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1.  Altered thermogenesis and impaired bone remodeling in Misty mice 
Fat mass may be modulated by the number of brown-like adipocytes in white adipose tissue (WAT) in humans and rodents. Bone remodeling is dependent on systemic energy metabolism and, with age, bone remodeling becomes uncoupled and brown adipose tissue (BAT) function declines. To test the interaction between BAT and bone, we employed Misty (m/m) mice, which were reported be deficient in BAT. We found that Misty mice have accelerated age-related trabecular bone loss and impaired brown fat function (including reduced temperature, lower expression of Pgc1a and less sympathetic innervation compared to wildtype (+/+)). Despite reduced BAT function, Misty mice had normal core body temperature, suggesting heat is produced from other sources. Indeed, upon acute cold exposure (4°C for 6 hr), inguinal WAT from Misty mice compensated for BAT dysfunction by increasing expression of Acadl, Pgc1a, Dio2 and other thermogenic genes. Interestingly, acute cold exposure also decreased Runx2 and increased Rankl expression in Misty bone, but only Runx2 was decreased in wildtype. Browning of WAT is under the control of the sympathetic nervous system (SNS) and, if present at room temperature, could impact bone metabolism. To test whether SNS activity could be responsible for accelerated trabecular bone loss, we treated wildtype and Misty mice with the β-blocker, propranolol. As predicted, propranolol slowed trabecular BV/TV loss in the distal femur of Misty mice without affecting wildtype. Finally, the Misty mutation (a truncation of DOCK7) also has a significant cell-autonomous role. We found DOCK7 expression in whole bone and osteoblasts. Primary osteoblast differentiation from Misty calvaria was impaired, demonstrating a novel role for DOCK7 in bone remodeling. Despite the multifaceted effects of the Misty mutation, we have shown that impaired brown fat function leads to altered SNS activity and bone loss, and for the first time that cold exposure negatively affects bone remodeling.
doi:10.1002/jbmr.1943
PMCID: PMC3743939  PMID: 23553822
bone; brown adipose tissue; DOCK7; Misty; thermogenesis
2.  Dysregulated Gene Expression in the Primary Osteoblasts and Osteocytes Isolated from Hypophosphatemic Hyp Mice 
PLoS ONE  2014;9(4):e93840.
Osteocytes express multiple genes involved in mineral metabolism including PHEX, FGF23, DMP1 and FAM20C. In Hyp mice, a murine model for X-linked hypophosphatemia (XLH), Phex deficiency results in the overproduction of FGF23 in osteocytes, which leads to hypophosphatemia and impaired vitamin D metabolism. In this study, to further clarify the abnormality in osteocytes of Hyp mice, we obtained detailed gene expression profiles in osteoblasts and osteocytes isolated from the long bones of 20-week-old Hyp mice and wild-type (WT) control mice. The expression of Fgf23, Dmp1, and Fam20c was higher in osteocytic cells than in osteoblastic cells in both genotypes, and was up-regulated in Hyp cells. Interestingly, the up-regulation of these genes in Hyp bones began before birth. On the other hand, the expression of Slc20a1 encoding the sodium/phosphate (Na+/Pi) co-transporter Pit1 was increased in osteoblasts and osteocytes from adult Hyp mice, but not in Hyp fetal bones. The direct effects of extracellular Pi and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on isolated osteoblastic and osteocytic cells were also investigated. Twenty-four-hour treatment with 10−8 M 1,25(OH)2D3 increased the expression of Fgf23 in WT osteoblastic cells but not in osteocytic cells. Dmp1 expression in osteocytic cells was increased due to the 24-hour treatment with 10 mM Pi and was suppressed by 10−8 M 1,25(OH)2D3 in WT osteocytic cells. We also found the up-regulation of the genes for FGF1, FGF2, their receptors, and Egr-1 which is a target of FGF signaling, in Hyp osteocytic cells, suggesting the activation of FGF/FGFR signaling. These results implicate the complex gene dysregulation in osteoblasts and osteocytes of Hyp mice, which might contribute to the pathogenesis.
doi:10.1371/journal.pone.0093840
PMCID: PMC3977859  PMID: 24710520
3.  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
4.  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
5.  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
6.  Insulin-like growth factor binding protein-2 is required for osteoclast differentiation 
Global deletion of the Igfbp2 gene results in the suppression of bone turnover. To investigate the role of IGFBP-2 in regulating osteoclast differentiation we cultured Igfbp2−/− bone marrow cells and found a reduction in the number of osteoclasts and impaired resorption. Addition of full length IGFBP-2 restored osteoclast differentiation, fusion and resorption. To determine the molecular domains of IGFBP-2 that were required for this effect to be manifest, Igfbp2−/− bone marrow cells mice were transfected with constructs in which the heparin binding (HBD) or the IGF- binding domains of IGFBP-2 were mutated. We found that both domains were necessary for osteoclastogenesis since expression of the mutated forms of either domain failed to support the formation of functionally mature osteoclasts. To discern the mechanism by which IGFBP-2 regulates osteoclast formation, PTEN abundance and phosphorylation status as well as AKT responsiveness to IGF-I were analyzed. Igfbp2−/− cells had elevated levels of PTEN and phospho-PTEN compared with controls. Expression of wild-type IGFBP-2 reduced the level of PTEN to that of wild-type cells. Cells expressing the IGF binding mutant showed suppression of PTEN and phospho-PTEN equivalent to the wild type protein, whereas those expressing the IGFBP-2 HBD mutant showed no PTEN suppression. When the ability of IGF-I to stimulate AKT activation, measured by Thr308 and Ser473 phosphorylation, was analyzed, stimulation of Ser473 in response to IGF-I in pre-osteoclasts required the presence of intact IGFBP-2. This effect was duplicated by the addition of a CK2 inhibitor that prevents the phosphorylation of PTEN. In contrast, in fully differentiated osteoclasts stimulation of Thr308 phosphorylation required the presence of intact IGFBP-2. We conclude that IGFBP-2 is an important regulator of osteoclastogenesis and that both the heparin and the IGF binding domains of IGFBP-2 are essential for the formation of fully differentiated and functional osteoclasts.
doi:10.1002/jbmr.545
PMCID: PMC3385417  PMID: 22006816
7.  Nocturnin: A Circadian Target of Pparg- Induced Adipogenesis 
Nuclear receptors (NRs) control cell fate and regulate tissue function. Some of the NRs are expressed in a circadian and tissue specific manner. Clock genes are part of the circadian network and fine tune gene expression in adipose and skeletal tissues. Pparg, a master transcription factor that determines adipogenesis exhibits a circadian expression pattern in white adipose tissue and liver. In this paper we found that message and protein for a peripheral clock gene, nocturnin, is markedly up-regulated with Pparg activation in adipocytes and bone marrow stromal cells. Nocturnin is also expressed in relatively high amounts in other tissues which may have physiologic relevance for bone, including the brain and hypothalamus. Importantly, we found polymorphic strain differences in bone marrow nocturnin expression that relate to phenotypic determinants of skeletal acquisition. Defining the function of nocturnin in peripheral tissues should provide new insights into lineage allocation and the intimate relationship between nuclear receptors and physiologic timekeeping.
doi:10.1111/j.1749-6632.2009.05221.x
PMCID: PMC3503505  PMID: 20392228
8.  An essential role for the circadian-regulated gene Nocturnin in osteogenesis: the importance of local timekeeping in skeletal homeostasis 
The role of circadian proteins in regulating whole body metabolism and bone turnover has been studied in detail and has led to the discovery of an elemental system for timekeeping involving the core genes Clock, Bmal1, Per, and Cry. Nocturnin, a peripheral circadian-regulated gene has been shown to play a very important role in regulating adipogenesis by deadenylation of key mRNAs and intra-cytoplasmic transport of PPARγ. The role that it plays in osteogenesis has previously not been studied in detail. In this report we examined in vitro and in vivo osteogenesis in the presence and absence of Nocturnin and show that loss of Nocturnin enhances bone formation and can rescue Rosiglitazone induced bone loss in mice. The circadian rhythm of Nocturnin is likely to be an essential element of marrow stromal cell fate.
doi:10.1111/j.1749-6632.2011.06213.x
PMCID: PMC3285261  PMID: 22082366
Nocturnin; rosiglitazone; PPARγ
9.  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
10.  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
11.  PPARγ: a circadian transcription factor in adipogenesis and osteogenesis 
Nature reviews. Endocrinology  2010;6(11):629-636.
Peroxisome proliferator-activated receptor γ (PPARγ) is a critical factor for adipogenesis and glucose metabolism, but accumulating evidence demonstrates the involvement of PPARγ in skeletal metabolism as well. PPARγ agonists, the thiazolidinediones (TZDs), have been widely used for the treatment of type 2 diabetes mellitus owing to their effectiveness in lowering blood glucose. However, the use of TZDs has been associated with bone loss and fractures. TZD-induced alterations in the bone marrow milieu—that is, increased marrow adiposity with suppression of osteogenesis—could partially explain the pathogenesis of TZD-induced bone loss Furthermore, several lines of evidence place PPARγ at the center of a regulatory loop between circadian networks and metabolic output. PPARγ exhibits a circadian expression pattern that is magnified by consumption of a high-fat diet. One of the circadian-regulated genes expressed in peripheral tissues, nocturnin (Noc), has been shown to enhance PPARγ activity. Importantly Noc-deficient mice are protected from diet-induced obesity, exhibit impaired circadian expression of PPARγ and have increased bone mass. This Review focuses on new findings regarding the role of PPARγ in adipose tissue and skeletal metabolism and summarizes the emerging role of PPARγ as an integral part of a complex circadian regulatory system that modulates food storage, energy consumption and skeletal metabolism.
doi:10.1038/nrendo.2010.155
PMCID: PMC3132113  PMID: 20820194
12.  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
13.  A Novel Spontaneous Mutation of Irs1 in Mice Results in Hyperinsulinemia, Reduced Growth, Low Bone Mass and Impaired Adipogenesis 
The Journal of endocrinology  2009;204(3):241-253.
A spontaneous mouse mutant, designated 'small' (sml), was recognized by reduced body size suggesting a defect in the IGF-I/GH axis. The mutation was mapped to the Chromosome 1 region containing Irs1, a viable candidate gene whose sequence revealed a single nucleotide deletion resulting in a premature stop codon. Despite normal mRNA levels in mutant and control littermate livers, Western blot analysis revealed no detectable protein in mutant liver lysates. When compared to control littermates, Irs1sml/Irs1sml (Irs1sml/sml) mice are small, lean, hearing impaired, have 20% less serum IGF-I, are hyperinsulinemic and are mildly insulin resistant. Irs1sml/sml mice have low bone mineral density, reduced trabecular and cortical thicknesses and low bone formation rates, while osteoblast and osteoclast numbers were increased in the females but not different in the males compared to Irs1+/+ controls. In vitro, Irs1sml/sml bone marrow stromal cell cultures showed decreased alkaline phosphatase positive colony forming units (pre-osteoblasts; CFU-AP+) and normal numbers of tartrate resistant acid phosphatase positive (TRAP) osteoclasts. Irs1sml/sml stromal cells treated with IGF-I exhibited a 50% decrease in AKT phosphorylation, indicative of defective downstream signaling. Similarities between engineered knockouts and the spontaneous mutation of Irs1sml were identified as well as significant differences with respect to heterozygosity and gender. In sum we have identified a spontaneous mutation in the Irs1 gene associated with a major skeletal phenotype. Changes in the heterozygous Irs1+/sml mice raise the possibility that similar mutations in humans are associated with short stature or osteoporosis.
doi:10.1677/JOE-09-0328
PMCID: PMC3033737  PMID: 20032200
Irs1; bone; growth; adipocytes; hyperinsulinemia

Results 1-13 (13)