Urszula T Iwaniec

Publications (30)103.83 Total impact

• Article: Intraperitoneal Injection of Ethanol Results in Drastic Changes in Bone Metabolism Not Observed when Ethanol Is Administered by Oral Gavage.

  Urszula T Iwaniec, Russell T Turner
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  ABSTRACT: BACKGROUND: Chronic alcohol abuse is associated with increased risk of osteoporosis while light-to-moderate alcohol intake correlates with reduced osteoporosis risk. Addition of alcohol to a liquid diet is often used to model chronic alcohol abuse. Methods to model intermittent drinking (including binge drinking and light-to-moderate consumption) include (i) intragastric administration of alcohol by oral gavage or (ii) intraperitoneal (ip) administration of alcohol by injection. However, it is unclear whether the latter 2 methods produce comparable results. The purpose of this investigation was to determine the skeletal response to alcohol delivered daily by oral gavage or ip injection. METHODS: Ethanol (EtOH) or vehicle was administered to 4-month-old female Sprague-Dawley rats once daily at 1.2 g/kg body weight for 7 days. Following necropsy, bone formation and bone architecture were evaluated in tibial diaphysis (cortical bone) and proximal tibial metaphysis (cancellous bone) by histomorphometry. mRNA was measured for bone matrix proteins in distal femur metaphysis. RESULTS: Administration of alcohol by gavage had no significant effect on body weight gain or bone measurements. In contrast, administration of the same dose of alcohol by ip injection resulted in reduced body weight, total suppression of periosteal bone formation in tibial diaphysis, decreased cancellous bone formation in proximal tibial metaphysis, and decreased mRNA levels for bone matrix proteins in distal femur. CONCLUSIONS: Our findings raise concerns regarding the use of ip injection of EtOH in rodents as a method for modeling the skeletal effects of intermittent exposure to alcohol in humans. This concern is based on a failure of the ip route to replicate the oral route of alcohol administration.
  Alcoholism Clinical and Experimental Research 03/2013; · 3.34 Impact Factor
• Article: Genistein administered as a once-daily oral supplement had no beneficial effect on the tibia in rat models for postmenopausal bone loss.

  Russell T Turner, Urszula T Iwaniec, Juan E Andrade, Adam J Branscum, Steven L Neese, Dawn A Olson, Lindsay Wagner, Victor C Wang, Susan L Schantz, William G Helferich
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  ABSTRACT: OBJECTIVE: Estrogen deficiency after menopause results in rapid bone loss, predisposing women to osteoporotic fractures. Genistein, a phytoestrogen present in high concentrations in soy, is an ingredient in dietary supplements aggressively marketed for bone health. However, in a recent long-duration clinical trial in postmenopausal women, the efficacy of soy extracts in reducing bone loss was disappointing. To better understand the failure of soy extracts to consistently induce a robust skeletal response in women, we investigated the long-term (5 mo) efficacy of genistein, administered as a daily oral supplement, (1) in preventing cancellous bone loss in skeletally mature virgin Long-Evans rats ovariectomized at 7 months of age and (2) in improving cancellous bone mass and architecture in aged retired-breeder rats ovariectomized at 16 or 22 months of age. METHODS: Rats within each age group were randomly assigned into one of three treatment groups (n = 7-12 rats/group): (1) vehicle control, (2) genistein 485 μg/day, or (3) genistein 970 μg/day, resulting in mean (SE) serum genistein levels of 0.18 (0.10), 0.76 (0.15), and 1.48 (0.31) μM, respectively. Total tibia bone mass and density were evaluated using dual-energy x-ray absorptiometry, whereas cancellous bone mass and architecture in the tibial metaphysis, as well as cortical bone mass and architecture in the tibial diaphysis, were evaluated by micro-CT. RESULTS: Oral genistein administered as a dietary supplement did not influence the cumulative effects of ovariectomy, aging, and/or reproductive history on cancellous and cortical bone mass and architecture. CONCLUSIONS: Serum levels of genistein similar to those in women consuming a high-soy diet are ineffective in preventing or treating bone loss in rat models for postmenopausal osteoporosis.
  Menopause (New York, N.Y.) 02/2013; · 3.08 Impact Factor
• Article: Failure to Generate Bone Marrow Adipocytes Does Not Protect Mice from Ovariectomy-Induced Osteopenia.

  Urszula T Iwaniec, Russell T Turner
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  ABSTRACT: A reciprocal association between bone marrow fat and bone mass has been reported in ovariectomized rodents, suggesting that bone marrow adipogenesis has a negative effect on bone growth and turnover balance. Mice with loss of function mutations in kit receptor (kit(W/W-v)) have no bone marrow adipocytes in tibia or lumbar vertebra. We therefore tested the hypothesis that marrow fat contributes to development of osteopenia by comparing the skeletal response to ovariectomy (ovx) in growing wild type (WT) and bone marrow adipocyte-deficient kit(W/W-v) mice. Mice were ovx at 4weeks of age and sacrificed 4 or 10weeks post-surgery. Body composition was measured at necropsy by dual-energy X-ray absorptiometry. Cortical (tibia) and cancellous (tibia and lumbar vertebra) bone architecture were evaluated by microcomputed tomography. Bone marrow adipocyte size and density, osteoblast- and osteoclast-lined bone perimeters, and bone formation were determined by histomorphometry. Ovx resulted in an increase in total body fat mass at 10weeks post-ovx in both genotypes, but the response was attenuated in the in kit(W/W-v) mice. Adipocytes were present in bone marrow of tibia and lumbar vertebra in WT mice and bone marrow adiposity increased following ovx. In contrast, marrow adipocytes were not detected in either intact or ovx kit(W/W-v) mice. However, ovx in WT and kit(W/W-v) mice resulted in statistically indistinguishable changes in cortical and cancellous bone mass, cortical and cancellous bone formation rate, and cancellous osteoblast and osteoclast-lined bone perimeters. In conclusion, our findings do not support a causal role for increased bone marrow fat as a mediator of ovx-induced osteopenia in mice.
  Bone 12/2012; · 4.02 Impact Factor
• Article: Voluntary Wheel Running in Growing Rats Does Not Protect Against Doxorubicin-induced Osteopenia.

  Reid Hayward, Urszula T Iwaniec, Russell T Turner, Chia-Ying Lien, Brock T Jensen, David S Hydock, Carole M Schneider
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  ABSTRACT: There is growing concern regarding the long-term negative side effects of chemotherapy in childhood cancer survivors. Doxorubicin (DOX) is commonly used in the treatment of childhood cancers and has been shown to be both cardiotoxic and osteotoxic. It is unclear whether exercise can attenuate the negative skeletal effects of this chemotherapy. Rat pups were treated with saline or DOX. Animals remained sedentary or voluntarily exercised. After 10 weeks, femoral bone mineral content and bone mineral density were measured using dual-energy x-ray absorptiometry. Cortical and cancellous bone architecture was then evaluated by microcomputed tomography. DOX had a profound negative effect on all measures of bone mass and cortical and cancellous bone architecture. Treatment with DOX resulted in shorter femora and lower femoral bone mineral content and bone mineral density, lower cross-sectional volume, cortical volume, marrow volume, cortical thickness, and principal (IMAX, IMIN) and polar (IPOLAR) moments of inertia in the femur diaphysis, and lower cancellous bone volume/tissue volume, trabecular number, and trabecular thickness in the distal femur metaphysis. Exercise failed to protect bones from the damaging effects of DOX. Other modalities may be necessary to mitigate the deleterious skeletal effects that occur in juveniles undergoing treatment with anthracyclines.
  Journal of Pediatric Hematology/Oncology 11/2012; · 1.16 Impact Factor
• Article: Moderate alcohol intake lowers biochemical markers of bone turnover in postmenopausal women.

  Jill A Marrone, Gianni F Maddalozzo, Adam J Branscum, Karin Hardin, Lynn Cialdella-Kam, Kenneth A Philbrick, Anne C Breggia, Clifford J Rosen, Russell T Turner, Urszula T Iwaniec
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  ABSTRACT: 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 of postmenopausal bone loss. This study investigated the hypothesis that moderate alcohol intake attenuates bone turnover after menopause. Bone mineral density was determined by dual-energy x-ray absorptiometry in 40 healthy postmenopausal women (mean ± SE age, 56.3 ± 0.5 y) who consumed alcohol at 19 ± 1 g/day. Serum levels of the bone formation marker osteocalcin and the resorption marker C-terminal telopeptide (CTx) were measured by immunoassay at baseline (day 0) and after alcohol withdrawal for 14 days. Participants then consumed alcohol and were assayed on the following morning. Bone mineral density at the trochanter and total hip were positively correlated to the level of alcohol consumption. Serum osteocalcin and CTx increased after abstinence (4.1 ± 1.6%, P = 0.01 and 5.8 ± 2.6%, P = 0.02 compared with baseline, respectively). Osteocalcin and CTx decreased after alcohol readministration, compared with 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). Abstinence from alcohol results in increased markers of bone turnover, whereas resumption of alcohol reduces 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.
  Menopause (New York, N.Y.) 09/2012; 19(9):974-9. · 3.08 Impact Factor
• Article: Androgen prevents hypogonadal bone loss via inhibition of resorption mediated by mature osteoblasts/osteocytes.

  Kristine M Wiren, Xiao-Wei Zhang, Dawn A Olson, Russell T Turner, Urszula T Iwaniec
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  ABSTRACT: Androgen receptor (AR) is expressed throughout the osteoblast lineage. Two different AR transgenic families (AR2.3-tg and AR3.6-tg mice) demonstrating overlapping and distinct expression profiles were employed to assess the effects of enhanced androgen sensitivity to ameliorate hypogonadal loss. Two different paradigms of steroid replacement following orchidectomy (ORX) were used as either preventative or therapeutic therapy. ORX was performed in male wild-type (WT), AR2.3-tg and AR3.6-tg mice at 5months with immediate DHT replacement (prevention, higher turnover) or at 3months with DHT treatment delayed for 2months (therapeutic, lower turnover), both with treatment for the last 6weeks. Dual energy X-ray absorptiometry (DXA), micro-computed tomography (μCT), and histomorphometry were performed. In the prevention model, ORX significantly reduced BMD and BMC in all genotypes compared to sham and DHT was effective at prevention of osteopenia. In the therapeutic model, all genotypes became osteopenic compared to sham, but after a prolonged hypogonadal period, delayed DHT treatment provided little benefit. μCT analysis of mid-shaft total bone in all genotypes generally showed reductions after ORX. Delayed DHT was ineffective at restoring bone volume in any genotype whereas immediate treatment prevented loss only in AR transgenic mice. Cortical thickness also decreased with ORX but immediate DHT treatment was effective to increase thickness only in WT mice, likely due to expansion of marrow volume in both AR-tg lines. In metabolically highly active cancellous bone, ORX resulted in lower bone volume/tissue volume (BV/TV) in all genotypes, consistent among 3 sites measured. Again with delayed treatment, there was little effect of DHT to restore BV/TV, but when administered at the time of ORX, DHT completely prevented the decrease in cancellous bone in all genotypes. Improvement in cancellous bone architecture was seen with immediate DHT replacement that was enhanced in AR transgenic lines compared to WT. In contrast, there were only modest changes in all genotypes using the delayed treatment paradigm. With ORX in both paradigms, trabecular number was decreased while spacing increased. Thus, androgen therapy is effective for the prevention of endosteal and cancellous osteopenia primarily through its anti-resorptive properties, but shows little anabolic action as a therapeutic strategy to restore bone. Given the similarity in response to androgen treatment in both AR transgenic lines, overlapping expression profiles suggest that the target cells mediating androgen action in vivo are mature osteoblast/osteocytes. Combined, these results demonstrate that in the adult mouse, androgen treatment can reduce bone resorption but has little overall anabolic activity.
  Bone 08/2012; 51(5):835-46. · 4.02 Impact Factor
• Article: Peripheral leptin regulates bone formation.

  Russell T Turner, Satya P Kalra, Carmen P Wong, Kenneth A Philbrick, Laurence B Lindenmaier, Stephane Boghossian, Urszula T Iwaniec
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  ABSTRACT: Substantial evidence does not support the prevailing view that leptin, acting through a hypothalamic relay, decreases bone accrual by inhibiting bone formation. To clarify the mechanisms underlying regulation of bone architecture by leptin, we evaluated bone growth and turnover in wild type (WT) mice, leptin receptor-deficient db/db mice, leptin-deficient ob/ob mice and ob/ob mice treated with leptin. We also performed hypothalamic leptin gene therapy to determine the effect of elevated hypothalamic leptin levels on osteoblasts. Finally, to determine the effects of loss of peripheral leptin signaling on bone formation and energy metabolism, we used bone marrow (BM) from WT or db/db donor mice to reconstitute the hematopoietic and mesenchymal stem cell compartments in lethally irradiated WT recipient mice. Decreases in bone growth, osteoblast-lined bone perimeter and bone formation rate were observed in ob/ob mice and greatly increased in ob/ob mice following subcutaneous administration of leptin. Similarly, hypothalamic leptin gene therapy increased osteoblast-lined bone perimeter in ob/ob mice. In spite of normal osteoclast-lined bone perimeter, db/db mice exhibited a mild but generalized osteopetrotic-like (calcified cartilage encased by bone) skeletal phenotype and greatly reduced serum markers of bone turnover. Tracking studies and histology revealed quantitative replacement of BM cells following BM transplantation. WT mice engrafted with db/db BM did not differ in energy homeostasis from untreated WT mice or WT mice engrafted with WT BM. Bone formation in WT mice engrafted with WT BM did not differ from WT mice, whereas bone formation in WT mice engrafted with db/db cells did not differ from the low rates observed in untreated db/db mice. In summary, our results indicate that leptin, acting primarily through peripheral pathways, increases osteoblast number and activity. © 2012 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 08/2012; · 6.04 Impact Factor
• Article: Moderate alcohol intake lowers biochemical markers of bone turnover in postmenopausal women.

  Jill A Marrone, Gianni F Maddalozzo, Adam J Branscum, Karin Hardin, Lynn Cialdella-Kam, Kenneth A Philbrick, Anne C Breggia, Clifford J Rosen, Russell T Turner, Urszula T Iwaniec
  [show abstract] [hide abstract]
  ABSTRACT: 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 of postmenopausal bone loss. This study investigated the hypothesis that moderate alcohol intake attenuates bone turnover after menopause. METHODS: Bone mineral density was determined by dual-energy x-ray absorptiometry in 40 healthy postmenopausal women (mean ± SE age, 56.3 ± 0.5 y) who consumed alcohol at 19 ± 1 g/day. Serum levels of the bone formation marker osteocalcin and the resorption marker C-terminal telopeptide (CTx) were measured by immunoassay at baseline (day 0) and after alcohol withdrawal for 14 days. Participants then consumed alcohol and were assayed on the following morning. RESULTS: Bone mineral density at the trochanter and total hip were positively correlated to the level of alcohol consumption. Serum osteocalcin and CTx increased after abstinence (4.1 ± 1.6%, P = 0.01 and 5.8 ± 2.6%, P = 0.02 compared with baseline, respectively). Osteocalcin and CTx decreased after alcohol readministration, compared with 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 results in increased markers of bone turnover, whereas resumption of alcohol reduces 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.
  Menopause (New York, N.Y.) 07/2012; · 3.08 Impact Factor
• Source

  Available from: InTech

  Chapter: Detrimental Effects of Alcohol on Bone Growth

  Russell T. Turner, Elizabeth Doran, Urszula T. Iwaniec
  02/2012; , ISBN: 978-953-51-0030-0
• Article: MicroRNAs control neurobehavioral development and function in zebrafish.

  Tamara L Tal, Jill A Franzosa, Susan C Tilton, Kenneth A Philbrick, Urszula T Iwaniec, Russell T Turner, Katrina M Waters, Robert L Tanguay
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  ABSTRACT: microRNAs (miRNAs) have emerged as regulators of a broad spectrum of neurodevelopmental processes, including brain morphogenesis, neuronal differentiation, and survival. While the role of miRNAs in establishing and maintaining the developing nervous system is widely appreciated, the developmental neurobehavioral role of miRNAs has yet to be defined. Here we show that transient disruption of brain morphogenesis by ethanol exposure results in behavioral hyperactivity in larval zebrafish challenged with changes in lighting conditions. Aberrations in swimming activity persist in juveniles that were developmentally exposed to ethanol. During early neurogenesis, multiple gene expression profiling studies revealed widespread changes in mRNA and miRNA abundance in ethanol-exposed embryos. Consistent with a role for miRNAs in neurobehavioral development, target prediction analyses identified multiple miRNAs misexpressed in the ethanol-exposed cohorts that were also predicted to target inversely expressed transcripts known to influence brain morphogenesis. In vivo knockdown of miR-9/9* or miR-153c persistently phenocopied the effect of ethanol on larval and juvenile swimming behavior. Structural analyses performed on adults showed that repression of miR-153c during development impacts craniofacial skeletal development. Together, these data support an integral role for miRNAs in the establishment of vertebrate neurobehavioral and skeletal systems.
  The FASEB Journal 01/2012; 26(4):1452-61. · 5.71 Impact Factor
• Article: Effect of reduced c-Kit signaling on bone marrow adiposity.

  Russell T Turner, Carmen P Wong, Urszula T Iwaniec
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  ABSTRACT: c-Kit (CD117) is required for normal differentiation of osteoblasts from bone marrow stromal cells and for normal bone formation. Osteoblasts and adipocytes originate from a common progenitor cell, and a reciprocal relationship in differentiation of the two lineages is often observed. Therefore, the effects of abnormal c-kit signaling on bone marrow adiposity and adipocyte precursor pool size were evaluated in mouse strains with loss of function mutations in kit receptor or kit ligand. Additionally, to determine whether short-duration pharmacological disruption of kit signaling influences bone marrow adiposity, we administered the kit receptor antagonist gleevec (imatinib mesilate) for 1 week to middle aged (13-month-old) male rats known to have high levels of bone marrow fat. Compared to wild-type littermates, adipocytes were absent and adipocyte precursors greatly reduced in bone marrow from kit receptor-deficient Kit(W/W-ν) mice. Administration of secreted kit ligand to membrane-associated kit ligand-deficient Kit(Sl/Sl-d) mice was ineffective in inducing bone marrow adipogenesis. These findings suggest that activation of kit receptor by the membrane-associated form of kit ligand is required for kit signaling to promote bone marrow adipogenesis in mice. Rats treated with gleevec had lower adipocyte density compared to age-matched controls, suggesting that kit signaling is required to maintain normal bone marrow adiposity. Taken together, our results indicate that c-Kit signaling plays an important but previously unsuspected role in regulating bone marrow adiposity.
  The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 07/2011; 294(7):1126-34. · 1.47 Impact Factor
• Article: Low dose parathyroid hormone maintains normal bone formation in adult male rats during rapid weight loss.

  Russell T Turner, Urszula T Iwaniec
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  ABSTRACT: A persistent negative energy balance results in bone loss. It is not clear whether the bone loss associated with chronic negative energy balance can be prevented. The objective of this study was to assess the efficacy of intermittent low dose parathyroid hormone (PTH) treatment in maintaining normal bone formation during severe energy restriction. Six-month-old male Fisher 344 rats were divided into 4 treatment groups: (1) baseline, (2) ad libitum (ad lib)-fed control, (3) energy-restricted (to consume 40% ad lib caloric intake), or (4) energy-restricted+low dose (1 μg/kg/d) PTH. Severe energy restriction for 14 d decreased body weight and serum leptin levels. Compared to ad lib-fed controls, energy-restricted rats had lower cancellous bone formation, higher osteoclast perimeter/bone perimeter and higher bone marrow adiposity in the proximal tibial metaphysis. Also, the energy-restricted rats had a lower periosteal bone formation rate at the tibia-fibula synostosis. Administration of PTH to energy-restricted rats had no effect on weight loss or osteoclast perimeter/bone perimeter. In contrast, energy-restricted rats treated with PTH had higher rates of cancellous and cortical bone formation compared to energy-restricted rats, and did not differ from the ad lib-fed control animals. Furthermore, PTH treatment maintained normal bone marrow adiposity. In conclusion, rapid weight loss in adult male rats was accompanied by decreased bone formation and increased bone marrow adiposity and these changes were prevented by low dose PTH treatment. Taken together, the results suggest that the energy cost of bone formation in adult rats is low and PTH therapy is effective in preventing the reduced bone formation associated with rapid weight loss.
  Bone 01/2011; 48(4):726-32. · 4.02 Impact Factor
• Source

  Available from: PubMed Central

  Article: The role of mast cells in parathyroid bone disease.

  Russell T Turner, Urszula T Iwaniec, Kevin Marley, Jean D Sibonga
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  ABSTRACT: Chronic hyperparathyroidism (HPT) is a common cause of metabolic bone disease. These studies investigated the underlying cellular and molecular mechanisms responsible for the detrimental actions of elevated parathyroid hormone (PTH) on the skeleton. Bone biopsies from hyperparathyroid patients revealed an association between parathyroid bone disease and increased numbers of bone marrow mast cells. We therefore evaluated the role of mast cells in the etiology of parathyroid bone disease in a rat model for chronic HPT. In rats, mature mast cells were preferentially located at sites undergoing bone turnover, and the number of mast cells at the bone-bone marrow interface was greatly increased following treatment with PTH. Time-course studies and studies employing parathyroid hormone-related peptide (PTHrP), as well as inhibitors of platelet-derived growth factor-A (PDGF-A, trapidil), kit (gleevec), and PI3K (wortmannin) signaling revealed that mature mast cell redistribution from bone marrow to bone surfaces precedes and is associated with osteitis fibrosa, a hallmark of parathyroid bone disease. Importantly, mature mast cells were not observed in the bone marrow of mice. Mice, in turn, were resistant to the development of PTH-induced bone marrow fibrosis. These findings suggest that the mast cell may be a novel target for treatment of metabolic bone disease.
  Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 01/2010; 25(7):1637-49. · 6.04 Impact Factor
• Source

  Available from: PubMed Central

  Article: Growth hormone regulates the balance between bone formation and bone marrow adiposity.

  Philip J Menagh, Russell T Turner, Donald B Jump, Carmen P Wong, Malcolm B Lowry, Shoshana Yakar, Clifford J Rosen, Urszula T Iwaniec
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  ABSTRACT: Cancellous bone decreases and bone marrow fat content increases with age. Osteoblasts and adipocytes are derived from a common precursor, and growth hormone (GH), a key hormone in integration of energy metabolism, regulates the differentiation and function of both cell lineages. Since an age-related decline in GH is associated with bone loss, we investigated the relationship between GH and bone marrow adiposity in hypophysectomized (HYPOX) rats and in mice with defects in GH signaling. HYPOX dramatically reduced body weight gain, bone growth and mineralizing perimeter, serum insulin-like growth factor 1 (IGF-1) levels, and mRNA levels for IGF-1 in liver and bone. Despite reduced body mass and adipocyte precursor pool size, HYPOX resulted in a dramatic increase in bone lipid levels, as reflected by increased bone marrow adiposity and bone triglyceride and cholesterol content. GH replacement normalized bone marrow adiposity and precursor pool size, as well as mineralizing perimeter in HYPOX rats. In contrast, 17beta -estradiol, IGF-1, thyroxine, and cortisone were ineffective. Parathyroid hormone (PTH) reversed the inhibitory effects of HYPOX on mineralizing perimeter but had no effect on adiposity. Finally, bone marrow adiposity was increased in mice deficient in GH and IGF-1 but not in mice deficient in serum IGF-1. Taken together, our findings indicate that the reciprocal changes in bone and fat mass in GH signaling-deficient rodents are not directly coupled with one another. Rather, GH enhances adipocyte as well as osteoblast precursor pool size. However, GH increases osteoblast differentiation while suppressing bone marrow lipid accumulation.
  Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 10/2009; 25(4):757-68. · 6.04 Impact Factor
• Article: Consumption of green tea extract results in osteopenia in growing male mice.

  Urszula T Iwaniec, Russell T Turner, Sung I Koo, Rouminder Kaur, Emily Ho, Carmen P Wong, Richard S Bruno
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  ABSTRACT: Consumption of green tea may reduce body weight gain. Although many disorders are related to obesity, bone mass is positively correlated with body mass. Therefore, our purpose in this study was to determine the effects of green tea extract (GTE) on bone mass and architecture in rapidly growing lean [C57BL/6 wild type (WT)] and genetically obese, leptin-deficient (ob/ob) male mice. Five-week-old lean and ob/ob mice were assigned to diets containing GTE at 0, 1, or 2% for 6 wk. Femoral and lumbar vertebral bone volume and architecture were evaluated by micro-computed tomography (muCT). Following muCT analysis, femora were ashed to determine bone mineral content and density. Compared with WT mice, ob/ob mice had shorter femora (P < 0.001), lower femoral bone volume (P < 0.001), and lower femoral bone mineral content (P < 0.001), but higher cancellous bone volume in lumbar vertebrae (P < 001). Neither genotype nor treatment affected femoral bone mineral density, indicating normal mineralization. GTE consumption resulted in lower femur length, volume, mineral content, cortical volume, and cortical thickness (P < 0.001), as well as lower cancellous bone volume/tissue volume (P < 0.008) and trabecular thickness (P < 0.004) in lumbar vertebrae. The results indicate that leptin is not essential for the reduced gains in body weight and bone mass due to GTE in growing mice and suggest that consumption of large quantities of green tea may reduce the rate of bone accumulation during growth.
  Journal of Nutrition 09/2009; 139(10):1914-9. · 3.92 Impact Factor
• Article: Leptin increases osteoblast-specific osteocalcin release through a hypothalamic relay.

  Satya P Kalra, Michael G Dube, Urszula T Iwaniec
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  ABSTRACT: Enhanced long-term expression of leptin by gene therapy selectively in the hypothalamus, without leakage to the systemic circulation, abrogated skeletal abnormalities and reinstated weight and insulin-glucose homeostasis in leptin-deficient ob/ob mice. Whether increases in osteocalcin, a hormone produced by osteoblasts and known to play a role in bone growth and recently in glucose-insulin homeostasis, may link these benefits of central leptin was assessed. The effects of a single intraventricular injection of non-immunogenic, non-pathogenic recombinant adeno-associated virus vector encoding leptin gene (rAAV-lep) or green fluorescent protein gene (rAAV-GFP, control) were studied in three genotypes, wild type (wt), obese diabetic, hyperinsulinemic ob/ob and non-obese, diabetic insulinopenic Akita mice. Selective hypothalamic leptin expression with central rAAV-lep treatment decreased weight, fat mass, food intake, suppressed insulin levels in ob/ob and wt mice, and conferred euglycemia by suppressing blood glucose in all three genotypes. Contemporaneously, rAAV-lep treatment also augmented blood osteocalcin levels. In wt mice, osteocalcin rose by 51% and, whereas, basal osteocalcin levels in ob/ob and Akita mice were significantly lower as compared to those in wt mice (26% and 55%, respectively), gene therapy reinstated levels to the control range in ob/ob mice, and raised 40% above the wt range even in the absence of insulin in Akita mice. These findings demonstrate that the central beneficial effects of leptin on bone growth involve increased hypothalamic relay of signals that augment osteocalcin efflux from osteoblasts into the general circulation, a response that, in turn, may also modulate glucose-insulin and weight homeostasis.
  Peptides 06/2009; 30(5):967-73. · 2.43 Impact Factor
• Article: Effects of voluntary wheel running on goserelin acetate-induced bone degeneration.

  David S Hydock, Urszula T Iwaniec, Russell T Turner, Chia-Ying Lien, Brock T Jensen, Traci L Parry, Carole M Schneider, Reid Hayward
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  ABSTRACT: A common treatment option for many breast and prostate cancer patients is the use of a luteinizing hormone-releasing hormone agonist such as goserelin acetate (GA) which reduces sex hormone levels. This treatment, however, is associated with bone degeneration, and exercise has been suggested as a means of preventing this side effect. Little is known about the effects of low intensity, low volume exercise on GA-induced bone loss. The purpose of this study, therefore, was to investigate the effects of voluntary wheel running on bone architecture in growing male (M) and female (F) rats receiving GA treatment. Rats received an 8-week GA treatment or placebo (CON) and were either housed in cages equipped with voluntary running wheels (WR) or remained sedentary (SED) in standard cages throughout the experimental period. Following treatments, tibiae were excised and analyzed for cortical bone (cross-sectional volume, cortical volume, marrow volume, cortical thickness) and cancellous bone (bone volume/total volume, trabecular number, trabecular thickness, trabecular spacing) using micro-computed tomography. Treatment with GA resulted in a significant reduction in running wheel distances in both sexes throughout the study period (P<0.05). GA treatment had no effect on cortical bone architecture in neither sex (P>0.05). Cancellous bone degeneration, however, was observed in M and F SED+GA (P<0.05). No significant differences were observed in M WR+GA animals in bone volume/total volume, trabecular number and trabecular spacing when compared to M SED+CON (P>0.05). In F WR+GA, trabecular thickness did not differ from that of F SED+CON (P>0.05), and trabecular spacing was found to be significantly lower than F SED+GA (P<0.05). The current report indicates that 8 weeks of GA treatment promotes cancellous bone degeneration, and voluntary wheel running provides no clear osteoprotection in growing male and female rats.
  Pathophysiology 01/2009; 15(4):253-9.
• Article: Osteitis fibrosa is mediated by Platelet-Derived Growth Factor-A via a phosphoinositide 3-kinase-dependent signaling pathway in a rat model for chronic hyperparathyroidism.

  Malcolm B Lowry, Sutada Lotinun, Alexey A Leontovich, Minzhi Zhang, Avudaiappan Maran, Kristen L Shogren, Brett K Palama, Kevin Marley, Urszula T Iwaniec, Russell T Turner
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  ABSTRACT: Abnormal secretion of PTH by the parathyroid glands contributes to a variety of common skeletal disorders. Prior studies implicate platelet-derived growth factor-A (PDGF-A) as an important mediator of selective PTH actions on bone. The present studies used targeted gene profiling and small-molecule antagonists directed against candidate gene products to elucidate the roles of specific PTH-regulated genes and signaling pathways. A group of 29 genes in rats continuously infused with PTH and cotreated with the PDGF receptor antagonist trapidil were differentially expressed compared with PTH treatment alone. Several of the identified genes were functionally clustered as regulators of fibroblast differentiation and extracellular matrix modeling, including the matrix cross-linking enzyme lysyl oxidase (LOX). Treatment with beta-aminopropionitrile, an irreversible inhibitor of LOX activity, dramatically reduced diffuse mineralization but had no effect on PTH-induced fibrosis. In contrast, the receptor tyrosine kinase inhibitor Gleevec and the phosphoinositide 3-kinase inhibitor wortmannin each reduced bone marrow fibrosis. In summary, the present studies support the hypotheses that PTH-induced bone marrow fibrosis is mediated by PDGF-A via a phosphoinositide 3-kinase-dependent signaling pathway and that increased LOX gene expression plays a key role in abnormal mineralization, a hallmark of chronic hyperparathyroidism.
  Endocrinology 11/2008; 149(11):5735-46. · 4.46 Impact Factor
• Article: Detrimental effects of reloading recovery on force, shortening velocity, and power of soleus muscles from hindlimb-unloaded rats.

  J J Widrick, G F Maddalozzo, H Hu, J C Herron, U T Iwaniec, R T Turner
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  ABSTRACT: To better understand how atrophied muscles recover from prolonged nonweight-bearing, we studied soleus muscles (in vitro at optimal length) from female rats subjected to normal weight bearing (WB), 15 days of hindlimb unloading (HU), or 15 days HU followed by 9 days of weight bearing reloading (HU-R). HU reduced peak tetanic force (P(o)), increased maximal shortening velocity (V(max)), and lowered peak power/muscle volume. Nine days of reloading failed to improve P(o), while depressing V(max) and intrinsic power below WB levels. These functional changes appeared intracellular in origin as HU-induced reductions in soleus mass, fiber cross-sectional area, and physiological cross-sectional area were partially or completely restored by reloading. We calculated that HU-induced reductions in soleus fiber length were of sufficient magnitude to overextend sarcomeres onto the descending limb of their length-tension relationship upon the resumption of WB activity. In conclusion, the force, shortening velocity, and power deficits observed after 9 days of reloading are consistent with contraction-induced damage to the soleus. HU-induced reductions in fiber length indicate that sarcomere hyperextension upon the resumption of weight-bearing activity may be an important mechanism underlying this response.
  AJP Regulatory Integrative and Comparative Physiology 09/2008; 295(5):R1585-92. · 3.34 Impact Factor
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  Available from: Teppo L N Järvinen

  Article: Treatment of experimental renal osteodystrophy with pamidronate.

  Jarkko Jokihaara, Ilkka H Pörsti, Peeter Kööbi, Pasi M Jolma, Jukka T Mustonen, Heikki H T Saha, Harri Sievänen, Pekka Kannus, Urszula T Iwaniec, Russell T Turner, Teppo L N Järvinen
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  ABSTRACT: We evaluated the effects of the bisphosphonate pamidronate on bone histomorphometry, structure and strength in male rats with uninephrectomy or with chronic renal disease induced by 5/6 nephrectomy. In rats with chronic renal disease the plasma urea, phosphate and parathyroid hormone levels were significantly increased compared to rats with a uninephroctomy and none of these parameters was affected by pamidronate treatment. In the femoral midshaft, chronic renal disease reduced cortical bone mineral density and content. No difference was observed in the breaking load of the femoral midshaft. In the distal femur, a high-turnover renal osteodystrophy was found but pamidronate suppressed this bone turnover and increased bone mineral content. Treatment had no effect on chronic disease-induced augmentation of osteoid volume or fibroblast surface. These studies show that in this model of stage 3 renal disease, pamidronate increased mineral content in the femoral midshaft and distal metaphysis primarily by adding bone to endocortical and trabecular surfaces but did not reduce osteitis fibrosa.
  Kidney International 09/2008; 74(3):319-27. · 6.61 Impact Factor