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1.  Bone as an Endocrine Organ 
Bone has classically been viewed as an inert structure that is necessary for mobility, calcium homeostasis, and maintenance of the hematopoietic niche. Recent advances in bone biology using complex genetic manipulations in mice have highlighted the importance of bone not only as a structural scaffold to support the human body, but also as a regulator of a number of metabolic processes that are independent of mineral metabolism. These advances point to the skeleton as an endocrine organ that modulates glucose tolerance and testosterone production by secretion of a bone-specific protein, osteocalcin. This review will detail how bone has emerged as a bona-fide endocrine “gland”, and with that, the potential therapeutic implications that could be realized for this hormone-secreting tissue.
doi:10.4158/EP12141.RA
PMCID: PMC3571654  PMID: 22784851
2.  IGFBP-2 is a negative predictor of cold-induced brown fat and bone mineral density in young non-obese women 
Bone  2013;53(2):336-339.
Recent studies have shown a positive correlation between brown adipose tissue (BAT) and bone mineral density (BMD). However, mechanisms underlying this relationship are unknown. Insulin-like growth factor 1 (IGF-1) is an important regulator of stem cell differentiation promoting bone formation. IGF binding protein 2 (IGFBP-2) binds IGF-1 in the circulation and has been reported to inhibit bone formation in humans. IGF-1 is also a crucial regulator of brown adipocyte differentiation. We hypothesized that IGFBP-2 is a negative and IGF-1 a positive regulator of BAT-mediated osteoblastogenesis. We therefore investigated a cohort of 15 women (mean age 27.7±5.7 years): 5 with anorexia nervosa (AN) in whom IGF-1 levels were low due to starvation, 5 recovered AN (AN-R), and 5 women of normal weight. All subjects underwent assessment of cold-activated BAT by PET/CT, BMD of the spine, hip, femoral neck, and total body by DXA, thigh muscle area by MRI, IGF-1 and IGFBP-2. There was a positive correlation between BAT and BMD and an inverse association between IGFBP-2 and both BAT and BMD. There was no association between IGF-1 and BAT. We show for the first time that IGFBP-2 is a negative predictor of cold-induced BAT and BMD in young non-obese women, suggesting that IGFBP-2 may serve as a regulator of BAT-mediated osteoblastogenesis.
doi:10.1016/j.bone.2012.12.046
PMCID: PMC3594375  PMID: 23291564
brown adipose tissue (BAT); IGFBP-2; bone mineral density (BMD); anorexia nervosa (AN)
3.  Vitamin D Safety and Requirements 
Vitamin D an ancient secosteroid is essential for mineral homeostasis, bone remodeling, immune modulation, and energy metabolism. Recently, debates have emerged about the daily vitamin D requirements for healthy and elderly adults, the safety and efficacy of long term supplementation and the role of vitamin D deficiency in several chronic disease states. Since this molecule acts as both a vitamin and a hormone, it should not be surprising that the effects of supplementation are multi-faceted and complex. Yet despite significant progress in the last decade, our understanding of vitamin D physiology and the clinical relevance of low circulating levels of this vitamin remains incomplete. The present review provides the reader with a comprehensive and up-to-date understanding of vitamin D requirements and safety. It also raises some provocative research questions.
doi:10.1016/j.abb.2011.12.002
PMCID: PMC3311750  PMID: 22179017
Vitamin D; diagnosis; treatment
4.  Single Cell Gene Expression Profiling of Cortical Osteoblast Lineage Cells 
Bone  2012;53(1):174-181.
In tissues with complex architectures such as bone, it is often difficult to purify and characterize specific cell types via molecular profiling. Single cell gene expression profiling is an emerging technology useful for characterizing transcriptional profiles of individual cells isolated from heterogeneous populations. In this study we describe a novel procedure for the isolation and characterization of gene expression profiles of single osteoblast lineage cells derived from cortical bone. Mixed populations of different cell types were isolated from adult long bones of C57BL/6J mice by enzymatic digestion, and subsequently subjected to FACS to purify and characterize osteoblast lineage cells via a selection strategy using antibodies against CD31, CD45, and Alkaline Phosphatase (AP), specific for mature osteoblasts. The purified individual osteoblast lineage cells were then profiled at the single cell level via nanofluidic PCR. This method permits robust gene expression profiling on single osteoblast lineage cells derived from mature bone, potentially from anatomically distinct sites. In conjunction with this technique, we have also shown that it is possible to carry out single cell profiling on cells purified from fixed and frozen bone samples without compromising the gene expression signal. The latter finding means the technique can be extended to biopsies of bone from diseased individuals. Our approach for single cell expression profiling provides a new dimension to the transcriptional profile of the primary osteoblast lineage population in vivo, and has the capacity to greatly expand our understanding of how these cells may function in vivo under normal and diseased states.
doi:10.1016/j.bone.2012.11.043
PMCID: PMC3589579  PMID: 23238121
5.  Temperatures Rising: Brown Fat and Bone 
Discovery medicine  2011;11(58):179-185.
Caloric restriction is associated with a reduction in body weight and temperature but a reduction in trabecular bone volume and paradoxically an increase in adipocytes within the bone marrow. The nature of these adipocytes is uncertain, although there is emerging evidence of a direct relationship between bone remodeling and brown adipocytes. For example, in heterotropic ossification, brown adipocytes set up a hypoxic gradient that leads to vascular invasion, chondrocyte differentiation and subsequent bone formation. Additionally, deletion of retinoblastoma protein in an osteosarcoma model leads to increased hibernosarcoma (brown fat tumor). Interestingly, brown adipose tissue (BAT) senescences with age at a time when thermoregulation becomes altered,, bone loss becomes apparent and sympathetic activity increases. Interestingly, heart rate is an unexpected but good predictor of fracture risk in elderly individuals, pointing to a key role for the sympathetic nervous system in senile osteoporosis. Hence the possibility exists that BAT could play an indirect role in age-related bone loss. However, evidence of an indirect effect from thermogenic dysfunction on bone loss is currently limited. Here, we present current evidence for a relationship between brown adipose tissue and bone as well as provide novel insights into the effects of thermoregulation on bone mineral density.
PMCID: PMC3629549  PMID: 21447277
6.  Placebo-Controlled Trials in Osteoporosis — Proceeding with Caution 
The New England journal of medicine  2010;363(14):1365-e22.
This article presents one viewpoint on the issues surrounding placebo-controlled trials in osteoporosis. The other Sounding Board article in this issue presents an opposing view. At NEJM.org, in a related interactive feature, the authors of each article give their Point of View about the other article. At NEJM.org, readers can participate in forming community opinion by choosing one of the viewpoints and, if they like, providing their reasons.
doi:10.1056/NEJMsb1002227
PMCID: PMC3901575  PMID: 20879887
7.  MODERATE ALCOHOL INTAKE LOWERS BIOCHEMICAL MARKERS OF BONE TURNOVER IN POSTMENOPAUSAL WOMEN 
Menopause (New York, N.Y.)  2012;19(9):10.1097/gme.0b013e31824ac071.
Objective
Epidemiological studies indicate that higher bone mass is associated with moderate alcohol consumption in postmenopausal women. However, the underlying cellular mechanisms responsible for the putative beneficial effects of alcohol on bone are unknown. Excessive bone turnover, combined with an imbalance whereby bone resorption exceeds bone formation, is the principal cause for postmenopausal bone loss. This study investigated the hypothesis that moderate alcohol attenuates bone turnover following menopause.
Methods
Bone mineral density (BMD) was determined by dual energy x-ray absorptiometry in 40 healthy postmenopausal women (56.3 ± 0.5 years of age, mean ± SE) who consumed 19 ± 1 g alcohol/day. Serum levels of the bone formation marker osteocalcin and resorption marker C-terminal telopeptide (CTx) were measured by immunoassay at baseline (day 0) and following alcohol withdrawal for 14 days. Participants then consumed alcohol and were assayed the following morning.
Results
BMD at the trochanter and total hip were positively correlated to level of alcohol consumption. Serum osteocalcin and CTx increased following abstinence (4.1 ± 1.6%; p = 0.01 and 5.8 ± 2.6%; p = 0.02 compared to baseline, respectively). Osteocalcin and CTx decreased following alcohol re-administration compared to the previous day (−3.4 ± 1.4%; p = 0.01 and −3.5 ± 2.1%; p = 0.05, respectively), to values that did not differ from baseline (p > 0.05).
Conclusions
Abstinence from alcohol resulted in increased markers of bone turnover whereas resumption of alcohol reduced bone turnover markers. These results suggest a cellular mechanism for the increased bone density observed in postmenopausal moderate alcohol consumers. Specifically, the inhibitory effect of alcohol on bone turnover attenuates the detrimental skeletal consequences of excessive bone turnover associated with menopause.
doi:10.1097/gme.0b013e31824ac071
PMCID: PMC3597753  PMID: 22922514
osteoporosis; DXA; osteocalcin; CTx; ethanol; serum estradiol
8.  The IGF-I regulatory system and its impact on skeletal and energy homeostasis 
Journal of Cellular Biochemistry  2010;111(1):14-19.
Insulin-like growth factor (IGF)-I is important in the acquisition and maintenance of both soft and hard tissues. Skeletal remodeling requires energy and recent work has demonstrated that bone can influence insulin sensitivity and thereby regulate metabolic processes. New insights from mouse models into the role of IGF-binding proteins (IGFBPs) as more than mere depots for the IGFs has reignited investigations into the metabolic targets influenced by the IGF regulatory system and the pathways that link bone to adipose tissue. Although there remains continued uncertainty about the relative balance between the effects of circulating vs tissue IGF-I actions, the role of the IGFBPs has been redefined both as modulators of IGF-I action and as independent signaling factors. This review highlights several recent findings that shed new light on the physiologic role of the IGF regulatory system and its influence on skeletal and fat metabolism.
doi:10.1002/jcb.22678
PMCID: PMC3276304  PMID: 20506515
9.  Emerging Therapeutic Opportunities for Skeletal Restoration 
Nature reviews. Drug discovery  2011;10(2):141-156.
Preface
Osteoporosis, a syndrome characterized by thin bones and fractures, has become more prevalent in both women and men. Established therapies for this disorder consist primarily of drugs that prevent bone loss, such as the bisphosphonates and selective estrogen receptor modulators. Although these drugs have been shown to reduce fractures in randomized trials, there is an urgent need for treatments that could lower fracture risk further without additional adverse effects. The introduction of parathyroid hormone (teriparatide), which significantly increases bone mineral density, albeit for a relatively short duration, raised expectations that drugs which stimulate bone formation might cure osteoporosis. After outlining current approaches to treating osteoporosis, this review focuses on emerging therapeutic opportunities for osteoporosis that are based on recent insights into skeletal physiology. Such novel strategies offer promise for not only reducing age-related bone loss and the associated risk of fractures, but restoring bone mineral density to healthy levels.
doi:10.1038/nrd3299
PMCID: PMC3135105  PMID: 21283108
10.  Novel Insights into the Relationship between Diabetes and Osteoporosis 
Only three decades ago adipose tissue was considered inert with little relationship to insulin resistance. Similarly bone has long been thought purely in its structural context. In the last decade, emerging evidence has revealed important endocrine roles for both bone and adipose tissue. The interaction between these two tissues is remarkable. Bone marrow mesenchymal stem cells give rise to both osteoblasts and adipocytes. Leptin and adiponectin, two adipokines secreted by fat tissue, control energy homeostasis, but also have complex actions on the skeleton. In turn, the activities of bone cells are not limited to their bone remodeling activities, but also to modulation of adipose sensitivity and insulin secretion. This review will discuss these new insights linking bone remodeling to the control of fat metabolism and the association between diabetes mellitus and osteoporosis.
doi:10.1002/dmrr.1135
PMCID: PMC3259009  PMID: 20938995
Osteoporosis; diabetes mellitus; obesity; leptin; osteocalcin
11.  Understanding leptin-dependent regulation of skeletal homeostasis 
Biochimie  2012;94(10):2089-2096.
Despite growing evidence for adipose tissue regulation of bone mass, the role of the adipokine leptin in bone remodeling remains controversial. The majority of in vitro studies suggest leptin enhances osteoblastic proliferation and differentiation while inhibiting adipogenic differentiation from marrow stromal cells. Alternatively, some evidence demonstrates either no effect or a pro-apoptotic action of leptin on stromal cells. Similarly, in vivo work has demonstrated both positive and negative effects of leptin on bone mass. Most of the literature supports the idea that leptin suppresses bone mass by acting in the brainstem to reduce serotonin-dependent sympathetic signaling from the ventromedial hypothalamus to bone. However, other studies have found partly or entirely contrasting actions of leptin. Recently one study found a significant effect of surgery alone with intracerebroventricular administration of leptin, a technique crucial for understanding centrally-mediated leptin regulation of bone. Thus, two mainstream hypotheses for the role of leptin on bone emerge: 1) direct regulation through increased osteoblast proliferation and differentiation and 2) indirect suppression of bone formation through a hypothalamic relay. At the present time, it remains unclear whether these effects are relevant in only extreme circumstances (i.e. models with complete deficiency) or play an important homeostatic role in the regulation of peak bone acquisition and skeletal remodeling. Ultimately, determining the actions of leptin on the skeleton will be critical for understanding how the obesity epidemic may be impacting the prevalence of osteoporosis.
doi:10.1016/j.biochi.2012.04.015
PMCID: PMC3512082  PMID: 22534195
Leptin; Bone remodeling; Adipocyte; Osteoblast; Sympathetic nervous system
12.  New Insights into Osteoporosis: The Bone-Fat Connection 
Journal of internal medicine  2012;272(4):317-329.
Osteoporosis and obesity are chronic disorders that are increasing in prevalence. The pathophysiology of these diseases is multifactorial and includes genetic, environmental and hormonal determinants. Long considered as distinct disorders that rarely are found in the same individual, emerging evidence from basic and clinical studies support an important interaction between adipose tissue and the skeleton. Adiposity can influence bone remodeling through three possible mechanisms including secretion of cytokines that directly target bone, adipokines that influence the central nervous system thereby changing sympathetic impulses to bone, and paracrine influences on adjacent skeletal cells. This review will focus on our current understanding of bone-fat interactions and the clinical implications of recent studies linking obesity to osteoporosis.
doi:10.1111/j.1365-2796.2012.02564.x
PMCID: PMC3634716  PMID: 22702419
13.  Tissue Specific Expression Of Sprouty1 In Mice Protects Against High Fat Diet Induced Fat Accumulation, Bone Loss, And Metabolic Dysfunction 
The British journal of nutrition  2011;108(6):1025-1033.
We recently characterized Sprouty1 (Spry1), a growth factor signaling inhibitor as a regulator of marrow progenitor cells promoting osteoblast differentiation at the expense of adipocytes. Adipose tissue specific Spry1 expression in mice resulted in increased bone mass and reduced body fat while conditional knockout of Spry1 had the opposite effect with decreased bone and increased body fat. Because Spry1 suppresses normal fat development, we tested the hypothesis that Spry1 expression prevents high fat diet-induced obesity, bone loss, and associated lipid abnormalities and demonstrate that Spry1 has a long-term protective effect on mice fed a high caloric diet. We studied diet-induced obesity in mice with fatty acid binding promoter (aP2)-driven expression or conditional knockout of Spry1 in adipocytes. Phenotyping was performed by whole body dual-energy X-ray absorptiometry, microCT, histology and blood analysis. In conditional Spry1 null mice, high fat diet increased body fat by 40%, impaired glucose regulation, and led to liver steatosis. However, over-expression of Spry1 led to 35% lower body fat, reduced bone loss, and normal metabolic function compared to single transgenics. This protective phenotype was associated with decreased circulating insulin (70%) and leptin (54%) compared to controls on a high fat diet. Additionally, Spry1 expression decreased adipose tissue inflammation by 45%. We show that conditional Spry1 expression in adipose tissue protects against high fat diet-induced obesity and associated bone loss.
doi:10.1017/S0007114511006209
PMCID: PMC3496386  PMID: 22142492
Sprouty; high fat diet; body fat; obesity; bone loss
14.  Skeletal aging and the adipocyte program 
Cell Cycle  2010;9(18):3648-3654.
Aging is associated with profound changes in bone mass and body composition. Emerging evidence supports the hypothesis that alterations in mesenchymal stromal cell fate are a critical etiologic factor. In addition, timekeeping at the cellular level is affected as aging progresses, particularly in the adipocyte. In this Extra View we discuss the interactive role of three molecules, PPARγ, nocturnin and IGF-I, in regulating stem cell fate in the marrow and the potential implications of this network for understanding cellular aging.
doi:10.4161/cc.9.18.13046
PMCID: PMC3047793  PMID: 20890120
aging; bone; PPARγ; nocturnin; IGF-I
15.  Sclerostin Levels and Bone Turnover Markers in Adolescents with Anorexia Nervosa and Healthy Adolescent Girls 
Bone  2012;51(3):474-479.
Sclerostin, product of the SOST gene, is an important determinant of bone formation and resorption. Adolescents with anorexia nervosa (AN) have low bone density and decreased levels of bone turnover markers. However, sclerostin has not been examined in AN as a potential mediator of impaired bone metabolism. Our study objectives were to (i) assess associations of sclerostin with surrogate bone turnover markers in girls with AN and controls and (ii) examine effects of transdermal estradiol on sclerostin in AN. 69 girls (44 with AN and 25 normal-weight controls) 13–18 years old were studied at baseline. 22 AN girls were randomized to transdermal estradiol (plus cyclic medroxyprogesterone) or placebo in a double-blind study for 12 months. Sclerostin correlated positively with P1NP and CTX in controls (r = 0. 67 and 0. 53, p = 0. 0002 and 0. 005, respectively) but not in AN despite comparable levels at baseline. Changes in sclerostin over twelve months did not differ in girls randomized to estradiol or placebo. The relationship between sclerostin and bone turnover markers is disrupted in adolescent girls with AN. Despite an increase in BMD with estradiol administration in AN, estrogen does not impact sclerostin levels in this group.
doi:10.1016/j.bone.2012.06.006
PMCID: PMC3412913  PMID: 22728230
anorexia nervosa; sclerostin; osteoporosis
16.  Marrow fat and preadipocyte factor-1 levels decrease with recovery in women with anorexia nervosa 
Women with anorexia nervosa (AN) have elevated marrow fat mass despite low visceral and subcutaneous fat depots, which is inversely associated with bone mineral density (BMD). Whether marrow fat mass remains persistently elevated or decreases with recovery from AN is currently unknown. In this study, we investigated changes in marrow fat with recovery from AN and the relationship between preadipocyte factor (Pref)-1 -- a member of the EGF-like family of proteins and regulator of adipocyte and osteoblast differentiation -- and fat depots and BMD in women who have recovered from AN (AN-R) compared to women with AN and healthy controls (HC). We studied 29 women: 14 with active or recovered AN (30.7 + 2.2 years (mean ± SEM)) and 15 normal-weight controls (27.8 ± 1.2 years). We measured marrow adipose tissue (MAT) of the L4 vertebra and femur by 1H-magnetic resonance spectroscopy, BMD of the spine, hip and total body by DXA and serum Pref-1 and leptin levels. We found that MAT of the L4 vertebra was significantly lower in AN-R as compared to AN (p = 0.03) and was comparable to levels in HC. Pref-1 levels were also significantly lower in AN-R as compared to AN (p = 0.02) and comparable to levels in healthy controls. Although Pref-1 was positively associated with MAT of the L4 vertebra in AN (R = 0.94; p = 0.002), we found that it was inversely associated with MAT of the L4 vertebra in HC (R = −0.71; p = 0.004). Therefore, we have demonstrated that MAT and Pref-1 levels decrease with recovery from AN. Our data suggest that Pref-1 may have differential effects in states of nutritional deprivation as compared to nutritional sufficiency.
doi:10.1002/jbmr.1640
PMCID: PMC3415584  PMID: 22508185
Marrow Adiposity; Anorexia Nervosa; Pref-1; Bone mineral density; Adipose depots
17.  Bone Morphogenetic Protein Receptor Type Ia Localization Causes Increased BMP2 Signaling in Mice Exhibiting Increased Peak Bone Mass Phenotype 
Journal of Cellular Physiology  2012;227(7):2870-2879.
Bone Morphogenetic Protein 2 (BMP2) is a growth factor that initiates osteoblast differentiation. Recent studies show that BMP2 signaling regulates bone mineral density (BMD). BMP2 interacts with BMP receptor type Ia (BMPRIa) and type II receptor leading to the activation of the Smad signaling pathway. BMPRIa must shuttle between distinct plasma membrane domains, enriched of Caveolin-1 alpha and Caveolin-1 beta isoforms, and receptor activation occurs in these domains. Yet it remains unknown whether the molecular mechanism that regulates BMP2 signaling is driving mineralization and BMD. Therefore the B6.C3H-1-12 congenic mouse model with increased BMD and osteoblast mineralization was utilized in this study. Using the Family Image Correlation Spectroscopy, we determined if BMP2 led to a significant re-localization of BMPRIa to caveolae of the alpha/beta isoforms in bone marrow stromal cells (BMSCs) isolated from B6.C3H-1-12 mice compared to the C57BL/6J mice, which served as controls. The control, C57BL/6J mice, was selected due to only 4Mb of Chromosome 1 from the C3H/HeJ mouse was backcrossed to a C57BL/6J background. Using reporter gene assays, the B6.C3H-1-12 BMSCs responded to BMP2 with increased Smad activation. Furthermore disrupting caveolae reduced the BMP2-induced Smad signaling in BMSCs isolated from B6.C3H-1-12 and C57BL/6J. This study suggests for the first time a regulatory mechanism of BMPRIa signaling at the plasma membrane of BMSCs that 1) associated with genetic differences in the distal Chromosome 1 segment carried by the B6.C3H-1-12 congenic and 2) contributes to increase BMD of the B6.C3H-1-12 compared to the C57BL/6J control mice.
doi:10.1002/jcp.23028
PMCID: PMC3309108  PMID: 22170575
Bone; Image Cross Correlation Spectroscopy; Membrane; Caveolae
18.  The effect of gonadal and adrenal steroid therapy on skeletal health in adolescents and young women with anorexia nervosa 
Anorexia nervosa (AN) is characterized by subnormal estrogen and dehydroepiandrosterone (DHEA) levels. We sought to determine whether the combination of DHEA + estrogen/progestin is superior to placebo in preserving skeletal health over 18 months in AN. Females with AN, aged 13 to 27 years, were recruited for participation in this double-blind, placebo-controlled, randomized trial. Ninety-four subjects were randomized, of whom 80 completed baseline assessments and received either study drug (oral micronized DHEA 50 mg + 20 µg ethinyl estradiol/0.1 mg levonorgestrel combined oral contraceptive pill [COC] daily; n = 43) or placebo (n = 37). Serial measurements of areal bone mineral density (aBMD), bone turnover markers, and serum hormone concentrations were obtained. Sixty subjects completed the 18-month trial. Spinal and whole-body aBMD z scores were preserved in the DHEA + COC group, but decreased in the placebo group (comparing trends, P = .008 and P = .001, respectively). Bone turnover markers initially declined in subjects receiving DHEA + COC and then returned to baseline. No differences in body composition, adverse effects of therapy, or alterations in biochemical safety parameters were observed. Combined therapy with DHEA + COC appears to be safe and effective for preventing bone loss in young women with AN, whereas placebo led to decreases in aBMD. Dehydroepiandrosterone + COC may be safely used to preserve bone mass as efforts to reverse the nutritional, psychological, and other hormonal components of AN are implemented.
doi:10.1016/j.metabol.2011.11.016
PMCID: PMC3465078  PMID: 22257645
19.  Marrow Fat and the Bone Microenvironment: Developmental, Functional, and Pathological Implications 
Bone marrow adipogenesis is a normal physiologic process in all mammals. However, its function is unknown. The mesenchymal stem cell is the marrow precursor for adipocytes as well as osteoblasts, and PPARγ is an essential differentiation factor for entrance into the fat lineage. Mouse models have provided significant insight into the molecular cues that define stromal cell fate. In humans, accelerated marrow adipogenesis has been associated with aging and several chronic conditions including diabetes mellitus and osteoporosis. Newer imaging techniques have been used to determine the developmental time course of fat generation in bone marrow. However, more studies are needed to understand the interrelationship among hematopoietic, osteoblastic, and adipogenic cells within the marrow niche.
PMCID: PMC2674609  PMID: 19392647
adipogenesis; marrow stromal cells; osteoblastogenesis; bone mass; aging
20.  The Insulin-Like Growth Factor System in Bone 
doi:10.1016/j.ecl.2012.04.013
PMCID: PMC3576021  PMID: 22682633
Insulin-like growth factors; Skeletal growth; Bone homeostasis; Insulin-like growth factor binding protein
21.  Fat Targets for Skeletal Health 
Nature reviews. Rheumatology  2009;5(7):365-372.
Emerging evidence points to a critical role for the skeleton in several homeostatic processes including energy balance. The connection between fuel utilization and skeletal remodeling begins in the bone marrow with lineage allocation of mesenchymal stromal cells into adipocytes or osteoblasts. Mature bone cells secrete factors that influence insulin sensitivity and fat cells synthesize cytokines that regulate osteoblast differentiation. The emerging importance of the bone-fat interaction suggests that novel molecules could be used as targets to enhance bone formation and possibly prevent fractures. In this review, we discuss three pathways that could favor pharmacologic intervention with the ultimate goal of enhancing bone mass and reducing osteoporotic fracture risk. Not surprisingly, because of the complex interactions across homeostatic networks, other pathways will likely be activated by this targeting and these could prove to be beneficial or detrimental for the organism. Hence a more complete picture of energy utilization and skeletal remodeling will be required to bring these potential agents into any future clinical armamentarium.
doi:10.1038/nrrheum.2009.102
PMCID: PMC3661210  PMID: 19468288
22.  Effects of growth hormone in women with abdominal adiposity: a 6-month randomized, double-blind, placebo-controlled trial 
Objective
Abdominal adiposity is associated with increased cardiovascular risk and decreased growth hormone (GH) secretion. The objective of our study was to determine the effects of GH in abdominally obese women on body composition and cardiovascular risk markers.
Materials and Methods
In this randomized, double-blind, placebo-controlled study, 79 obese premenopausal women received GH vs. placebo for six months. Primary endpoints were: 1) total abdominal (TAT) fat by CT (body composition) and 2) high-sensitivity C-reactive protein (hsCRP) (cardiovascular risk marker). Body composition was assessed by CT, DXA and proton MR spectroscopy. Serum cardiovascular risk markers, carotid intima-media thickness and endothelial function were measured.
Results
Mean 6-month GH dose was 1.7±0.1 mg/day, resulting in a mean IGF-1 SDS increase from −1.7±0.08 to −0.1±0.3 in the GH group. GH administration decreased TAT and hsCRP compared with placebo. In addition, it increased thigh muscle mass and lean body mass, and decreased subcutaneous abdominal and trunk fat, tPA, apoB, and apoB/LDL compared with placebo. Visceral adipose tissue decreased and IMCL increased within the GH group. Six-month change in IGF-1 levels was negatively associated with 6-month decrease in TAT and VAT. One subject had a 2-hour glucose >200 mg/mL at 3 months; four subjects, three of whom were randomized to GH, had 2-hour glucose levels >200 mg/mL at study end.
Conclusion
GH administration in abdominally obese premenopausal women exerts beneficial effects on body composition and cardiovascular risk markers, but is associated with a decrease in glucose tolerance in a minority of women.
doi:10.1530/EJE-11-1068
PMCID: PMC3651853  PMID: 22275471
growth hormone; visceral obesity; body composition; cardiovascular risk
23.  Altered Plasma Membrane Dynamics of Bone Morphogenetic Protein Receptor Type Ia in a Low Bone Mass Mouse Model 
Bone  2011;50(1):10.1016/j.bone.2011.10.016.
Bone Morphogenetic Proteins (BMPs) are growth factors that initiate differentiation of bone marrow stromal cells to osteoblasts and adipocytes, yet the mechanism that decides which lineage the cell will follow is unknown. BMP2 is linked to the development of osteoporosis and variants of BMP2 gene have been reported to increase the development of osteoporosis. Intracellular signaling is transduced by BMP Receptors (BMPRs) of type I and type II that are serine/threonine kinase receptors. The BMP type I a receptor (BMPRIa) is linked to osteogenesis and bone mineral density (BMD). BMPRs are localized to caveloae enriched with Caveolin1 alpha/beta and Caveolin beta isoforms to facilitate signaling. BMP2 binding to caveolae was recently found to be crucial for the initiation of the Smad signaling pathway. Here we determined the role of BMP receptor localization within caveolae isoforms and aggregation of caveolae as well as BMPRIa in bone marrow stromal cells (BMSCs) on bone mineral density using the B6.C3H-6T as a model system. The B6.C3H-6T is a congenic mouse with decreased bone mineral density (BMD) with increased marrow adipocytes and decreased osteoprogenitor proliferation. C57BL/6J mice served as controls since only a segment of Chr6 from the C3H/HeJ mouse was backcrossed to a C57BL/6J background. Family of Image Correlation Spectroscopy was used to analyze receptor cluster density and co-localization of BMPRIa and caveolae. It was previously shown that BMP2 stimulation results in an aggregation of caveolae and BMPRIa. Additionally, BMSCs isolated from the B6.C3H-6T mice showed a dispersion of caveolae domains compared to C57BL/6J. The aggregation of BMPRIa that is necessary for signaling to occur was inhibited in BMSCs isolated from B6.C3H-6T. Additionally, we analyzed the co-localization of BMPRIa with caveolin-1 isoforms. There was increased percentage of BMPRIa co-localization with caveolae compared to C57BL/6J. BMP2 stimulation had no effect on the colocalization of BMPRIa with caveolin-1. Disrupting caveolae initiated Smad signaling in the isolated BMSCs from B6.C3H-6T. These data suggest that in congenic 6T mice BMP receptors aggregation is inhibited causing an inhibition of signaling and reduced bone mass.
doi:10.1016/j.bone.2011.10.016
PMCID: PMC3651650  PMID: 22036911
Image Cross Correlation Spectroscopy; Caveolae; Caveolin; Osteoblast; Mineralization; Family Image Correlation Spectroscopy
24.  Insulin-Like Growth Factor (IGF) Binding Protein 2 Functions Coordinately with Receptor Protein Tyrosine Phosphatase β and the IGF-I Receptor To Regulate IGF-I-Stimulated Signaling 
Molecular and Cellular Biology  2012;32(20):4116-4130.
Insulin-like growth factor I (IGF-I) is a mitogen for vascular smooth muscle cells (VSMC) and has been implicated in the development and progression of atherosclerosis. IGF binding proteins (IGFBPs) modify IGF-I actions independently of IGF binding, but a receptor-based mechanism by which they function has not been elucidated. We investigated the role of IGFBP-2 and receptor protein tyrosine phosphatase β (RPTPβ) in regulating IGF-I signaling and cellular proliferation. IGFBP-2 bound RPTPβ, which led to its dimerization and inactivation. This enhanced PTEN tyrosine phosphorylation and inhibited PTEN activity. Utilization of substrate trapping and phosphatase-dead mutants showed that RPTPβ bound specifically to PTEN and dephosphorylated it. IGFBP-2 knockdown led to decreased PTEN tyrosine phosphorylation and decreased AKT Ser473 activation. IGFBP-2 enhanced IGF-I-stimulated VSMC migration and proliferation. Analysis of aortas obtained from IGFBP-2−/− mice showed that RPTPβ was activated, and this was associated with inhibition of IGF-I stimulated AKT Ser473 phosphorylation and VSMC proliferation. These changes were rescued following administration of IGFBP-2. These findings present a novel mechanism for coordinate regulation of IGFBP-2 and IGF-I signaling functions that lead to stimulation of VSMC proliferation. The results have important implications for understanding how IGFBPs modulate the cellular response to IGF-I.
doi:10.1128/MCB.01011-12
PMCID: PMC3457336  PMID: 22869525
25.  Vertebral Bone Marrow Fat Is Positively Associated With Visceral Fat and Inversely Associated With IGF-1 in Obese Women 
Obesity (Silver Spring, Md.)  2010;19(1):49-53.
Recent studies have demonstrated an important physiologic link between bone and fat. Bone and fat cells arise from the same mesenchymal precursor cell within bone marrow, capable of differentiation into adipocytes or osteoblasts. Increased BMI appears to protect against osteoporosis. However, recent studies have suggested detrimental effects of visceral fat on bone health. Increased visceral fat may also be associated with decreased growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels which are important for maintenance of bone homeostasis. The purpose of our study was to assess the relationship between vertebral bone marrow fat and trabecular bone mineral density (BMD), abdominal fat depots, GH and IGF-1 in premenopausal women with obesity. We studied 47 premenopausal women of various BMI (range: 18–41 kg/m2, mean 30 ± 7 kg/m2) who underwent vertebral bone marrow fat measurement with proton magnetic resonance spectroscopy (1H-MRS), body composition, and trabecular BMD measurement with computed tomography (CT), and GH and IGF-1 levels. Women with high visceral fat had higher bone marrow fat than women with low visceral fat. There was a positive correlation between bone marrow fat and visceral fat, independent of BMD. There was an inverse association between vertebral bone marrow fat and trabecular BMD. Vertebral bone marrow fat was also inversely associated with IGF-1, independent of visceral fat. Our study showed that vertebral bone marrow fat is positively associated with visceral fat and inversely associated with IGF-1 and BMD. This suggests that the detrimental effect of visceral fat on bone health may be mediated in part by IGF-1 as an important regulator of the fat and bone lineage.
doi:10.1038/oby.2010.106
PMCID: PMC3593350  PMID: 20467419

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