Campbell River, Canada
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Yaden B.,Musculoskeletal Research | Yaden B.,Indiana University – Purdue University Indianapolis | Yaden B.,Eli Lilly and Company | Krishnan V.,Musculoskeletal Research | And 3 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2013

Human follistatin is a regulatory glycoprotein with widespread biologic functions, including antiinflammatory activities, woundhealing properties, and muscle-stimulating effects. The role of follistatin in a wide range of biologic activities shows promise for potential clinical application, which has prompted considerable interest in the investigation of the protein as a potential diseasemodifying agent. In spite of this potential, the development of follistatin as a broad use biotherapeutic has been severely hindered by a poor understanding and characterization of its pharmacokinetic/pharmacodynamic (PK/PD) relationships.Therefore, to better define these relationships, we performed in-depth analyses of the PK/PD relationships of native follistatin-315 (FST315). Our data indicate that the intrinsic PK/PD properties of native FST315 are poorly suited for acting as a parentally administered biotherapeutic with broad systemic effects. Here, we leveraged protein engineering to modify the PK characteristics of the native molecule by fusing FST315 to a murine IgG1 Fc and removing the intrinsic heparan sulfate-binding activity of follistatin. The engineered variant molecule had ̃100- and ̃1600-fold improvements in terminal half-life and exposure, respectively. In contrast to the native FST315, the variant showed a robust, dose-dependent pharmacological effect when administered subcutaneously on a weekly basis in mouse models of muscle atrophy and degeneration. These studies highlight the underappreciated and critical relationship between optimizing multiple physical and chemical properties of follistatin on its overall PK/PD profile. Moreover, our findings provide the first documented strategy toward the development of a follistatin therapeutic with potential use in patients affected with skeletal muscle diseases. © 2013 by The American Society for Pharmacology and Experimental Therapeutics.


Hardwick M.E.,Musculoskeletal Research | Pulido P.A.,Musculoskeletal Research | Adelson W.S.,University of California at San Francisco
Orthopaedic Nursing | Year: 2012

Purpose: Healing touch (HT), a nurse-initiated modality, has potential to improve postoperative pain control and restore balance to a patient's energy field to facilitate self-healing. We hypothesized that addition of HT to standard pharmacologic intervention would reduce pain, anxiety, and opioid consumption, and would improve ambulation distance, knee flexion, and patient satisfaction with quality of care in bilateral total knee arthroplasty. Sample: Forty-one patients were prospectively randomized to an HT group (n = 20) or a standard treatment (ST) group (n = 21). Methods: For the HT group, HT was administered once daily between 2 daily physical therapy sessions. Pain was assessed using a visual analog scale (VAS) before surgery, before and after HT daily (HT group), or between physical therapy sessions daily (ST group). Anxiety was measured using State-Trait Anxiety Inventory (STAI). Opioid analgesic consumption was converted into dose equivalents (DE; 10 mg morphine intravenous = 1 DE). Satisfaction was assessed at the 1-month postoperative visit. Findings: Demographics were similar. Pain VAS was lower in the HT group than in the ST group but was not significant. Within the HT group, pain VAS after the HT treatment was significantly diminished compared with pre-HT pain VAS (p < .05) except on postoperative Day 1. State anxiety was lower in the HT group but reached significance (p = .046) only on postoperative Day 2. Total opioid DE was lower in the ST group by 0.5 DE. Twenty percent more in the ST group reported overall pain as moderate/severe. One month after surgery, 95% of the HT group, compared with 87% of the ST group, felt that their pain was adequately controlled during the hospital stay. Discussion: Healing touch provides another tool that nurses can use to decrease pain in patients undergoing postoperative bilateral total knee arthroplasty. © 2012 National Association of Orthopaedic Nurses.


News Article | October 31, 2016
Site: www.eurekalert.org

Scientific review describes key central regulators of bone metabolism and points to future directions and challenges in this promising area of research. "The best news is that the brain has become front and centre in the regulation of bone modelling", conclude authors Professors Paul Dimitri and Cliff Rosen in their concise review of the complex role of the central nervous system in bone metabolism. The review "The Central Nevous System and Bone Metablism: An Evolving Story", published in Calcified Tissue International & Musculoskeletal Research, shows how our understanding of the control of skeletal metabolism has undergone a dynamic shift in the last two decades, primarily driven by greater understanding of energy metabolism. It also points to future directions and challenges faced by researchers as they try to better understand the complex interaction between the musculoskeletal and central nervous systems. The authors review the latest research into the role of central regulators of bone metabolism, including leptin, neuropeptide Y (NPY), serotonin, endocannabinoids, cocaine- and amphetamine-regulated transcript (CART), adiponectin, melatonin and neuromedin U. They also discuss the role of the sympathetic and parasympathetic nervous systems in the control of skeletal metabolism, as evidence for the broader autonomic skeletal regulation. Sensory innervation of bone is also a focus, further extending our understanding of the complex neuronal regulation of bone mass. Professor Dimitri, Professor of Child Health & Director of Research & Innovation at Sheffield Children's Hospital NHS Foundation Trust, UK stated: "Whilst scientific advance in this field of bone metabolism has been rapid, progress is still required to understand how these model systems work in relation to the numerous and complex factors that influence skeletal metabolism, particularly in humans. Our rapidly evolving understanding of the physiological aspects of bone remodelling together with the development of more sophisticated technology will in time help us to reach this goal." Dimitri, P. & Rosen, C. The Central Nevous System and Bone Metablism: An Evolving Story. Calcified Tissue International & Musculoskeletal Research is a peer-reviewed journal which publishes original preclinical, translational and clinical research, and reviews concerning the structure and function of bone, and other musculoskeletal tissues in living organisms, as well as clinical studies of musculoskeletal disease. It includes studies of cell biology, molecular biology, intracellular signaling, and physiology, as well as research into the hormones, cytokines and other mediators that influence the musculoskeletal system. The journal also publishes clinical studies of relevance to bone disease, mineral metabolism, muscle function, and musculoskeletal interactions. Become an IOF Professional member to freely access IOF scientific journals via the IOF website: https:/ The International Osteoporosis Foundation (IOF) is the world's largest nongovernmental organization dedicated to the prevention, diagnosis and treatment of osteoporosis and related musculoskeletal diseases. IOF members, including committees of scientific researchers as well as 234 patient, medical and research societies in 99 locations, work together to make bone, joint and muscle health a worldwide heath care priority. http://www. / http://www. @iofbonehealth http://www.


News Article | December 1, 2016
Site: www.eurekalert.org

Systematic review looks at which DXA-based measurements can be used to help identify patients at increased risk of fracture Increased risk of fracture has been shown to be one of the complications arising from longstanding diabetes. With the worldwide increase in Type 2 Diabetes (T2D), in part due to aging populations, there is also increasing concern about how to identify and manage patients with diabetes who are at high risk of osteoporotic fracture. Osteoporosis is usually diagnosed from bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA). The authors reviewed data on skeletal parameters and techniques readily available from DXA scanning, and considered their utility in routine clinical practice for predicting fracture risk. DXA measures BMD as well these other applications and measurements: trabecular bone score (TBS), skeletal geometry and DXA-based finite-element analysis, vertebral fracture assessment (VFA), and body composition. They also looked at fracture prediction tools, and specifically at the widely used Fracture Risk Assessment Tool (FRAX®) which is incorporated into modern DXA scanners. FRAX underestimates fracture risk in individuals with T2D - with factors contributing to this underestimation including the higher BMD observed in T2D, the greater risk for falls, and alterations in material strength. Nevertheless, several methods have been proposed to improve the performance FRAX in T2D. The review summarizes the evidence for the effect of various DXA-derived skeletal parameters in T1D and T2D. In regard to whether they can be used to account for the excess fracture risk, the review concludes: Lead author Professor William D. Leslie of the Department of Medicine, University of Manitoba, Canada stated: "Diabetes is associated with increased fracture risk that is only partially reflected by the BMD reductions see in in T1D, and is underestimated in T2D where BMD is increased. While BMD from DXA still stratifies fracture risk in those with diabetes, additional measures that can be obtained from DXA help to identify high-risk patients. Incorporating this additional information into risk prediction models may help to avoid systematically underestimating the risk of osteoporosis-related fractures in people with diabetes." Reference: Schacter G I, Leslie W D. DXA-Based Measurements in Diabetes: Can They Predict Fracture Risk? Calcif Tissue Int. DOI 10.1007/s00223-016-0191-x https:/ Calcified Tissue International & Musculoskeletal Research is a peer-reviewed journal which publishes original preclinical, translational and clinical research, and reviews concerning the structure and function of bone, and other musculoskeletal tissues in living organisms, as well as clinical studies of musculoskeletal disease. It includes studies of cell biology, molecular biology, intracellular signalling, and physiology, as well as research into the hormones, cytokines and other mediators that influence the musculoskeletal system. The journal also publishes clinical studies of relevance to bone disease, mineral metabolism, muscle function, and musculoskeletal interactions. > Become an IOF Professional member to freely access IOF scientific journals via the IOF website: https:/ The International Osteoporosis Foundation (IOF) is the world's largest nongovernmental organization dedicated to the prevention, diagnosis and treatment of osteoporosis and related musculoskeletal diseases. IOF members, including committees of scientific researchers as well as 234 patient, medical and research societies in 99 locations, work together to make fracture prevention and healthy mobility a worldwide heath care priority. http://www. / http://www. @iofbonehealth


Cawthorn W.P.,University of Michigan | Cawthorn W.P.,Musculoskeletal Research | Scheller E.L.,University of Michigan | Learman B.S.,University of Michigan | And 23 more authors.
Cell Metabolism | Year: 2014

Summary The adipocyte-derived hormone adiponectin promotes metabolic and cardiovascular health. Circulating adiponectin increases in lean states such as caloric restriction (CR), but the reasons for this paradox remain unclear. Unlike white adipose tissue (WAT), bone marrow adipose tissue (MAT) increases during CR, and both MAT and serum adiponectin increase in many other clinical conditions. Thus, we investigated whether MAT contributes to circulating adiponectin. We find that adiponectin secretion is greater from MAT than WAT. Notably, specific inhibition of MAT formation in mice results in decreased circulating adiponectin during CR despite unaltered adiponectin expression in WAT. Inhibiting MAT formation also alters skeletal muscle adaptation to CR, suggesting that MAT exerts systemic effects. Finally, we reveal that both MAT and serum adiponectin increase during cancer therapy in humans. These observations identify MAT as an endocrine organ that contributes significantly to increased serum adiponectin during CR and perhaps in other adverse states. © 2014 Elsevier Inc.


Suzuki H.,University of Houston | Barros R.P.A.,University of Houston | Sugiyama N.,University of Houston | Krishnan V.,Musculoskeletal Research | And 6 more authors.
Molecular Psychiatry | Year: 2013

The serotonergic neurons of the dorsal raphe (DR) nucleus in the CNS are involved in fear, anxiety and depression. Depression and anxiety occur quite frequently in postmenopausal women, but estrogen replacement to correct these CNS disorders is at present not favored because estrogen carries with it an increased risk for breast cancer. Serotonin synthesis, release and reuptake in the DR are targets of pharmaceuticals in the treatment of depression. In the present study we have examined by immunohistochemistry, the expression of two nuclear receptors, that is, the estrogen receptors ERα and ERβ. We found that ERβ but not ERα is strongly expressed in the DR and there is no sex difference and no change with ageing in the number of tryptophan hydroxylase (TPH)-positive neurons in the DR of wild-type (WT) mice. However, in ovariectomized (OVX) WT and in ERβ -/- mice, there was a marked reduction in the number of TPH-positive normal-looking neurons and a marked increase in TPH-positive spindle-shaped cells. These neuronal changes were prevented in mice 1-3 weeks (but not 10 weeks) after OVX by the selective ERβ agonist, LY3201, given as continuous release pellets for 3 days. The ERβ agonist had no effects on glucose homeostasis. Thus, the onset of action of the ERβ agonist is rapid but there is a limited window in time after estrogen loss when the drug is useful. We conclude that, rather than estradiol, ERβ agonists could be useful pharmaceuticals in maintaining functional DR neurons to treat postmenopausal depression. © 2013 Macmillan Publishers Limited. All rights reserved 1359-4184/13.


PubMed | Novartis and Musculoskeletal Research
Type: Journal Article | Journal: Calcified tissue international | Year: 2016

Bimagrumab (BYM338) is a novel fully human monoclonal antibody that exerts strong promyogenic effects on skeletal muscle by blocking activin type II receptors (ActRII). We investigated whether such blockade of ActRII by bimagrumab manifests any detrimental effect on outcomes of bone healing in a rat fibula osteotomy model. Animals (n=150) were divided into 11 groups and received weekly treatment with either bimagrumab (10 or 100mg/kg) or vehicle. Progression and outcomes of bone healing were assessed by lateral radiographs in vivo as well as by peripheral quantitative computed tomography (pQCT), 4-point bending test, and microscopic examination of the excised fibula at Day 29 or later. The radiographic progression of bone healing showed no significant differences between treatment groups in any comparative setting. In 3-month-old animals, pQCT revealed slightly reduced immature callus size and bone mineral content in bimagrumab-treated animals compared with vehicle-treated animals at Day 29 (p<0.05). There were, however, no differences in mature callus size, bone mineral density, or biomechanical competency. The aforementioned effects on immature callus size were not present when the treatment was initiated 4weeks post osteotomy or when treating 6-month-old animals. In summary, these findings suggest that there is no major impact of ActRII blockade on overall fracture healing, and delayed treatment initiation can bypass the small and transient effect of the therapy on immature callus formation observed in younger animals. Verification of these findings in humans is the subject of an ongoing clinical trial on elderly hip fracture patients.


Kostenuik P.J.,Amgen Inc. | Smith S.Y.,Musculoskeletal Research | Samadfam R.,Musculoskeletal Research | Jolette J.,Musculoskeletal Research | And 2 more authors.
Journal of Bone and Mineral Research | Year: 2015

Postmenopausal osteoporosis is a chronic disease wherein increased bone remodeling reduces bone mass and bone strength. Antiresorptive agents including bisphosphonates are commonly used to mitigate bone loss and fracture risk. Osteoclast inhibition via denosumab (DMAb), a RANKL inhibitor, is a newer approach for reducing fracture risk in patients at increased risk for fracture. The safety of transitioning from bisphosphonate therapy (alendronate; ALN) to DMAb was examined in mature ovariectomized (OVX) cynomolgus monkeys (cynos). One day after OVX, cynos (7-10/group) were treated with vehicle (VEH, s.c.), ALN (50 μg/kg, i.v.; twice monthly) or DMAb (25 mg/kg/month, s.c.) for 12 months. Other animals received VEH or ALN for 6 months and then transitioned to 6 months of DMAb. DMAb caused significantly greater reductions in serum CTx than ALN, and transition from ALN to DMAb caused further reductions relative to continued ALN. DMAb and ALN decreased serum calcium (Ca), and transition from ALN to DMAb resulted in a lesser decline in Ca relative to DMAb or to VEH-DMAb transition. Bone histomorphometry indicated significantly reduced trabecular and cortical remodeling with DMAb or ALN. Compared with ALN, DMAb caused greater reductions in osteoclast surface, eroded surface, cortical porosity and fluorochrome labeling, and transition from ALN to DMAb reduced these parameters relative to continued ALN. Bone mineral density increased in all active treatment groups relative to VEH controls. Destructive biomechanical testing revealed significantly greater vertebral strength in all three groups receiving DMAb, including those receiving DMAb after ALN, relative to VEH controls. Bone mass and strength remained highly correlated in all groups at all tested skeletal sites, consistent with normal bone quality. These data indicate that cynos transitioned from ALN to DMAb exhibited reduced bone resorption and cortical porosity, and increased BMD and bone strength, without deleterious effects on Ca homeostasis or bone quality. © 2014 American Society for Bone and Mineral Research. © 2014 American Society for Bone and Mineral Research.


Gerin I.,University of Michigan | Gerin I.,Catholic University of Louvain | Bommer G.T.,University of Michigan | Bommer G.T.,Catholic University of Louvain | And 4 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2010

In this study, we explored the roles of microRNAs in adipocyte differentiation and metabolism. We first knocked down Argonaute2 (Ago2), a key enzyme in the processing of micro-RNAs (miRNAs), to investigate a potential role for miRNAs in adipocyte differentiation and/or metabolism. Although we did not observe dramatic differences in adipogenesis between Ago2 knock-down and control 3T3-L1 cells, incorporation of [14C]glucose or acetate into triacylglycerol, and steady-state levels of triacyglycerol were all reduced, suggesting a role for miRNAs in adipocyte metabolism. To study roles of specific miRNAs in adipocyte biology, we screened for miRNAs that are differentially expressed between preadipocytes and adipocytes for the 3T3-L1 and ST2 cell lines. Distinct subsets of miRNAs decline or increase during adipocyte conversion, whereas most miRNAs are not regulated. One locus encoding two miRNAs, 378/378*, contained within the intron of PGC-1β is highly induced during adipogenesis. When overexpressed in ST2 mesenchymal precursor cells, miRNA378/378* increases the size of lipid droplets and incorporation of [14C]acetate into triacylglycerol. Although protein and mRNA expression levels of C/EBPα, C/EBPβ, C/EBPδ, and PPARγ1 are unchanged, microarray and quantitative RT-PCR analyses indicate that a set of lipogenic genes are upregulated, perhaps due to increased expression of PPARγ2. Knockdown of miRNA378 and/or miRNA378* decreases accumulation of triacylglycerol. Interestingly, we made the unexpected finding that miRNA378/378* specifically increases transcriptional activity of C/EBPα and C/EBPβ on adipocyte gene promoters. Copyright © 2010 the American Physiological Society.


PubMed | University of Michigan, Queens Medical Research Institute, University of Edinburgh and Musculoskeletal Research
Type: | Journal: Frontiers in endocrinology | Year: 2016

Bone marrow adipose tissue (MAT) contributes to increased circulating adiponectin, an insulin-sensitizing hormone, during caloric restriction (CR), but whether this occurs in other contexts remains unknown. The antidiabetic thiazolidinediones (TZDs) also promote MAT expansion and hyperadiponectinemia, even without increasing adiponectin expression in white adipose tissue (WAT).To test the hypothesis that MAT expansion contributes to TZD-associated hyperadiponectinemia, we investigated the effects of rosiglitazone, a prototypical TZD, in wild-type (WT) or Male and female WT or In WT mice, rosiglitazone caused hyperadiponectinemia and MAT expansion. Compared to WT mice, TZD-induced hyperadiponectinemia is closely associated with increased adiponectin production in MAT but is not prevented by the partial loss of MAT that occurs in

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