using a combination of magnetic- and fluorescence-activated cell sorting, yielding a previously characterized mesenchymal cell population (lin. -/CD34. -/CD31. - cells) that is capable of osteoblast differentiation. Whole transcriptome RNA sequencing (RNAseq) of freshly isolated cells (without in vitro culture) identified 279 differentially expressed genes (p < 0.05, false discovery rate [q]. < 0.10) between the young and old subjects. Pathway analysis revealed statistically significant (all p < 0.05) alterations in protein synthesis and degradation pathways, as well as mTOR, gap junction, calcium, melatonin and NFAT signaling pathways. Further, Reduced Representational Bisulphite sequencing (RRBS DNA methylation sequencing) revealed significant differences in methylation between the young and old subjects surrounding the promoters of 1528 target genes that also exhibited significant differences in gene expression by RNAseq. In summary, these studies provide novel insights into potential pathways affected by aging in a highly enriched human mesenchymal cell population analyzed without the confounding effects of in vitro culture. Specifically, our finding of alterations in several genes and pathways leading to impaired protein synthesis and turnover with aging in bone marrow mesenchymal cells points to the need for further studies examining how these changes, as well as the other alterations with aging that we identified, may contribute to the age-related impairment in osteoblast formation and/or function. © 2015 Elsevier Inc. Source


Roforth M.M.,Endocrine Research Unit and Kogod Center on Aging | Fujita K.,Endocrine Research Unit and Kogod Center on Aging | McGregor U.I.,Endocrine Research Unit and Kogod Center on Aging | Kirmani S.,Endocrine Research Unit and Kogod Center on Aging | And 5 more authors.
Bone | Year: 2014

Although aging is associated with a decline in bone formation in humans, the molecular pathways contributing to this decline remain unclear. Several previous clinical studies have shown that circulating sclerostin levels increase with age, raising the possibility that increased production of sclerostin by osteocytes leads to the age-related impairment in bone formation. Thus, in the present study, we examined circulating sclerostin levels as well as bone mRNA levels of sclerostin using quantitative polymerase chain reaction (QPCR) analyses in needle bone biopsies from young (mean age, 30.0. years) versus old (mean age, 72.9. years) women. In addition, we analyzed the expression of genes in a number of pathways known to be altered with skeletal aging, based largely on studies in mice. While serum sclerostin levels were 46% higher (p. <. 0.01) in the old as compared to the young women, bone sclerostin mRNA levels were no different between the two groups (p. =0.845). However, genes related to notch signaling were significantly upregulated (p. =0.003 when analyzed as a group) in the biopsies from the old women. In an additional analysis of 118 genes including those from genome-wide association studies related to bone density and/or fracture, BMP/TGFβ family genes, selected growth factors and nuclear receptors, and Wnt/Wnt-related genes, we found that mRNA levels of the Wnt inhibitor, SFRP1, were significantly increased (by 1.6-fold, p. =0.0004, false discovery rate [q]. =0.04) in the biopsies from the old as compared to the young women.Our findings thus indicate that despite increases in circulating sclerostin levels, bone sclerostin mRNA levels do not increase in elderly women. However, aging is associated with alterations in several key pathways and genes in humans that may contribute to the observed impairment in bone formation. These include notch signaling, which represents a potential therapeutic target for increasing bone formation in humans. Our studies further identified mRNA levels of SFRP1 as being increased in aging bone in humans, suggesting that this may also represent a viable target for the development of anabolic therapies for age-related bone loss and osteoporosis. © 2013 Elsevier Inc. Source

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