Clifford J Rosen

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

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Publications (428)3032.28 Total impact

  • Gang Xi · Clifford J Rosen · David R Clemmons ·
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    ABSTRACT: IGF-I / IGF BP-2 coordinately stimulate osteoblast differentiation but the mechanisms by which they function have not been determined. AMP-activated protein kinase (AMPK) is induced during differentiation and AMPK knockout mice have reduced bone mass. IGF-I modulates AMPK in other cell types therefore these studies determined whether IGF-I/ IGFBP-2 stimulate AMPK activation and the mechanism by which AMPK modulates differentiation. Calvarial osteoblasts and MC-3T3 cells expressed activated AMPK early in differentiation and AMPK inhibitors attenuated differentiation. However expression of constitutively activated AMPK inhibited differentiation. To resolve this discrepancy we analyzed the time course of AMPK induction. AMPK activation was required early in differentiation (days 3-6) but downregulation of AMPK after day 9 was also necessary. IGF-I/ IGFBP-2 induced AMPK through their respective receptors and blocking receptor activation blocked AMPK induction. To determine the mechanism by which AMPK functioned we analyzed components of the autophagosome. Activated AMPK stimulated ULK-1 S555 phosphorylation as well as beclin-1 and LC3II induction. Inhibition of AMPK attenuated these changes and direct inhibition of autophagy inhibited differentiation. Conversely expression of activated AMPK was associated with persistence of these changes beyond day 9 and inhibited differentiation. Blocking AMPK activation after day 9 downregulated these autophagosome components and rescued differentiation. This allowed induction of mTOR and AKT which suppressed autophagy. The results show that early induction of AMPK in response to IGF-I/IGFBP-2 followed by suppression is required for osteoblast differentiation. AMPK functions through stimulation of autophagy. The findings suggest that these early catabolic changes are important for determining the energy source for osteoblast respiration and downregulation of these components may be required for induction of glycolysis which is required for the final anabolic stages of differentiation.
    Endocrinology 11/2015; DOI:10.1210/en.2015-1690 · 4.50 Impact Factor

  • International journal of radiation oncology, biology, physics 11/2015; 93(3):E618. DOI:10.1016/j.ijrobp.2015.07.2124 · 4.26 Impact Factor
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    ABSTRACT: Bone minerals are acquired during growth and are key determinants of adult skeletal health. During puberty, the serum levels of growth hormone (GH) and its downstream effector IGF-1 increase and play critical roles in bone acquisition. The goal of the current study was to determine how bone cells integrate signals from the GH/IGF-1 to enhance skeletal mineralization and strength during pubertal growth. Osteocytes, the most abundant bone cells, were shown to orchestrate bone modeling during growth. We used dentin matrix protein (Dmp)-1-mediated Ghr gene deletion in mice (DMP-GHRKO) to address the role of the GH/IGF axis in osteocytes. We found that DMP-GHRKO did not affect linear growth but compromised overall bone accrual. DMP-GHRKO mice exhibited reduced serum inorganic phosphate (Pi) and parathyroid hormone (PTH) levels and decreased bone formation indices and were associated with an impaired response to intermittent PTH treatment. Using an osteocyte-like cell line along with in vivo studies, we found that PTH sensitized the response of bone to GH by increasing Janus kinase-2 and IGF-1R protein levels. We concluded that endogenously secreted PTH and GHR signaling in bone are necessary to establish radial bone growth and optimize mineral acquisition during growth.-Liu, Z., Kennedy, O. D., Cardoso, L., Basta-Pljakic, J., Partridge, N. C., Schaffler, M. B., Rosen, C. J., Yakar, S. DMP-1-mediated Ghr gene recombination compromises skeletal development and impairs skeletal response to intermittent PTH.
    The FASEB Journal 10/2015; DOI:10.1096/fj.15-275859 · 5.04 Impact Factor
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    ABSTRACT: Heterochromatin protein 1 binding protein 3 (HP1BP3) is a recently described histone H1-related protein with roles in chromatin structure and transcriptional regulation. To explore the potential physiological role of HP1BP3 we have previously described an Hp1bp3(-/-) mouse model with reduced postnatal viability and growth. We now find that these mice are proportionate dwarfs, with reduction in body weight, body length and organ weight. In addition to their small size, micro-CT analysis showed that Hp1bp3(-/-) mice present a dramatic impairment of their bone development and structure. By three weeks of age, mice of both sexes have severely impaired cortical and trabecular bone, and these defects persist into adulthood and beyond. Primary cultures of both osteoblasts and osteoclasts from Hp1bp3(-/-) bone marrow and splenocytes respectively showed normal differentiation and function, strongly suggesting that the impaired bone accrual is due to non-cell autonomous systemic cues in-vivo. One major endocrine pathway regulating both body growth and bone acquisition is the IGF regulatory system, composed of insulin like growth factor 1 (IGF-1), the IGF receptors (IGFR) and the IGF binding proteins (IGFBPs). At 3 weeks of age Hp1bp3(-/-) mice exhibited a 60 reduction in circulating IGF-1 and a four-fold increase in the levels of IGFBP-1 and IGFBP-2. These alterations were reflected in similar changes in the hepatic transcripts of the Igf1, Igfbp1 and Igfbp2 genes. Collectively, these results suggest that HP1BP3 plays a key role in normal growth and bone development by regulating transcription of endocrine IGF-1 components.
    Endocrinology 09/2015; 156(12):en20151668. DOI:10.1210/en.2015-1668 · 4.50 Impact Factor
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    ABSTRACT: Substantial evidence shows that skeletal fragility should be considered among the complications associated with type 2 diabetes. Individuals with type 2 diabetes have increased fracture risk, despite normal bone mineral density (BMD) and high BMI-factors that are generally protective against fractures. The mechanisms underlying skeletal fragility in diabetes are not completely understood, but are multifactorial and likely include effects of obesity, hyperglycaemia, oxidative stress, and accumulation of advanced glycation end products, leading to altered bone metabolism, structure, and strength. Clinicians should be aware that BMD measurements underestimate fracture risk in people with type 2 diabetes, and that new treatments for diabetes, with neutral or positive effects on skeletal health, might play a part in the management of diabetes in those at high risk of fracture. Data for the optimum management of osteoporosis in patients with type 2 diabetes are scarce, but in the absence of evidence to the contrary, physicians should follow guidelines established for postmenopausal osteoporosis.
    09/2015; DOI:10.1016/S2213-8587(15)00283-1
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    ABSTRACT: Marrow adipose tissue (MAT) accumulates in diverse clinical conditions but remains poorly understood. Here we show region-specific variation in MAT adipocyte development, regulation, size, lipid composition, gene expression and genetic determinants. Early MAT formation in mice is conserved, whereas later development is strain dependent. Proximal, but not distal tibial, MAT is lost with 21-day cold exposure. Rat MAT adipocytes from distal sites have an increased proportion of monounsaturated fatty acids and expression of Scd1/Scd2, Cebpa and Cebpb. Humans also have increased distal marrow fat unsaturation. We define proximal 'regulated' MAT (rMAT) as single adipocytes interspersed with active haematopoiesis, whereas distal 'constitutive' MAT (cMAT) has low haematopoiesis, contains larger adipocytes, develops earlier and remains preserved upon systemic challenges. Loss of rMAT occurs in mice with congenital generalized lipodystrophy type 4, whereas both rMAT and cMAT are preserved in mice with congenital generalized lipodystrophy type 3. Consideration of these MAT subpopulations may be important for future studies linking MAT to bone biology, haematopoiesis and whole-body metabolism.
    Nature Communications 08/2015; 6:7808. DOI:10.1038/ncomms8808 · 11.47 Impact Factor
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    ABSTRACT: Previously, we reported sexually dimorphic bone mass and body composition phenotypes in Igfbp2(-)(/-) mice (-/-), where male mice exhibited decreased bone and increased fat mass, while female mice displayed increased bone but no changes in fat mass. To investigate the interaction between IGFBP-2 and estrogen, we subjected Igfbp2 -/- and +/+ female mice to ovariectomy (OVX) or sham surgery at 8 weeks of age. At 20 weeks of age, mice underwent metabolic cage analysis and insulin tolerance tests prior to sacrifice. At harvest, femurs were collected for μ CT, serum for protein levels, brown (BAT) and inguinal (IWAT) adipose depots for histology, gene expression, and XF24 mitochondrial analysis of whole tissue. In +/+ mice, serum IGFBP-2 dropped 30 with OVX. In the absence of IGFBP-2, OVX had no effect on pre-formed BAT; however, there was significant 'browning' of the IWAT depot coinciding with less weight gain, increased insulin sensitivity, lower intra-abdominal fat, and increased bone loss due to higher resorption and lower formation. Likewise, after OVX, energy expenditure (EE), physical activity and BAT mitochondrial respiration were decreased less in the OVX -/- compared to OVX +/+. Mitochondrial respiration of IWAT was reduced in OVX +/+ yet remained unchanged in OVX -/- mice. These changes were associated with significant increases in Fgf21 and Foxc2 expression, two proteins known for their insulin sensitizing and browning of WAT effects. We conclude that estrogen deficiency has a profound effect on body and bone composition in the absence of IGFBP-2 and may be related to changes in FGF-21.
    Endocrinology 07/2015; 156(11):en20141452. DOI:10.1210/en.2014-1452 · 4.50 Impact Factor
  • Beata Lecka-Czernik · Clifford J Rosen ·
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    ABSTRACT: New evidence has recently emerged defining a close relationship between fat and bone metabolism. Adipose tissue is one of the largest organs in the body but its functions vary by location and origin. Adipocytes can act in an autocrine manner to regulate energy balance by sequestering triglycerides and then, depending on demand, releasing fatty acids through lipolysis for energy utilization, and in some cases through uncoupling protein 1 for generating heat. Adipose tissue can also act in an endocrine or paracrine manner by releasing adipokines that modulate the function of other organs. Bone is one of those target tissues, although recent evidence has emerged that the skeleton reciprocates by releasing its own factors that modulate adipose tissue and beta cells in the pancreas. Therefore, it is not surprising that these energy- modulating tissues are controlled by a central regulatory mechanism, primarily the sympathetic nervous system. Disruption in this complex regulatory circuit and its downstream tissues is manifested in a wide range of metabolic disorders, for which the most prevalent is type 2 diabetes mellitus. The aim of this review is to summarize our knowledge of common determinants in bone and adipose function and the translational implications of recent work in this emerging field. Copyright © 2015. Published by Elsevier Inc.
    Bone 07/2015; DOI:10.1016/j.bone.2015.07.026 · 3.97 Impact Factor
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    Ryan Berry · Matthew S. Rodeheffer · Clifford J. Rosen · Mark C. Horowitz ·
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    ABSTRACT: The formation of brown, white and beige adipocytes have been a subject of intense scientific interest in recent years due to the growing obesity epidemic in the United States and around the world. This interest has led to the identification and characterization of specific tissue resident progenitor cells that give rise to each adipocyte population in vivo. However, much still remains to be discovered about each progenitor population in terms of their "niche" within each tissue and how they are regulated at the cellular and molecular level during healthy and diseased states. While our knowledge of brown, white and beige adipose tissue is rapidly increasing, little is still known about marrow adipose tissue and its progenitor despite recent studies demonstrating possible roles for marrow adipose tissue in regulating the hematopoietic space and systemic metabolism at large. This chapter focuses on our current knowledge of brown, white, beige and marrow adipose tissue with a specific focus on the formation of each tissue from tissue resident progenitor cells.
    07/2015; 1(3). DOI:10.1007/s40610-015-0018-y
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    ABSTRACT: This study investigated the effects of loss of Cthrc1 on adipogenesis, body composition, metabolism, physical activity, and muscle physiology. Complete metabolic and activity monitoring as well as grip strength measurements and muscle myography was performed in Cthrc1 null and wildtype mice. Compared to wildtypes, Cthrc1 null mice had similar body weights but significantly reduced energy expenditure, decreased lean mass, and increased fat mass, especially visceral fat. In vitro studies demonstrated that Cthrc1 inhibited adipocyte differentiation as well as PPAR and CREB reporter activity, while preadipocytes isolated from Cthrc1 null mice exhibited enhanced adipogenic differentiation. Voluntary physical activity in Cthrc1 null mice as assessed by wheel running was reduced to approximately half the distance covered by wildtypes. Reduced grip strength was observed in Cthrc1 null mice at the age of 15 weeks or older with reduced performance and mass of hyphenate muscle. In the brain, Cthrc1 expression was most prominent in neurons of thalamic and hypothalamic nuclei with evidence for secretion into the circulation in the median eminence. Our data indicate that Cthrc1 regulates body composition through inhibition of adipogenesis. In addition, central Cthrc1 may be a mediator of muscle function and physical activity. © 2015 The Obesity Society.
    Obesity 07/2015; 23(8). DOI:10.1002/oby.21144 · 3.73 Impact Factor
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    ABSTRACT: There is considerable consumer and physician interest in vitamin D as a possible therapeutic agent for a range of clinical conditions, and despite mixed evidence the interest does not appear to lessen. Some clinicians believe that consumption of vitamin D is inadequate and, in turn, advocate vitamin D supplementation to increase serum levels of the nutrient. However, evidence concerning the role of vitamin D in health and disease is conflicting, and primary care physicians have little time to sort through the data and may find it difficult to advise their patients. To better understand the challenges that primary care physicians face regarding vitamin D, and to help inform those who provide guidance for clinical decision-making, the Office of Dietary Supplements at the National Institutes of Health, with co-sponsorship from other federal health agencies, held a conference titled Vitamin D: Moving Toward Evidence-based Decision Making in Primary Care in December 2014.(1) More than 20 invited presenters and panelists considered laboratory methods for measuring vitamin D status, discussed how clinical studies of vitamin D should be evaluated and used in developing recommendations, noted the role of values and preferences in clinical decision making, debated the current science related to at-risk groups, and described emerging data about health risks of excessive intakes of vitamin D. Eight questions about vitamin D stem from the Conference presentations as well as other expert sources. Copyright © 2015 Elsevier Inc. All rights reserved.
    The American journal of medicine 06/2015; 128(11). DOI:10.1016/j.amjmed.2015.05.025 · 5.00 Impact Factor
  • Beata Lecka-Czernik · Clifford J Rosen ·
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    ABSTRACT: Skeletal complications have recently been recognized as another of the several co-morbidities associated with diabetes. Clinical studies suggest that disordered glucose and lipid metabolism have a profound effect on bone. Diabetes-related changes in skeletal homeostasis result in a significant increased risk of fractures, although the pathophysiology may differ from postmenopausal osteoporosis. Efforts to understand the underlying mechanisms of diabetic bone disease have focused on the direct interaction of adipose tissue with skeletal remodeling and the potential influence of glucose utilization and energy uptake on these processes. One aspect that has emerged recently is the major role of the central nervous system in whole body metabolism, bone turnover, adipose tissue remodeling and beta cell secretion of insulin. Importantly the skeleton contributes to the metabolic balance inherent in physiologic states. New animal models have provided the insights necessary to begin to dissect the effects of obesity and insulin resistance on the acquisition and maintenance of bone mass. In this Perspective, we will focus on potential mechanisms that underlie the complex interactions between adipose tissue and skeletal turnover by focusing on the clinical evidence and on pre-clinical studies indicating that glucose intolerance may have a significant impact on the skeleton. In addition, we will raise fundamental questions that need to be addressed in future studies to resolve the conundrum associated with glucose intolerance, obesity, and osteoporosis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 06/2015; 30(8). DOI:10.1002/jbmr.2574 · 6.83 Impact Factor
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    ABSTRACT: Severe burn results in acute bone resorption followed by an adynamic state, most likely due to changes brought about by the inflammatory and glucocorticoid responses to the injury. There is a consequent increase in annual extrapolated fracture incidence in children. While osteoblasts have been reported to disappear from the bone surface and stem cell differentiation into osteoblasts is impaired, the effect of burns on osteocyte function is unknown. We measured serum concentrations of two osteocyte proteins, sclerostin and fibroblast growth factor (FGF)-23 between 6 and 60 days post-burn in pediatric patients, ages 5-18 years who had participated in a randomized controlled double-blind study of acute administration of pamidronate to prevent the resorptive bone loss. While FGF-23 was undetectable in all samples, the plot of sclerostin concentration versus time post-burn yielded a statistically significant difference between slopes, -2.5 in the placebo control group and +3.5 in the group receiving pamidronate, p=0.016 by ANCOVA. The FGF23 data suggest that osteocytes may be apoptotic, although the sclerostin data may indicate partial preservation of osteocyte function in subjects receiving pamidronate or an ectopic source of sclerostin. Copyright © 2015 Elsevier Ltd and ISBI. All rights reserved.
    Burns: journal of the International Society for Burn Injuries 04/2015; 41(7). DOI:10.1016/j.burns.2015.04.001 · 1.88 Impact Factor
  • Anjali Sharma · Peter L Flom · Clifford J Rosen · Ellie E Schoenbaum ·
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    ABSTRACT: To characterize changes in bone mineral density (BMD) according to race among HIV-infected and uninfected women, and to evaluate the relationship between race and menopause-related bone loss. Dual x-ray absorptiometry measured BMD on study entry and a minimum of 18 months later in 246 HIV-infected and 219 HIV-uninfected women in the Menopause Study. Linear regression analyses determined percent annual BMD change at total hip (TH), femoral neck (FN), and lumbar spine (LS) after adjusting for potential confounders. Race-stratified and HIV-infected subgroup analyses were performed. At baseline, mean age was 45 years, 19% of women were postmenopausal. HIV-infected women were more likely to be black (58% vs. 38%), and had lower BMI and less cigarette exposure when compared to HIV-uninfected women. Women who were perimenopausal at baseline and postmenopausal at follow-up had the greatest TH bone loss (-1.68%/yr, p<.0001) followed by those postmenopausal throughout (-1.02%/yr, p=.007). We found a significant interaction between HIV status and race in multivariate analyses of BMD change at the FN and TH. In race-stratified analyses, HIV infection was associated with TH BMD loss in non-black women. Black women experienced greater menopause-associated decline in TH BMD compared with non-black women. The association of HIV and BMD differs strikingly by race, as do the effects of the menopausal transition on bone. Determining the extent to which the effect of HIV on fracture risk varies by race will be crucial to identify HIV-infected women at greatest risk for osteoporotic fracture, particularly as they enter menopause. Copyright © 2015. Published by Elsevier Inc.
    Bone 04/2015; 77. DOI:10.1016/j.bone.2015.04.018 · 3.97 Impact Factor
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    ABSTRACT: Anorexia nervosa (AN) is a psychiatric disorder characterized by self-induced starvation and low body weight. Women with AN have impaired bone formation, low bone mass and an increased risk of fracture. FGF-21 is a hormone secreted by the liver in starvation and FGF-21 transgenic mice have significant bone loss due to an uncoupling of bone resorption and bone formation. We hypothesized that FGF-21 may contribute to the low bone mass state of AN. We studied 46 women: 20 with AN (median age [interquartile range]: 27.5 [25, 30.75] years) and 26 normal-weight controls (NWC) of similar age (25 [24, 28.5] years). We investigated associations between serum FGF-21 and 1) aBMD measured by dual energy X-ray absorptiometry, 2) parameters of bone microarchitecture in the distal radius and tibia measured by high-resolution peripheral quantitative CT and 3) bone strength, estimated by microfinite element analysis. FGF-21 levels were similar in AN and NWC (AN: 33.1 [18.1, 117.0] pg/ml vs NWC: 57.4 [23.8, 107.1] pg/ml; p=0.54). There was a significant inverse association between log FGF-21 and trabecular number in the radius in both AN (R=-0.57, p<0.01) and NWC (R=-0.53, p<0.01) and a significant positive association between log FGF-21 and trabecular separation in the radius in AN (R=0.50, p<0.03) and NWC (R=0.52, p<0.01). Estimates of radial bone strength were inversely associated with log FGF-21 in AN (R=-0.50, p<0.03 for both stiffness and failure load). There were no associations between FGF-21 and aBMD, cortical parameters or tibial parameters in the AN or NWC groups. FGF-21 may be an important determinant of trabecular skeletal homeostasis in AN. Copyright © 2015. Published by Elsevier Inc.
    Bone 04/2015; 77. DOI:10.1016/j.bone.2015.04.001 · 3.97 Impact Factor
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    ABSTRACT: Atypical antipsychotic (AA) drugs cause significant metabolic side effects and clinical data are emerging that demonstrate increased fracture risk and bone loss after treatment with the AA, risperidone (RIS). The pharmacology underlying the adverse effects on bone is unknown. However, RIS action in the central nervous system (CNS) could be responsible because the sympathetic nervous system (SNS) is known to uncouple bone remodeling. RIS treatment in mice significantly lowered trabecular bone volume fraction (BV/TV), due to increased osteoclast-mediated erosion and reduced osteoblast-mediated bone formation. Daytime energy expenditure was also increased and was temporally associated with the plasma concentration of RIS. Even a single dose of RIS transiently elevated expression of brown adipose tissue markers of SNS activity and thermogenesis, Pgc1a and Ucp1. Rankl, an osteoclast recruitment factor regulated by the SNS, was also increased 1 hr after a single dose of RIS. Thus, we inferred that bone loss from RIS was regulated, at least in part, by the SNS. To test this, we administered RIS or vehicle to mice that were also receiving the non-selective β-blocker propranolol (PRO). Strikingly, RIS did not cause any changes in trabecular BV/TV, erosion or formation while PRO was present. Furthermore, β2 adrenergic receptor null (Adrb2-/-) mice were also protected from RIS-induced bone loss. This is the first report to demonstrate SNS-mediated bone loss from any AA. Since AA medications are widely prescribed especially to young adults, clinical studies are needed to assess whether β-blockers will prevent bone loss in this vulnerable population.
    Endocrinology 04/2015; 156(7):en20151099. DOI:10.1210/en.2015-1099 · 4.50 Impact Factor
  • Michaela R Reagan · Lucy Liaw · Clifford J Rosen · Irene M Ghobrial ·
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    ABSTRACT: Multiple myeloma is a B-cell malignancy characterized by the unrelenting proliferation of plasma cells. Multiple myeloma causes osteolytic lesions and fractures that do not heal due to decreased osteoblastic and increased osteoclastic activity. However, the exact relationship between osteoblasts and myeloma cells remains elusive. Understanding the interactions between these dynamic bone-forming cells and myeloma cells is crucial to understanding how osteolytic lesions form and persist, and how tumors grow within the bone marrow. This review provides a comprehensive overview of basic and translational research focused on the role of osteoblasts in multiple myeloma progression and their relationship to osteolytic lesions. Importantly, current challenges for in vitro studies exploring direct osteoblastic effects on myeloma cells, and gaps in understanding the role of the osteoblast in myeloma progression are delineated. Finally, successes and challenges in myeloma treatment with osteoanabolic therapy (i.e. any treatment that induces increased osteoblastic number or activity) are enumerated. Our goal is to illuminate novel mechanisms by which osteoblasts may contribute to multiple myeloma disease progression and osteolysis to better direct research efforts. Ultimately, we hope this may provide a roadmap for new approaches to the pathogenesis and treatment of multiple myeloma with a particular focus on the osteoblast. Copyright © 2015. Published by Elsevier Inc.
    Bone 02/2015; 75. DOI:10.1016/j.bone.2015.02.021 · 3.97 Impact Factor
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    ABSTRACT: Obesity has been associated with high bone mineral density (BMD) but a greater propensity to fracture. Some obese individuals have increased marrow adipose tissue (MAT), but the impact of MAT on bone turnover remains controversial, as do changes in BMD associated with a high fat diet (HFD). In this study we hypothesized that MAT volume would increase in response to HFD but would be independent of changes in BMD. Hence, we fed C57BL/6J (B6) male mice at 3 weeks of age either a high fat diet (60 kcal %) or regular diet (10 kcal %) for 12 weeks (n = 10/group). We measured MAT volume by osmium staining and micro-CT (µCT) as well as bone parameters by µCT, histomorphometry, and dual-energy X-ray absorptiometry. We also performed a short-term pilot study using 13-week-old B6 males and females fed a HFD (58 kcal %) for 2 weeks (n = 3/sex). Both long- and short-term HFD feedings were associated with high MAT volume, however, femoral trabecular bone volume fraction (BV/TV), bone formation rate and cortical bone mass were not altered in the long-term study. In the short-term pilot study, areal BMD was unchanged after two weeks of HFD. We conclude that, for B6 mice fed a HFD starting at wean or 13 weeks of age, MAT increases whereas bone mass is not altered. More studies are needed to define the mechanism responsible for the rapid storage of energy in the marrow and its distinction from other adipose depots. This article is protected by copyright. All rights reserved
    Journal of Cellular Physiology 02/2015; 230(9). DOI:10.1002/jcp.24954 · 3.84 Impact Factor
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    ABSTRACT: Obstructive sleep apnea (OSA) and low bone mass are two prevalent conditions, particularly among older adults, a section of the U.S. population that is expected to grow dramatically over the coming years. OSA, the most common form of sleep disordered breathing, has been linked to multiple cardiovascular, metabolic, hormonal and inflammatory derangements and may have adverse effects on bone. However, little is known about how OSA (including the associated hypoxia and sleep loss) affects bone metabolism. In order to gain insight into the relationship between sleep and bone, we review the growing information on OSA and metabolic bone disease and discuss the pathophysiological mechanisms by which OSA may affect bone metabolism/architecture. This article is protected by copyright. All rights reserved
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 02/2015; 30(2). DOI:10.1002/jbmr.2446 · 6.83 Impact Factor
  • Casey R Doucette · Clifford J Rosen ·
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    ABSTRACT: Bone is an essential organ that not only confers structural stability to the organism, but also serves as a reservoir for hematopoietic elements and is thought to affect systemic homeostasis through the release of endocrine factors as well as calcium. The loss of bone mass due to an uncoupling of bone formation and bone resorption leads to increased fragility that can result in devastating fractures. Further understanding of the effects of environmental stimuli on the development of bone disease in humans is needed, and can be studied using animal models. In this chapter, we present established and novel methods for the induction of bone loss in mice, including manipulation of diet and environment, drug administration, irradiation, and hormone deficiency. All of these models are directly related to human cases, and can thus be used to investigate the causes of bone loss resulting from these interventions.
    01/2015; 2014. DOI:10.1002/9780470942390.mo140071

Publication Stats

19k Citations
3,032.28 Total Impact Points


  • 2008-2015
    • Maine Medical Center Research Institute
      Scarborough, Maine, United States
  • 2008-2014
    • Maine Medical Center
      Portland, Maine, United States
  • 1994-2014
    • University of Maine
      Orono, Minnesota, United States
    • Society for Experimental Biology & Medicine
      Society Hill, New Jersey, United States
    • Richmond VA Medical Center
      Ричмонд, Virginia, United States
  • 2012-2013
    • Tufts University
      Бостон, Georgia, United States
    • Oregon State University
      • School of Biological and Population Health Sciences
      Corvallis, OR, United States
    • University of North Carolina at Chapel Hill
      • Department of Medicine
      North Carolina, United States
  • 1999-2011
    • Creighton University
      • Department of Medicine
      Omaha, Nebraska, United States
  • 1997-2011
    • The Jackson Laboratory
      Bar Harbor, Maine, United States
  • 1990-2011
    • St. Joseph's Hospital
      Savannah, Georgia, United States
  • 2009
    • Icahn School of Medicine at Mount Sinai
      • Department of Medicine
      Borough of Manhattan, New York, United States
    • Beverly Hospital, Boston MA
      BVY, Massachusetts, United States
    • Mayo Clinic - Rochester
      • Department of Health Science Research
      Rochester, Minnesota, United States
  • 2006
    • University of Texas Health Science Center at San Antonio
      • Department of Biochemistry
      San Antonio, Texas, United States
    • Cornell University
      • Department of Animal Science
      Итак, New York, United States
  • 2002-2006
    • Brigham and Women's Hospital
      Boston, Massachusetts, United States
    • Loma Linda University
      • Department of Medicine
      لوما ليندا، كاليفورنيا, California, United States
  • 2003-2005
    • University of California, San Francisco
      • Department of Epidemiology and Biostatistics
      San Francisco, CA, United States
    • National Eye Institute
      Maryland, United States
    • National Institutes of Health
      베서스다, Maryland, United States
  • 2002-2004
    • Columbia University
      • Department of Genetics and Development
      New York, New York, United States
  • 2000
    • Dalhousie University
      Halifax, Nova Scotia, Canada
  • 1998
    • Sir Charles Gairdner Hospital
      Perth City, Western Australia, Australia
    • Beth Israel Medical Center
      • Division of Rheumatology
      New York City, New York, United States
  • 1996-1997
    • Husson College
      Saint Joseph, Missouri, United States
    • Society for Clinical Trials
      Society Hill, New Jersey, United States