Clifford J Rosen

Maine Medical Center Research Institute, Scarborough, Maine, United States

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Publications (273)1897.04 Total impact

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    ABSTRACT: Observational studies suggest that vitamin D may lower the risk of type 2 diabetes. However, data from long-term trials are lacking. The Vitamin D and Type 2 Diabetes (D2d) study is a randomized clinical trial designed to examine whether a causal relationship exists between vitamin D supplementation and the development of diabetes in people at high risk for type 2 diabetes.
    Diabetes care. 09/2014;
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    ABSTRACT: Osteocyte activity is crucial to maintenance of bone quality. Sclerostin, an osteocyte product, inhibits bone formation, yet higher circulating sclerostin is associated with higher bone density (BMD). Bone marrow fat (MF) is associated with osteoporosis but little is known about the relationship between osteocyte activity and MF.
    The Journal of clinical endocrinology and metabolism. 08/2014;
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    Nicolas Bonnet, Emmanuel Somm, Clifford J Rosen
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    ABSTRACT: Diets rich in omega-3s have been thought to prevent both obesity and osteoporosis. However, conflicting findings are reported, probably as a result of gene by nutritional interactions. Peroxisome proliferator-activated receptor-gamma (PPARγ), is a nuclear receptor that improves insulin sensitivity but causes weight gain and bone loss. Fish oil is a natural agonist for PPARγ and thus may exert its actions through PPARγ pathway. We examined the role of PPARγ in body composition changes induced by a fish or safflower oil diet using two strains of C57BL6J (B6); i.e. B6.C3H-6T (6T) congenic mice created by backcrossing a small locus on Chr 6 from C3H carrying 'gain of function' polymorphisms in the Pparγ gene onto a B6 background, and C57BL6J mice. After 9months of feeding both diets to female mice, body weight, percent fat and leptin levels were less in mice fed the fish oil vs those fed safflower oil, independent of genotype. At the skeletal level, fish oil preserved vertebral bone mineral density (BMD) and microstructure in B6 but not in 6T mice. Moreover, fish oil consumption was associated with an increase in bone marrow adiposity and a decrease in BMD, cortical thickness, ultimate force and plastic energy in femur of the 6T but not B6 mice. These effects paralleled an increase in adipogenic inflammatory and resorption markers in 6T but not B6. Thus, compared to safflower oil, fish oil (high ratio omega-3/-6) prevents weight gain, bone loss, and changes in trabecular microarchitecture in the spine with age. These beneficial effects are absent in mice with polymorphisms in the Pparγ gene (6T), supporting the tenet that the actions of n-3 fatty acids on bone microstructure are likely to be genotype dependent. Thus caution must be used in interpreting dietary intervention trials with skeletal endpoints in mice and in humans.
    Bone 07/2014; · 3.82 Impact Factor
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    ABSTRACT: PPARγ, a ligand-activated nuclear receptor, regulates fundamental aspects of bone homeostasis and skeletal remodeling. PPARγ-activating anti-diabetic thiazolidinediones in clinical use promote marrow adiposity, bone loss, and skeletal fractures. As such, delineating novel regulatory pathways that modulate the action of PPARγ, and its obligate heterodimeric partner RXR, may have important implications for our understanding and treatment of disorders of low bone mineral density. We present data here establishing retinaldehyde dehydrogenase 1 (Aldh1a1) and its substrate retinaldehyde (Rald) as novel determinants of PPARγ-RXR actions in the skeleton. When compared to wild type (WT) controls, retinaldehyde dehydrogenase-deficient (Aldh1a1(-/-)) mice were protected against bone loss and marrow adiposity induced by either the thiazolidinedione rosiglitazone or a high fat diet, both of which potently activate the PPARγ-RXR complex. Consistent with these results, Rald, which accumulates in vivo in Aldh1a1(-/-) mice, protects against rosiglitazone-mediated inhibition of osteoblastogenesis in vitro. In addition, Rald potently inhibits in vitro adipogenesis and osteoclastogenesis in WT mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) respectively. Primary Aldh1a1(-/-) HSCs also demonstrate impaired osteoclastogenesis in vitro compared to WT controls. Collectively, these findings identify Rald and retinoid metabolism through Aldh1a1 as important novel modulators of PPARγ-RXR transactivation in the marrow niche.
    Bone 07/2014; · 3.82 Impact Factor
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    ABSTRACT: The adipocyte-derived hormone adiponectin promotes metabolic and cardiovascular health. Circulating adiponectin increases in lean states such as caloric restriction (CR), but the reasons for this paradox remain unclear. Unlike white adipose tissue (WAT), bone marrow adipose tissue (MAT) increases during CR, and both MAT and serum adiponectin increase in many other clinical conditions. Thus, we investigated whether MAT contributes to circulating adiponectin. We find that adiponectin secretion is greater from MAT than WAT. Notably, specific inhibition of MAT formation in mice results in decreased circulating adiponectin during CR despite unaltered adiponectin expression in WAT. Inhibiting MAT formation also alters skeletal muscle adaptation to CR, suggesting that MAT exerts systemic effects. Finally, we reveal that both MAT and serum adiponectin increase during cancer therapy in humans. These observations identify MAT as an endocrine organ that contributes significantly to increased serum adiponectin during CR and perhaps in other adverse states.
    Cell metabolism. 07/2014;
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    ABSTRACT: Women with anorexia nervosa (AN) have increased marrow fat despite severe depletion of body fat. Recent studies have suggested that marrow fat composition may serve as a biomarker for bone quality. The purpose of our study was to investigate marrow fat composition of the femur using proton MR spectroscopy (1H-MRS), and the relationship between measures of marrow fat composition and BMD and body composition in women with AN and normal-weight controls.
    Bone 06/2014; · 3.82 Impact Factor
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    ABSTRACT: Lactation is associated with significant alterations in both body composition and bone mass. Systemic and local skeletal factors such as RANKL, PTHrP, calcitonin, and estrogen are known to regulate bone remodeling during and after lactation. FGF21 may function as an endocrine factor to regulate body composition changes during lactation by inducing gluconeogenesis and fatty acid oxidation. In this study, we hypothesized that the metabolic changes during lactation were due in part to increased circulating FGF-21, which in turn could accentuate bone loss. We longitudinally characterized body composition in C57BL/6J (B6) mice during (d7Lac and d21Lac) and after normal lactation (d21Post). At day 7(d7Lac) of lactation, areal bone density declined by 10% (aBMD: p<0.001) bone resorption increased (p<0.0001), percent fat decreased by 20%, energy expenditure increased (p<0.01), and markers of brown-like adipogenesis were suppressed in the inguinal depot and in pre-formed brown adipose tissue. At d7Lac there was a 2.4 fold increase in serum FGF-21 vs. baseline (p<0.0001), a 8-fold increase in hepatic FGF-21 mRNA (p<0.03), a 2-fold increase in undercarboxylated osteocalcin (p<0.01) and enhanced insulin sensitivity. Recovery of total aBMD was noted at d21Lac, while femoral trabecular bone volume fraction (BV/TV) was still reduced (p<0.01). Since FGF-21 levels rose rapidly at d7Lac in B6 lactating mice, we next examined lactating mice with a deletion in the Fgf21 gene. Trabecular as well as cortical bone mass were maintained throughout lactation in FGF-21-/- mice, while pup growth was normal. Compared to lactating control mice, lactating FGF-21-/- mice exhibited an increase in bone formation, but no change in bone resorption. In conclusion, in addition to changes in calcitropic hormones, systemic FGF-21 plays a role in skeletal remodeling and changes in body composition during lactation in B6 mice.
    Endocrinology 06/2014; · 4.72 Impact Factor
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    ABSTRACT: Insulin like growth factor binding protein two (IGFBP-2) is important for acquisition of normal bone mass in mice; however, the mechanism by which IGFBP-2 functions is not defined. These studies investigated the role of IGFBP-2 in stimulating osteoblast differentiation. MC-3T3 preosteoblasts expressed IGFBP-2, and IGFBP-2 knockdown resulted in a substantial delay in osteoblast differentiation, reduced osteocalcin expression and Alizarin red staining. These findings were replicated in primary calvarial osteoblasts obtained from IGFBP-2 -/- mice and addition of IGFBP-2 rescued the differentiation program. In contrast, overexpression of IGFBP-2 accelerated the time course of differentiation as well as increasing the total number of differentiating cells. By day 6 IGFBP-2 overexpressing cells expressed twice as much osteocalcin as control cultures and this difference persisted. To determine the mechanism by which IGFBP-2 functions, the interaction between IGFBP-2 and receptor tyrosine phosphatase β (RPTPβ) was examined. Disruption of this interaction inhibited the ability of IGFBP-2 to stimulate AKT activation and osteoblast differentiation. Knockdown of RPTPβ enhanced osteoblast differentiation whereas overexpression of RPTPβ was inhibitory. Adding back IGFBP-2 to RPTPβ overexpressing cells was able to rescue cell differentiation via enhancement of AKT activation. To determine the region of IGFBP-2 that mediated this effect an IGFBP-2 mutant that contained substitutions of key amino acids in the heparin binding domain-1 (HBD-1) was prepared. This mutant had a major reduction in its ability to stimulate differentiation of calvarial osteoblasts from IGFBP-2 -/- mice. Addition of a synthetic peptide that contained the HBD-1 sequence to calvarial osteoblasts from IGFBP-2 -/- mice rescued differentiation and osteocalcin expression. In summary, the results clearly demonstrate that IGFBP-2 stimulates osteoblast differentiation and that this effect is mediated through its heparin binding domain-1 interacting with RPTPβ. The results suggest that stimulation of differentiation is an important mechanism by which IGFBP-2 regulates the acquisition of normal bone mass in mice. © 2014 American Society for Bone and Mineral Research.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 05/2014; · 6.04 Impact Factor
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    ABSTRACT: Patient bone mineral density (BMD) predicts the likelihood of osteoporotic fracture. While substantial progress has been made toward elucidating the genetic determinants of BMD, our understanding of the factors involved remains incomplete. Here, using a systems genetics approach in the mouse, we predicted that bicaudal C homolog 1 (Bicc1), which encodes an RNA-binding protein, is responsible for a BMD quantitative trait locus (QTL) located on murine chromosome 10. Consistent with this prediction, mice heterozygous for a null allele of Bicc1 had low BMD. We used a coexpression network-based approach to determine how Bicc1 influences BMD. Based on this analysis, we inferred that Bicc1 was involved in osteoblast differentiation and that polycystic kidney disease 2 (Pkd2) was a downstream target of Bicc1. Knock down of Bicc1 and Pkd2 impaired osteoblastogenesis, and Bicc1 deficiency-dependent osteoblast defects were rescued by Pkd2 overexpression. Last, in 2 human BMD genome-wide association (GWAS) meta-analyses, we identified SNPs in BICC1 and PKD2 that were associated with BMD. These results, in both mice and humans, identify Bicc1 as a genetic determinant of osteoblastogenesis and BMD and suggest that it does so by regulating Pkd2 transcript levels.
    The Journal of clinical investigation 05/2014; · 15.39 Impact Factor
  • Clifford J Rosen, Christine L Taylor
    The lancet. Diabetes & endocrinology. 04/2014;
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    Erica L. Scheller, Clifford J. Rosen
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    ABSTRACT: Marrow adipose tissue (MAT) is functionally distinct from both white and brown adipose tissue and can contribute to systemic and skeletal metabolism. MAT formation is a spatially and temporally defined developmental event, suggesting that MAT is an organ that serves important functions and, like other organs, can undergo pathologic change. The well-documented inverse relationship between MAT and bone mineral density has been interpreted to mean that MAT removal is a possible therapeutic target for osteoporosis. However, the bone and metabolic phenotypes of patients with lipodystrophy argues that retention of MAT may actually be beneficial in some circumstances. Furthermore, MAT may exist in two forms, regulated and constitutive, with divergent responses to hematopoietic and nutritional demands. In this review, we discuss the role of MAT in lipodystrophy, bone loss, and metabolism, and highlight our current understanding of this unique adipose tissue depot.
    Annals of the New York Academy of Sciences 03/2014; · 4.38 Impact Factor
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    ABSTRACT: The purpose of this study was to develop a longitudinal non-invasive functional imaging method using a dual-radioisotope hybrid micro-positron emission tomography/computed tomography (PET/CT) scanner in order to assess both the skeletal metabolic heterogeneity and the effect of localized radiation that models therapeutic cancer treatment on marrow and bone metabolism. Skeletally mature BALB/c female mice were given clinically relevant local radiation (16 Gy) to the hind limbs on day 0. Micro-PET/CT acquisition was performed serially for the same mice on days -5 and +2 with FDG and days -4 and +3 with NaF. Serum levels of pro-inflammatory cytokines were measured. Significant differences (p < 0.0001) in marrow metabolism (measured by FDG) and bone metabolism (measured by NaF) were observed among bones before radiation, which demonstrates functional heterogeneity in the marrow and mineralized bone throughout the skeleton. Radiation significantly (p < 0.0001) decreased FDG uptake but increased NaF uptake (p = 0.0314) in both irradiated and non-irradiated bones at early time points. An increase in IL-6 was observed with a significant abscopal (distant) effect on marrow and bone metabolic function. Radiation significantly decreased circulating IGF-1 (p < 0.01). Non-invasive longitudinal imaging with dual-radioisotope micro-PET/CT is feasible to investigate simultaneous changes in marrow and bone metabolic function at local and distant skeletal sites in response to focused radiation injury. Distinct local and remote changes may be affected by several cytokines activated early after local radiation exposure. This approach has the potential for longer-term studies to clarify the effects of radiation on marrow and bone.
    Calcified Tissue International 02/2014; · 2.50 Impact Factor
  • Maureen J Devlin, Clifford J Rosen
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    ABSTRACT: Obesity and osteoporosis are two of the most common chronic disorders of the 21st century. Both are accompanied by significant morbidity. The only place in the mammalian organism where bone and fat lie adjacent to each other is in the bone marrow. Marrow adipose tissue is a dynamic depot that probably exists as both constitutive and regulated compartments. Adipocytes secrete cytokines and adipokines that either stimulate or inhibit adjacent osteoblasts. The relationship of marrow adipose tissue to other fat depots is complex and might play very distinct parts in modulation of metabolic homoeostasis, haemopoiesis, and osteogenesis. Understanding of the relationship between bone and fat cells that arise from the same progenitor within the bone marrow niche provides insight into the pathophysiology of age-related osteoporosis, diabetes, and obesity.
    The lancet. Diabetes & endocrinology. 02/2014;
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    ABSTRACT: Osteoblastogenesis is the process by which mesenchymal stem cells differentiate into osteoblasts that synthesize collagen and mineralize matrix. The pace and magnitude of this process is determined by multiple genetic and environmental factors. Two inbred strains of mice, C3H/HeJ and C57BL/6J, exhibit differences in peak bone mass and bone formation. Although all the heritable factors that differ between these strains have not been elucidated, a recent F1 hybrid expression panel (C3H x B6) revealed major genotypic differences in osteoblastic genes related to cellular respiration and oxidative phosphorylation. Thus, we hypothesized that the metabolic rate of energy utilization by osteoblasts differed by strain and would ultimately contribute to differences in bone formation. In order to study the bioenergetic profile of osteoblasts, we measured oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) first in a preosteoblastic cell line MC3T3E-1C4 and subsequently in primary calvarial osteoblasts (COBs) from C3H and B6 mice at days 7, 14 and 21 of differentiation. During osteoblast differentiation in media containing ascorbic acid and β-glycerophosphate all three cell types increased their oxygen consumption and extra cellular acidification rates compared to the same cells grown in regular media. These increases are sustained throughout differentiation. Importantly, C3H COBs had greater OCR than B6 consistent with their in vivo phenotype of higher bone formation. Interestingly, osteoblasts utilized both oxidative phosphorylation and glycolysis during the differentiation process although mature osteoblasts were more dependent on glycolysis at the 21day time point than oxidative phosphorylation. Thus, determinants of oxygen consumption reflect strain differences in bone mass and provide the first evidence that during collagen synthesis osteoblasts utilize both glycolysis and oxidative phosphorylation to synthesize and mineralize matrix.
    Endocrinology 01/2014; · 4.72 Impact Factor
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    ABSTRACT: Adipocytes reside in discrete, well-defined depots throughout the body. In addition to mature adipocytes, white adipose tissue depots are composed of many cell types, including macrophages, endothelial cells, fibroblasts, and stromal cells, which together are referred to as the stromal vascular fraction (SVF). The SVF also contains adipocyte progenitors that give rise to mature adipocytes in those depots. Marrow adipose tissue (MAT) or marrow fat has long been known to be present in bone marrow (BM) but its origin, development, and function remain largely unknown. Clinically, increased MAT is associated with age, metabolic diseases, drug treatment, and marrow recovery in children receiving radiation and chemotherapy. In contrast to the other depots, MAT is unevenly distributed in the BM of long bones. Conventional quantitation relies on sectioning of the bone to overcome issues with distribution but is time-consuming, resource intensive, inconsistent between laboratories and may be unreliable as it may miss changes in MAT volume. Thus, the inability to quantitate MAT in a rapid, systematic, and reproducible manner has hampered a full understanding of its development and function. In this chapter, we describe a new technique that couples histochemical staining of lipid using osmium tetroxide with microcomputerized tomography to visualize and quantitate MAT within the medullary canal in three dimensions. Imaging of osmium staining provides a high-resolution map of existing and developing MAT in the BM. Because this method is simple, reproducible, and quantitative, we expect it will become a useful tool for the precise characterization of MAT.
    Methods in enzymology 01/2014; 537C:123-139. · 1.90 Impact Factor
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    ABSTRACT: Purpose Abdominal adiposity is associated with low BMD and decreased growth hormone (GH) secretion, an important regulator of bone homeostasis. The purpose of our study was to determine the effects of a short course of GH on markers of bone turnover and bone marrow fat in premenopausal women with abdominal adiposity. Materials and Methods In a 6-month, randomized, double-blind, placebo-controlled trial we studied 79 abdominally obese premenopausal women (21-45y) who underwent daily sc injections of GH vs. placebo. Main outcome measures were body composition by DXA and CT, bone marrow fat by proton MR spectroscopy, P1NP, CTX, 25(OH)D, hsCRP, undercarboxylated osteocalcin (ucOC), preadipocyte factor 1 (Pref 1), apolipoprotein B (ApoB), and IGF-1. Results GH increased IGF-1, P1NP, 25(OH)D, ucOC, bone marrow fat and lean mass, and decreased abdominal fat, hsCRP, and ApoB compared with placebo (p < 0.05). There was a trend toward an increase in CTX and Pref-1. Among all participants, 6-month increase in IGF-1 correlated with 6-month increase in P1NP (p = 0.0005), suggesting that subjects with the greatest increases in IGF-1 experienced the greatest increases in bone formation. Six-month decrease in abdominal fat, hsCRP, and ApoB inversely predicted 6-month change in P1NP, and 6-month increase in lean mass and 25(OH)D positively predicted 6-month change in P1NP (p ≤ 0.05), suggesting that subjects with greatest decreases in abdominal fat, inflammation and ApoB, and the greatest increases in lean mass and 25(OH)D experienced the greatest increases in bone formation. Six-month increase in bone marrow fat correlated with 6-month increase in P1NP (trend), suggesting that subjects with the greatest increases in bone formation experienced the greatest increases in bone marrow fat. Forward stepwise regression analysis indicated that increase in lean mass and decrease in abdominal fat were positive predictors of P1NP. When IGF-1 was added to the model, it became the only predictor of P1NP. Conclusion GH replacement in abdominally obese premenopausal women for 6 months increased bone turnover and bone marrow fat. Reductions in abdominal fat, and inflammation, and increases in IGF-1, lean mass and vitamin D were associated with increased bone formation. The increase in bone marrow fat may reflect changes in energy demand from increased bone turnover.
    Bone 01/2014; · 3.82 Impact Factor
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    ABSTRACT: Recent studies suggest a link between brown adipose tissue (BAT) and bone. The purpose of our study was to investigate the effects of BAT on femoral bone structure. We studied 105 patients (19 m, 86 f. mean age 45.5±16.1years) who underwent F18-FDG positron emission tomography/computed tomography (PET/CT) for benign etiologies (n=20) or follow-up of successfully treated malignancies (n=85); mean time between PET/CT and last form of treatment was 14.8±18.0months. BAT volume by PET/CT; femoral bone structure by CT (total femoral cross-sectional area (CSA), cortical CSA); and thigh muscle CSA and thigh subcutaneous fat CSA by CT was assessed. There were positive correlations between BAT volume and total femoral CSA and cortical CSA, independent of age, BMI and history of malignancy (p<0.05). BAT volume correlated positively with thigh muscle CSA and thigh fat CSA (p<0.05). When total femoral CSA was entered as a dependent variable and BAT volume, age and BMI as independent variables in a forward stepwise regression model, BAT volume was the only predictor of total femoral CSA. When femoral cortical CSA was entered as a dependent variable and BAT volume, age and BMI as independent variables, BAT volume was the only predictor of femoral cortical CSA. BAT volume is a positive predictor of femoral bone structure and correlates positively with thigh muscle and subcutaneous fat, possibly mediated by muscle. These results provide further evidence of a positive effect of BAT on bone.
    Bone 10/2013; · 3.82 Impact Factor
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    ABSTRACT: Sef (similar expression to fgf genes) is a feedback inhibitor of fibroblast growth factor (FGF) signaling and functions in part by binding to FGF receptors and inhibiting their activation. Genetic studies in mice and humans indicate an important role for fibroblast growth factor signaling in bone growth and homeostasis. We therefore investigated whether Sef had a function role in skeletal acquisition and remodeling. Sef expression is increased during osteoblast differentiation in vitro, and LacZ staining of Sef + /- mice showed high expression of Sef in the periosteum and chondro-osseous junction of neonatal and adult mice. Mice with a global deletion of Sef showed increased cortical bone thickness, bone volume and increased periosteal perimeter by μCT. Histomorphometric analysis of cortical bone revealed a significant increase in osteoblast number. Interestingly, Sef-/- mice showed very little difference in trabecular bone by μCT and histomorphometry compared to wild type mice. Bone marrow cells from Sef-/- mice grown in osteogenic medium showed increased proliferation and increased osteoblast differentiation compared to wild type bone marrow cells. Bone marrow cells from Sef-/- mice showed enhanced FGF2-induced activation of the ERK pathway, whereas bone marrow cells from Sef transgenic mice showed decreased FGF2-induced signaling. FGF2-induced acetylation and stability of Runx2 was enhanced in Sef -/- bone marrow cells, whereas overexpression of Sef inhibited Runx2-responsive luciferase reporter activity. Bone marrow from Sef-/- mice showed enhanced hematopoietic lineage-dependent and osteoblast-dependent osteoclastogenesis and increased bone resorptive activity relative to wild type controls in in vitro assays, while overexpression of Sef inhibited osteoclast differentiation. Taken together, these studies indicate that Sef has specific roles in osteoblast and osteoclast lineages, and that its absence results in increased osteoblast and osteoclast activity with a net increase in cortical bone mass. © 2013 American Society for Bone and Mineral Research.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 10/2013; · 6.04 Impact Factor
  • Clifford J Rosen
    The Lancet 10/2013; · 39.06 Impact Factor

Publication Stats

8k Citations
1,897.04 Total Impact Points

Institutions

  • 2008–2014
    • Maine Medical Center Research Institute
      Scarborough, Maine, United States
  • 2013
    • New York University College of Dentistry
      New York City, New York, United States
  • 2009–2013
    • Massachusetts General Hospital
      • Department of Radiology
      Boston, MA, United States
    • Mayo Clinic - Rochester
      Rochester, Minnesota, United States
  • 2003–2013
    • University of North Carolina at Chapel Hill
      • Department of Medicine
      Chapel Hill, NC, United States
    • National Eye Institute
      Maryland, United States
  • 1999–2013
    • Columbia University
      • • Department of Radiology
      • • Department of Medicine
      New York City, New York, United States
    • Lady Davis Institute for Medical Research
      Montréal, Quebec, Canada
  • 2012
    • Tufts University
      Georgia, United States
    • Oregon State University
      • School of Biological and Population Health Sciences
      Corvallis, OR, United States
    • Northwest University
      Northwest Harborcreek, Pennsylvania, United States
    • Osaka Medical Center and Research Institute for Maternal and Child Health
      Izumi, Ōsaka, Japan
  • 2009–2012
    • Maine Medical Center
      Portland, Maine, United States
  • 2002–2012
    • University of California, San Francisco
      • • Department of Epidemiology and Biostatistics
      • • Division of Endocrinology and Metabolism
      • • Division of Hospital Medicine
      San Francisco, CA, United States
    • Boston Children's Hospital
      Boston, Massachusetts, United States
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2011
    • Pennsylvania State University
      • Department of Nutritional Sciences
      University Park, MD, United States
    • Creighton University
      Omaha, Nebraska, United States
  • 2010–2011
    • University of São Paulo
      • Faculdade de Medicina de Ribeirão Preto (FMRP)
      São Paulo, Estado de Sao Paulo, Brazil
    • Mount Sinai School of Medicine
      • Department of Medicine
      Manhattan, NY, United States
    • Yale University
      • Department of Orthopaedics and Rehabilitation
      New Haven, CT, United States
  • 2002–2011
    • The Jackson Laboratory
      Bar Harbor, Maine, United States
  • 1992–2009
    • Saint Joseph Hospital
      Chicago, Illinois, United States
  • 2005–2007
    • Mayo Foundation for Medical Education and Research
      • Department of Biochemistry and Molecular Biology
      Scottsdale, AZ, United States
    • University of California, San Diego
      • Department of Medicine
      San Diego, CA, United States
  • 2006
    • The National Institute of Diabetes and Digestive and Kidney Diseases
      Maryland, United States
    • University of Texas Health Science Center at San Antonio
      • Department of Biochemistry
      San Antonio, TX, United States
    • University of Leuven
      Louvain, Flanders, Belgium
  • 2005–2006
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, Massachusetts, United States
  • 2003–2006
    • Emory University
      • • Department of Internal Medicine
      • • School of Medicine
      Atlanta, GA, United States
  • 2004–2005
    • Beth Israel Deaconess Medical Center
      Boston, Massachusetts, United States
    • St. Joseph's Hospital
      Savannah, Georgia, United States
  • 2002–2003
    • University of Cincinnati
      Cincinnati, Ohio, United States
  • 1990
    • University of Maine
      Orono, Minnesota, United States