Scientific Program


    2012 Sun Valley Workshop- Scientific Program
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    Sun Valley Workshop 2012 Abstract Book

    Saturday, August 4 - 7:00-10:00 PM
    Socializer at Dr. Burr's Lodge Apartment 
    Check with the Sun Valley Lodge to get the exact address.

    Sunday, August 5 - 8:00 AM - Noon (Continental Room)
    Glucocorticoid-induced Osteoporosis (Chair: Nancy Lane)
    Supported by a grant from Warner Chilcott
    a. The Epidemiology of GIOP (Nancy Lane, UC-Davis)
    b. Bone Biology, Autophagy and Glucocorticoids (W. Yao, UC-Davis)
    c. The Effects of Glucocorticoids on Bone Remodeling and Fragility (R. Recker)
    d. Osteonecrosis and Glucocorticoids (R. Weinstein, Univ of Arkansas)
    e. Treatment of GIOP- The Science Behind it (N. Lane, UCSF)
    f.  Glucocorticoids Inhibit Bone Formation Independent of miRNA Regulation. (P. Liu, Fritz Lipmann Institute: Alice L. Jee Award Winner)
    g. Atrophy is a Common Pathway Activated by Glucocorticoids in Bone and Muscle. (N. Bivi: Indiana University School of Medicine)

    Glucocorticoid-induced osteoporosis
    Glucocorticoids (GCs)are frequently used in clinical medicine for the treatment of inflammatory and autoimmune diseases. Today, nearly 50% of individuals with rheumatoid arthritis take chronic GCs.  These agents are beneficial, but the side effects including bone loss and fractures are frequent.   Interestingly, GC induced bone fragility is unique in that it occurs in all ages, and individuals on GCs fracture at relatively normal bone mineral density scans.  This suggests a significant component of the bone fragility in GC treated patients is the result of impaired tissue quality.  The epidemiology and  pathophysiology of GC induced osteoporosis, including GC affects on bone cells, changes in the bone microenvironment with GCs that may predispose to bone death or necrosis, how GCs affect bone structure and strength and the science behind the treatments that we use today to both prevent and treat GIOP will be explored by an all-star panel of experts.  The session will be chaired by Dr. Nancy Lane, who holds the Endowed Chair of Healthy Aging Geriatric Medicine and Professor of Medicine and Rheumatology at UC-Davis.  She is Past-President of the United States Bone and Joint Decade (USBJD), and Chair, USBJD Young Investigators Initiative. Dr. Robert Recker is a Professor of Medicine at Creighton University.He is widely considered to be the foremost authority on skeletal histomorphometry in the U.S. He is former President of the ASMBR. Dr. Robert Weinstein is Professor of Medicine at the University of Arkansas, and Director of the Bone Histomorphometry Lab. Talks in the session will be rounded out by Dr. Wei Yao, who works with Dr. Lane at UC-Davis, and by two winners of Young Investigator Awards from the ASBMR and the Workshop.

    Sunday, August 5 - 2:00-4:00 PM
    Volleyball game at the lake
    Everyone is welcome to join.  Drinks and snacks provided.

    Sunday, August 5 - 7:30-8:30 PM (Continental Room)
    The RIB Award/Plenary Lecture
    Nancy Lane (UCSF): Wnt Signaling: The Bone and Joint Connection


    Sunday, August 5 – 8:30-10:30 PM (Continental Room)
    Poster Session with wine and cheese follows the Plenary Lecture.

    Alice L. Jee Award Winners

    Connexin 43 Deficiency Reduces the Sensitivity of Bone to the Effects of Mechanical Unloading (S. Lloyd, Penn State)
    Dynamin GTPase Activity is Regulated by PTP-PEST and Controls Osteoblast Migration and Differentiation (P. Eleniste, Indiana University)
    Heat-Shock Induced Cellular Responses to Temperature Elevation Occuring During Orthopaedic Cutting (E. Dolan, National University of Ireland)
    Mechanoregulation of Skeletal Tissue Phenotypes during Bone Healing (G. Miller, Boston University)
    Capase-2 Deficiency Results in Age-Related Bone Loss via Multiple Cell-Specific Effects (R. Sharma, UT Health Science Center San Antonio) 

    Additional Alice L. Jee Award Winners who are presenting in other sessions:

    P. Liu, Fritz Lipmann Institute: Presenting in session: Glucocorticoid-induced Osteoporosis.  Glucocorticoids Inhibit Bone Formation Independent of miRNA Regulation.
    V. Saini, Harvard Medical School: Presenting in session: Update on Osteocytes. PTH/PTHrp Receptor (PPR) Signaling in Osteocytes Regulates Bone Remodeling via Sclerostin and RANKL Expression.   

    Under-Represented Minority Travel Grant Winners

    Thrombopoietin: A Novel Regulator of Bone Healing (M. Bethel, University of Melbourne)
    Differential Gene Expression Associated with Chondrocyte Hyperthrophy in Equine Growth Cartilage (B. Ayobami, University of Melbourne)
    Effects of Cyclical Treatments with Anabolic and Anti-Resorptive Agents on Cortical Bone Mass and Strength (S. Amugongo, University of California Davis)
    Comparison of Bone Quality of Mouse Models with Collagenous and Non-collagenous Genetic Mutations using Fourier- transformed Infrared Imaging (R. Coleman, Hospital for Special Surgery)

    Additional Under-Represented Minority Travel Grant Winner presenting in another session:

    G. Mbalaviele, Washington University: Presenting in session: Biological Control of Peri-Implant Bone Remodeling and Implant Loosening Activation of the NLRP3 Inflammasome Causes Inflammation and Abnormal Skeletal Development in Mice.

    Poster Session
    Maintenance of Bone Fracture Resistance Requires Perilacunar Remodeling by MMP-13 (T. Alliston, University of California, San Francisco)
    Deletion of the Rho-GEF Kalirin leads to a Decrease in Bone Formation and Trabecular Bone Mass Through (A. Bruzzaniti, Indiana University)
    In Vitro Investigation of White-tailed Deer Antlerogenic Progenitor Cells (E. Daley, University of Michigan)
    Modulating Osteogenic Differentiation of iPSCs Through Direct Inhibition of SOX9 by MiR335- 5p/342-3p (M. Huang, Tufts University)
    Role of Scavenger Receptor of Class B and Type I (SR-BI) in Bone Metabolism (C. Martineau, Université du Québec a Montréal)
    Loss of Insulin Signaling in Osteoprogenitor Cells Impairs Structural Strength of Bone without Affecting Glucose and Insulin Metabolism (J. Nyman, Vanderbilt University)
    Epigenetic Regulation of Osteogenic Transcription Factor SATB2 by PHF8, a Jumonji Family Histone D (Q. Tu, Tufts University)
    Dual Effects of Adiponectin During Osteoblast Differentiation Through pSmad 1/5/8 Signaling Pathway (L. Yu, Tufts University)
    Isopsoralan Inhibits RANKL-induced Osteoclastic Differentiation of RAW264.7 Cells by Suppression c-f (J. Zhang, Tufts University)
    Effect of Adiponectin on AdipoR1/2 in Osteoblasts and Osteoclasts Under Inflammatory Conditions (L. Zhang, Tufts University)


    Monday, August 6 – 8:00 AM – Noon (Continental Room)
    Principles of Engineering Tissue Regeneration (Chair: Robert Guldberg)
    a. Limb Regeneration: Effects of Local Biomechanical and Biologic Factors (R. Guldberg, Georgia Tech)
    b. Effects of Interstitial Flow, Shear Stress, and Mass Transport on Engineered ECM Heterogeneity (H. Awad, Univ of Rochester)
    c. Biomimetic Platforms for Human Stem Cell Repair (G. Vunjak-Novakovic, Columbia Univ)
    d. Biophysical Stimulation of Stem Cell Differentiation (H. Donahue, Penn State Univ)
    e. Local Delivery of Sphingosine1- Phosphate Receptor Specific Small Molecules in Nanofiber Scaffolds Enhance Mandibular Defect Healing by Recruiting Progenitor Cells and Increasing Vascularization (A. Das, University of Viriginia: ASBMR Harold M. Frost Award Winner)
    Principles of Engineering Tissue Regeneration
    Tissue engineering and regenerative medicine is an interdisciplinary field requiring the integration of bioengineering principles, fundamental biological discoveries, and clinical insight to achieve the ultimate goal of restoring function to injured or degenerated tissues. Damaged musculoskeletal tissues collectively represent the most common cause of pain and functional disability worldwide. Clinical efforts to restore structural integrity and function to non-healing musculoskeletal tissues are often complicated by challenging biomechanical conditions, advanced age, adjacent tissue trauma, infection risks, ischemia conditions, or general disease status of the patient. Recent biological discoveries have introduced candidate growth factors, small molecules, and stem cells that may be used to promote endogenous repair mechanisms by modulating inflammation, vascularization, cellular function, and tissue formation. However, successful delivery of regenerative biological signals requires careful consideration of bioengineering factors related to biomaterial scaffold design, mass transport, and biomechanical environment. 

    This session will explore recent advances in regenerative medicine enabled by the marriage of biology and engineering. The chair of the session will be Dr. Robert Guldberg, the Petit Director's Chair of Bioengineering and Bioscience at Georgia Tech. He is the current chair of the Americas Chapter of the Tissue Engineering and Regenerative Medicine International Society (TERMIS-AM), chair of the NIH Musculoskeletal Tissue Engineering study section, and an Armed Forces Institute for Regenerative Medicine (AFIRM) investigator. Dr. Hani Awad, Associate Professor of Biomedical Engineering and Orthopaedics at the University of Rochester, has considerable expertise in both in vivo repair models and in vitro bioreactor systems and will address how interstitial flow, shear stress, and mass transport affect the heterogeneity of extracellular matrix synthesis within engineered tissues. Dr. Gordana Vunjak-Novakovic is the Mikati Foundation Professor of Biomedical Engineering and Medical Sciences, Director of the Laboratory for Stem Cells and Tissue Engineering at Columbia University, and a member of the National Academy of Engineering. She will discuss biomimetic platforms for human stem cell-based repair. Dr. Hank Donahue, Professor of Orthopaedics at Penn State, is a leading authority on the influence of biophysical factors on stem cell differentiation. The session will conclude with a talk on small molecule delivery to enhance mandibular repair from an up-and-coming star, Dr. Anusuya Das, an ASBMR Harold M. Frost Award Winner.
    Monday, August 6 - 7:30-10:00 PM (Continental Room)
    Presentations from the winners of the ASBMR/Harold M. Frost Young Investigator Awards

    Disruptions in TGFβ Signaling Alters Sclerostin Expression and Load-Mediated Bone Formation (S. Tang, University of California, San Francisco)
    PTHrP Regulates the Modeling of Entheses During Growth (M. Wang, Yale University)
    High-Resolution Magnetic Resonance Imaging to Assess Bone Microarchitecture and Mechanical Properties in Vivo (G. Chang, NYU Langone Medical Center)
    Stem Cell Mobilization to Enhance Bone Regeneration (M. McNulty, Rush University Medical Center)
    Estrogen Receptor Alpha is Critical to the Anabolic Response of Cancellous and Cortical Bone to Mechanical Load (R. Main, Purdue University)
    Epidermal Growth Factor Receptor Regulates Cartilage Matrix Remodeling During Endochondral Ossification through β-catenin-dependent and independent Pathways (X. Zhang, University of Pennsylvania)
    Crosstalk Between Parathyroid Hormone Related Protein and Minor Fibrillar Collagens (M. Hiremath, Boise State University)
    Suppressive Effects of BRD4 Inhibitor on Inflammatory Cytokine Expression and RANKL-Induced Osteoclastogenesis (S. Meng, Tufts University)

    Additional ASBMR/ Harold M. Frost Young Investigator Award Winner presenting in another session:

    A. Das, University of Viriginia: Presenting in session: Principles of Engineering Tissue Regeneration:Local Delivery of Sphingosine1- Phosphate Receptor Specific Small Molecules in Nanofiber Scaffolds Enhance Mandibular Defect Healing by Recruiting Progenitor Cells and Increasing Vascularization

    Tuesday, August 7 – 8:00 AM – Noon (Continental Room)
    Biological Control of Peri-Implant Bone Remodeling and Implant Loosening (Chair: Rick Sumner)
    a. The Inflammasome, Implant Debris, and Implant Loosening (N. Hallab, Rush Univ Medical Center)
    b. Systemic Cell Trafficking in Response to Particulate Debris (S. Goodman, Stanford University)
    c. Importance of Fluid Flow and Pressure in Implant Loosening (Per Aspenberg, Linköping University)
    d. Bone Remodeling and the Wnt Signaling Pathway in Implant Loosening (R. Sumner, Rush Univ Medical Center)
    e. Activation of the NLRP3 Inflammasome Causes Inflammation and Abnormal Skeletal Development in Mice (G. Mbalaviele, Washington   University: Under-Represented Minority Travel Grant Winner)

    "Orthopedics" session – Biological Control of Peri-Implant Bone Remodeling and Implant Loosening
    Implant loosening is a significant limitation of the longevity of orthopedic implants used in joint replacement. Alterations in the mechanical environment of the peri-implant bone ("stress shielding") and the negative effects of particles shed from the implant ("particle-induced osteolysis") probably both play a role. This session will focus on particle-induced loosening, but will also discuss the possibility that altered fluid flow and pressure are precedent over the particles. The talks will concentrate on mechanisms, including the inflammasome and danger signals, systemic cell mobilization and the role of these cells in inflammation and repair, the roles of fluid pressure and flow, and altered bone remodeling kinetics. There will be discussion of possible therapeutic strategies, including the use of bisphosphonates, RANK ligand inhibitors, and Wnt signaling modulators.

    The Inflammasome, Implant Debris, and Implant Loosenging: Nadim Hallab, Ph.D., Department of Orthopaedic Surgery, Rush University Medical Center
    Brief synopsis: Immune reactivity to soluble and particulate implant debris remains the primary cause of aseptic inflammation and implant loosening. New pathways such as inflammasome activated danger signaling are central intracellular mechanisms that trigger immune cells to sense and respond to exogenous non-biological challenge agents including all types of implant particles/debris including released metal ions. Recently a great deal has been learned about these pathway components and how they related to other cellular pathways involved in inflammation, increasing the likelihood of successful therapeutic strategies to pharmacologically treat implant debris induced inflammation/ aseptic osteolysis.

    Systemic Cell Trafficking in Response to Particulate Debris: Stuart Goodman, MD, Ph.D., Department of Orthopedic Surgery, Stanford University

    Brief synopsis: The biological reaction to wear debris has been previously thought of as a localized response to byproducts of artificial implants. Recent in vivo studies have found that wear particles elicit systemic cell trafficking, of not only macrophages, but also of osteoprogenitors. It would appear that particle-induced release of chemokines and other substances from local cells results in more widespread cellular mobilization to induce a cycle of inflammation and repair.

    Importance of Fluid Flow and Pressure in Implant Loosening: Per Aspenberg, MD, Ph.D., Department of Clinical and Experimental Medicine, Linköping University

    Brief synopsis: There are studies suggesting that particles are of minor importance compared to the effects of fluid pressure and flow. As a treatment option, RANK ligand inhibitors such as Denosumab, are likely to be more potent than bisphosphonates for reducing resorption around a loose implant as supported by recent rat data.

    Bone Remodeling and the Wnt Signaling Pathway in Implant Loosening: Rick Sumner, Ph.D., Department of Anatomy & Cell Biology, Rush University Medical Center
    Brief synopsis: Implant placement increases rates of bone formation and resorption. In the presence of particles at the interface, resorption parameters are further increased, but formation markers are decreased, leading to impaired implant fixation. Modulating the Wnt signaling pathway through the use of sclerostin antibody increases bone formation and suppresses bone resorption, leading to enhanced implant fixation in the absence of particles and complete abrogation of particle-induced loss of fixation.

    Discussion points:
    Can we link the molecular and cellular mechanisms (inflammasome) to the tissue level mechanisms (altered remodeling kinetics) and eventual loss of fixation?
    What are the relative roles of particles and the altered mechanical environment (in this case, fluid flow and pressure)?
    Have the mechanistic studies led to therapeutic strategies or do they, at least, help to explain why some of the therapies seem to work and some do not?

    Tuesday, August 7 - 4:30-9:00 PM
    Banquet at the Sun Valley Symphony
    Wednesday, August 8 - 8:00 AM – Noon (Continental Room)
    Developmental Effects on Mechanical Signaling (Chair: Alex Robling)
    a. Mechanisms of Mechanically Induced Joint and Bone Ridge Formation (E. Zelzer, Weizman Inst)
    b. Mechanoregulation of Skeletal Development: Using Animal Models to Excavate the Molecular Mechanisms (P. Murphy, Trinity College, Dublin)
    c. Mechanomodulation in Joint and Chondrogenesis and Cavity Formation (A. Pitsillides, Royal Veterinary College, London)
    d. PTHrp Regulates the Modeling of Entheses During Growth (M. Wang, Yale University: ASBMR Harold M. Frost Award Winner)

    Developmental Effects on Mechanical Signaling
    Mechanical input to skeletal tissues is imperative for maintenance of proper bone and joint health. The vast majority of in vivo work done on mechanotransduction (e.g., biological signal reception, signal transduction, properties of the physical environment) has been gleaned from experiments performed on juvenile and adult animals. Those experiments have revealed key biological signaling pathways and physical conditions that are crucial for mechanical loading to exert its effects on the tissue. Apart from the progress made in postnatal mechanobiology, much less is known about the process and biology of mechanical signaling during embryonic development. Appropriate mechanical stimulation during development is crucial for attaining the proper size, shape, and function of bone and joints in the newborn and beyond. Moreover, the gene expression profile of skeletal tissues during development appears to vary considerably from that expressed by growing or mature bone. Mechanical signaling in embryonic skeletal tissues likely occurs under different cellular conditions; consequently, mechanotransduction might involve different or modified cellular pathways than have been proposed in mechanically stimulated postnatal bone. An understanding of the particular cellular events that occur during developmental mechanotransduction have very practical implications for treatment of disease and injury, as many skeletal regenerative processes (e.g., fracture repair, cartilage regeneration) recapitulate developmental programming. Thus an understanding of the mechanical control of bone and cartilage development is fundamental to a molecular approach to many skeletal diseases.

    A number of experimental models have been developed to explore the role of mechanical inputs on developing bone and cartilage, including both genetic and chemically-induced muscular paralysis in the embryo. This area of research has shed light on the role of mechanical forces on synovial joint and bone development, where these tissues can be studied in the absence of the principal source of loading in utero, i.e. muscle contraction. The “Developmental Effects on Mechanical Signaling” session of the Sun Valley Workshop highlights many new insights into the influence of mechanical loading on embryonic bone and joint formation, and explores some of the molecular mechanisms responsible for those effects.

    Wednesday, August 8 - 12:30 – 5:00 PM 
    Guided hike to Pioneer Cabin
    Meet outside the back door of the Sun Valley Inn at 12:15PM.  More information provided on-site.

    Wednesday, August 8 – 7:00 – 10:00 PM (Continental Room)
    Update on Osteocytes (Chair: Lynda Bonewald)
    a. Overview and Relationship to Muscle (L. Bonewald, Univ Missouri, Kansas City)
    b. Osteocyte Regulation of Osteoclastic Bone Resorption Through RANK/OPG Expression (H Takayanagi, Tokyo Medical and Dental University)
    c. PTH, the Master Regulator of Osteocyte Function (T. Bellido, Indiana University)
    d. PTH/PTHrp Receptor (PPR) Signaling in Osteocytes Regulates Bone Remodeling via Sclerostin and RANKL Expression (V. Saini, Harvard Medical School: Alice L. Jee Award Winner)  
    e. Live Imaging of Src Activation in Osteoctyes in Response to Mechanotransduction (J. Hum, Indiana University: Charles H. Turner Award Winner)

    This session investigates several novel functions of osteocytes in interaction with muscle during age-related declines, coordination of bone resorption through the RANKL/OPG system, and as mediators in the connection between hormonal regulation and bone formation. Our understanding of the contribution of osteocytes to these systems has been expanded greatly in the past few years, and these novel functions will be explored in this session. The session will also include new data from two young investigators who will receive awards for their outstanding research during the Workshop.

    Update on Osteocytes
    Overview of osteocyte function and interactions with muscle (L. Bonewald, Univ Missouri- Kansas City) Recent research has shown that osteocytes are major regulators of the function of osteoblasts and osteoclasts and may play a centralized role in regulating bone mass. Osteocytes also appear to act as endocrine factors targeting other organs such as kidney, the immune system, and others. While dogma assumes that the muscle-bone relationship is driven purely by mechanical factors, bone can act, in effect, as an “endocrine organ” to control muscle physiology and disease.The traditional view of skeletal muscle and bone interaction is that skeletal muscle loads bone and bone provides an attachment site for muscle. This mechanical perspective implies that as muscle function declines, this would result in decreased loading of the skeleton and therefore would result in a decrease in bone mass. However, muscle atrophy alone cannot fully explain the totality of osteoporosis and, reciprocally, aging associated decreases in bone mass do not fully explain sarcopenia. We have begun to examine the molecular and cellular mechanisms that contribute to the coordinated development of bone and muscle conditions. With age, a factor produced by muscle and which acts on the osteocyte and enhances both its viability and ability to respond to exercise, is no longer being made. Identification of this factor is in process.

    Osteocyte regulation of osteoclastic bone resorption through RANK/OPG expression (H Takayanagi, Tokyo Medical and Dental University) Osteocytes are thought to orchestrate bone homeostasis by regulating both bone-forming osteoblasts and bone-resorbing osteoclasts. It is well know that osteoclast differentiation and function is regulated by receptor activator NF-κB ligand, RANKL. Previously it was assumed that RANKL was mainly expressed by osteoblasts or stromal cells in bone marrow. We showed that osteocytes within the bone matrix are the critical source of RANKL, that osteocytes express five times greater amounts of RANKL than osteoblasts, and that targeted deletion of RANKL in osteocytes results in a severe osteopetrotic phenotype. Therefore a major means by which the osteocyte regulates osteoclastic bone resorption is through the expression of RANKL.

    PTH, the master regulator of osteocyte function (T. Bellido, Indiana University) The discovery that parathyroid hormone (PTH), a central regulator of bone homeostasis, inhibits the expression of sclerostin, the osteocyte-produced inhibitor of bone formation, initiated a cascade of studies that had revealed that osteocytes are crucial target cells of the actions of PTH. Transgenic mice expressing a constitutive active PTH receptor (PTHR1) in osteocytes exhibit reduced sclerostin expression and increased bone mass; and bone anabolism in this model strictly depends on downregulation of sclerostin. Unexpectedly, activation of PTHR1 signaling in osteocytes also increases RANKL expression and bone resorption; and the converse effect is found in mice lacking PTHR1 in osteocytes. However, control of osteoclast generation and resorption does not depend on sclerostin downregulation, demonstrating that PTH acts on osteocytes to regulate bone formation and resorption by separate mechanisms. PTHR1 signaling also increases the expression of FGF23, an osteocyte product that inhibits phosphate re-absorption in the kidney and regulates matrix mineralization. The FGF23 receptor complex (FGFR1/Klotho) is expressed in osteocytes and osteoblasts, and FGF23 signaling is enhanced in bone by PTHR1 activation. Thus, regulation of osteocytic FGF23 by PTH might modulate mineral homeostasis by endocrine as well as auto/paracrine mechanisms. Signaling downstream of the PTHR1 in osteocytes also cross-talks with mechanotransduction, as evidenced by a deficient response to loading of mice lacking the PTHR1 in osteocytes. These findings demonstrate that direct actions PTH on osteocytes regulate the expression of genes that impact skeletal homeostasis and suggest that the PTH receptor expressed in osteocytes participates also in the coordinated regulation of bone formation by hormonal and mechanical stimuli.

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