Past Bone Seminars

Fall 2003 Series

___September 4, 2003 ___
Speaker: Robert J. Majeska PhD, Research Associate Professor, Department of Orthopaedics, Mount Sinai School of Medicine
Topic: The Vasculature in Fracture Healing

Dr. Majeska’s Research Interests: Cell biology of skeletal tissues, with emphasis on the cells that form bone and cartilage (i.e. the osteoblast and chondrocyte lineages). A combination of in vitro and in vivo studies are used to understand the regulation of bone cell activities by a variety of stimuli including hormones, growth factors and the extracellular matrix. In recent years, these studies have largely focused on bone and cartilage formation during fracture healing.

Abstract
Proper vascular function is universally acknowledged to be essential for fracture healing; however, the precise role played by the blood vessels during the healing process remains poorly understood. Angiogenesis inhibitors that selectively target cells of the vascular system are potentially useful tools to manipulate the development of blood vessels with minimal direct effects on the tissues in which they reside. Utilizing this experimental approach, we and others have shown that angiogenesis inhibitors can impair fracture healing in animal models. Studies from our laboratory have shown that the angiogenesis inhibitor TNP-470 dramatically inhibited fracture healing in rats, suppressing both intramembranous and endochondral pathways of bone formation. The initial phase of healing appeared to be most sensitive to inhibition. Impairment of fracture healing was associated with reduced vascularization and altered gene expression in developing callus tissue. More recent in vitro studies showed that high concentrations of of angiogenesis inhibitor reduced growth of cells derived from bone and bone marrow, but did not impair responsiveness to BMP, supporting the concept that the failure to heal fractures properly was a result of impaired blood vessel development. Current studies are aimed at identifying crucial early events in healing that are affected by angiogenesis inhibitors, and determining whether fracture healing inhibition is reversible.

___October 15, 2003 ___
Speaker: Michael P. Whyte MD, Division of Bone and Mineral Diseases, Washington University School of Medicine; and Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children, St. Louis, MO
Topic: When Osteoclasts Run Amok: Heritable Disorders of the RANKL/OPG/RANK/NF-kB Signaling Pathway

Dr. Whyte’s Research Interests: Heritable disorders of bone and mineral metabolism

Abstract
Soon after the discovery and characterization of the receptor activator of nuclear factor-kB (RANK) and the decoy receptor osteoprotegerin (OPG) and their ligand RANKL among the tumor necrosis factor (TNF) superfamily, the important RANKL/OPG/RANK/NF-kB signaling pathway became understood for osteoclast formation and action. Subsequently, the genetic basis of several rare metabolic bone diseases confirmed the major role these proteins play in human skeletal homeostasis. Familial expansile osteolysis (FEO), early-onset Paget bone disease in Japan (PBD2), and expansile skeletal hyperphosphatasia (ESH) are all inherited as autosomal dominant traits. Each condition is caused by a tandem duplication of different length in exon 1 of the TNFRSF11A gene encoding RANK. Trapping of RANK within osteoclasts because its signal peptide sequence is elongated seems to activate the NF-kB pathway leading to these systemic skeletal disorders featuring accelerated bone turnover. Deafness during infancy or early childhood together with the onset of lytic skeletal lesions that expand bone and can mimic Paget bone disease (PBD) characterize the pediatric and young adult manifestations of FEO and ESH, respectively. In fact, patients with FEO and ESH respond well to bisphosphonate therapy. Reports of additional cases or families with ESH, FEO, and PBD2 will be essential to know if there is greater phenotypic overlap among these disorders that differ merely by the insertion of 5, 6, or 9 amino acids, respectively, in the signal peptide of RANK. Juvenile Paget disease (JPD), also called "idiopathic hyperphosphatasia," is caused by autosomal recessive inheritance of deletion or deactivating mutations in TNFRSF11B - the gene which encodes OPG. OPG gene deletion can lead to high circulating levels of RANKL and exuberant RANK effect causes this generalized skeletal disorder also featuring accelerated bone turnover manifesting during infancy or early childhood with deafness, skeletal deformity, and recurrent fracture which can be lethal by early adult life unless there is antiresorptive therapy.

___November 6, 2003 ___
Speaker: E. Dianne Rekow DDS, PhD, Director of Translational Research, NYU College of Dentistry, Division of Biological Science, Medicine, and Surgery
Topic: Effects of Scaffold Micro architecture Features on Bone Formation

Dr. Rekow’s Research Interests: Bone response to scaffold features, especially in length scales of 1-100 micrometers. The interaction between features including pore size, connectivity, and density as well as surface texture and microporosity of the supporting walls within the scaffold has not yet been elucidated and offers some interesting challenges in defining efficient and cost-effective studies. While the results apply to all bone repair, as an orthodontist and biomedical engineer, her concern is primarily motivated by restoring form and function in the craniofacial complex. The research group includes collaborations with investigators from New York University and the University of Medicine and Dentistry of New Jersey.

Abstract
Scaffold features at all length scales affect bone formation within the scaffold. At the nano-scale, surface chemistry plays an important role, especially related to biocompatibility. On the other end of the spectrum, the macro design of implants can create form and, in the short term, contribute to restoration of strength for function. In the middle length scales, surface texture (the microstructure) has been shown to be particularly important in the success of dental endosseous implants. Our investigations indicate that other micro architecture (mesoscale in the ten to hundreds of micrometer length) also plays an important role. This presentation will describe differences in bone response in large trephine defects (in skeletally mature New Zealand white rabbits) filled with scaffolds fabricated from different materials with prescribed micro architectures created using solid-free-form fabrication technologies. Scaffold micro architecture did not alter the rate of bone development but did substantially alter the patterns of bone that develops. Identical micro architecture in scaffolds fabricated from different materials elicits different bone response. Some material and micro architecture combinations created multiple sites of seemingly independent bone islands scattered throughout the scaffolds. Unexpectedly bone ingrowth was shown (and confirmed with a second set of experiments) to develop in materials with pore sizes nearly an order of magnitude smaller than expected. This suggests that by appropriately tailoring material and micro architecture combinations, time to fill a scaffold could be accelerated.

___December 10, 2003 ___
Speaker: Timothy M. Wright PhD, Senior Member, Research Division, Hospital for Special Surgery, Professor of Applied Biomechanics, Department of Orthopaedic Surgery, Weill Medical College of Cornell University
Topic: Biomechanical Challenges in Joint Reconstruction

Dr. Wright’s Research Interests: Performance of bone-implant systems, with an emphasis on the influence of design and material properties on wear behavior of total joint replacements, and on the relation between composition, structure, and function in bone tissue

Abstract
Total joint arthroplasty is among the most successful and cost effective surgical procedures and remains the best treatment for long-term pain relief and restoration of function for patients suffering with diseased or damaged joints. Nonetheless, the desire by both patients and surgeons to treat joint problems at earlier stages than might be indicated for conventional joint replacement has spurred increased interest in the development of a much broader spectrum of possible solutions from more functional implant designs to interpositional spacers to synthetic plugs to autografts and finally to engineered tissues. In many respects, the biomechanical problems involved in all these solutions are the same - transferring large loads across the joints into the remaining healthy skeleton. At the same time, the ability to manipulate existing bone tissue through mechanical and biological influences and to control the development of engineered tissues through similar approaches raises exciting possibilities for joint reconstruction. Important first steps are to determine how significantly mechanical influences can alter bone tissue and what mechanical factors are key in controlling the alteration. Our research group has begun this examination by applying controlled loads to both cancellous and cortical bone in animal models. Such platforms provide effective tools for pursuing research questions in this vital area.