Vertebral Bone Marrow Fat Associated With Lower Trabecular BMD and Prevalent Vertebral Fracture in Older Adults

Schwartz, Ann V.; Sigurðsson, Sigurður; Hue, Trisha F.; Lang, Thomas; Harris, Tamara B.; Rosen, Clifford J.; Vittinghoff, Eric; Siggeirsdóttir, Kristín; Sigurðsson, Gunnar; Oskarsdóttir, Díana; Shet, Keerthi; Palermo, Lisa; Gudnason, Vilmundur; Li, Xiaojuan

doi:10.1210/jc.2012-3949

Cited by 207 publications

(183 citation statements)

References 29 publications

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“…The late perimenopause, in particular, is associated with rising FSH levels in the face of normal estrogen (4), raising the question whether estrogen deficiency is the sole cause of these physiologic aberrations. Third, bone marrow adiposity, often seen as a function of aging and sex steroid deficiency, is linked with osteoporosis (21,22). These associations lay the basis not only for overlapping molecular mechanisms that underpin both osteoporosis and obesity, but also for a new therapeutic approach to treat these two diseases simultaneously.…”

Section: Discussionmentioning

confidence: 99%

Epitope-specific monoclonal antibodies to FSHβ increase bone mass

Liu

Yuen

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Pituitary hormones have long been thought solely to regulate single targets. Challenging this paradigm, we discovered that both anterior and posterior pituitary hormones, including FSH, had other functions in physiology. We have shown that FSH regulates skeletal integrity, and, more recently, find that the inhibition of FSH reduces body fat and induces thermogenic adipose tissue. A polyclonal antibody raised against a short, receptor-binding epitope of FSHβ was found not only to rescue bone loss post-ovariectomy, but also to display marked anti-obesity and pro-beiging actions. Questioning whether a single agent could be used to treat two medical conditions of public health importance -osteoporosis and obesity -we developed two further monoclonal antibodies, Hf2 and Mf4, against computationally defined receptor-binding epitopes of FSHβ. Hf2 has already been shown to reduce body weight, fat mass and cause beiging in mice on a high-fat diet. Here, we show that Hf2, which binds mouse Fsh in immunoprecipitation assays, also increases cortical thickness and trabecular bone volume, and microstructural parameters, in sham-operated and ovariectomized mice, noted on micro-computed tomography.This effect was largely recapitulated with Mf4, which inhibited bone resorption by osteoclasts and stimulated new bone formation by osteoblasts. These effects were exerted in the absence of alterations in serum estrogen in wild type mice. We also re-confirm the existence of Fshrs in bone by documenting the specific binding of fluorescently labeled FSH, FSH-CH, in vivo. Our study provides the framework for the future development of an FSH-based therapeutic that could potentially target both bone and fat. 3 SIGNIFICANCE STATEMENTWe have addressed the question whether osteoporosis and obesity, which often occur concurrently in postmenopausal women, can be targeted by a single agent. We have shown previously that the reproductive hormone FSH, the levels of which rise after menopause, regulates both body fat and bone mass. We now show that blocking FSH action using two purposefully designed epitope-specific antibodies protects against bone loss in mice. This positions both FSH antibodies as lead molecules for clinical development towards future use in people.

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Section: Discussionmentioning

confidence: 99%

Epitope-specific monoclonal antibodies to FSHβ increase bone mass

Liu

Yuen

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…The epigenetically preprogrammed pathway for marrow-derived MSCs appears to be osteogenic; however, the potential for adipocyte differentiation remains intact, despite expression of the reported adipocyte defying Grem1 in the MSCs and MSC-B7 cells (40). This differentiation potential is highlighted in the pathology associated with skeletal fragility, including increased marrow adiposity due to less physical exertion, aging, and estrogen deficiency (65)(66)(67). The marrow microenvironment and resulting MSCs may react and respond to the increased adiposity, causing an increase in the propensity for MSCs to become adipose or even for existing osteogenic cells to be trans-differentiated into fat.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Plasticity Drives Adipogenic and Osteogenic Differentiation of Marrow-derived Mesenchymal Stem Cells

Meyer

Benkusky

Sen

et al. 2016

Journal of Biological Chemistry

154

124

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Terminal differentiation of multipotent stem cells is achieved through a coordinated cascade of activated transcription factors and epigenetic modifications that drive gene transcription responsible for unique cell fate. Within the mesenchymal lineage, factors such as RUNX2 and PPAR␥ are indispensable for osteogenesis and adipogenesis, respectively. We therefore investigated genomic binding of transcription factors and accompanying epigenetic modifications that occur during osteogenic and adipogenic differentiation of mouse bone marrow-derived mesenchymal stem cells (MSCs). As assessed by ChIP-sequencing and RNA-sequencing analyses, we found that genes vital for osteogenic identity were linked to RUNX2, C/EBP␤, retinoid X receptor, and vitamin D receptor binding sites, whereas adipocyte differentiation favored PPAR␥, retinoid X receptor, C/EBP␣, and C/EBP␤ binding sites. Epigenetic marks were clear predictors of active differentiation loci as well as enhancer activities and selective gene expression. These marrow-derived MSCs displayed an epigenetic pattern that suggested a default preference for the osteogenic pathway; however, these patterns were rapidly altered near the Adipoq, Cidec, Fabp4, Lipe, Plin1, Pparg, and Cebpa genes during adipogenic differentiation. Surprisingly, we found that these cells also exhibited an epigenetic plasticity that enabled them to transdifferentiate from adipocytes to osteoblasts (and vice versa) after commitment, as assessed by staining, gene expression, and ChIP-quantitative PCR analysis. The osteogenic default pathway may be subverted during pathological conditions, leading to skeletal fragility and increased marrow adiposity during aging, estrogen deficiency, and skeletal unloading. Taken together, our data provide an increased mechanistic understanding of the epigenetic programs necessary for multipotent differentiation of MSCs that may prove beneficial in the development of therapeutic strategies.

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“…Animal and human data have demonstrated that marrow adipose tissue is context-specific and, in many situations, is inversely related to the structural integrity of the skeleton. 19,[32][33][34] In OP, increased marrow adipocyte production is counterbalanced by decreased generation of osteogenic cells. Many pieces of evidence have indicated an important role for PPARg2 in bone metabolism.…”

Section: Fan Et Almentioning

confidence: 99%

Panax notoginseng saponins mitigate ovariectomy-induced bone loss and inhibit marrow adiposity in rats

et al. 2015

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Vertebral Bone Marrow Fat Associated With Lower Trabecular BMD and Prevalent Vertebral Fracture in Older Adults

Abstract: Higher marrow fat correlated with lower trabecular, but not cortical, BMD in older women but not men. Higher marrow fat was associated with prevalent vertebral fracture in men, even after adjustment for BMD.

Cited by 207 publications

References 29 publications

Epitope-specific monoclonal antibodies to FSHβ increase bone mass

Epitope-specific monoclonal antibodies to FSHβ increase bone mass

Epigenetic Plasticity Drives Adipogenic and Osteogenic Differentiation of Marrow-derived Mesenchymal Stem Cells

Panax notoginseng saponins mitigate ovariectomy-induced bone loss and inhibit marrow adiposity in rats

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