Past Bone Seminars
Fall 2004 Series
___September 2004___
Speaker: David T. Denhardt PhD, Department of Cell Biology and Neuroscience,
Rutgers University, Piscataway, NJ
Topic: Osteopontin, a Cytokine and Bone Matrix Protein, Augments Bone Remodeling, Metastasis, and Autoimmune Disease Progression
Dr. Denhardt’s Research Interests: His research interests currently focus on the systems physiology of osteopontin (OPN) and TIMP-1 (tissue inhibitor of metalloproteinases-1). Both in different ways stimulate tumor cell metastasis and he would like to know why. With respect to OPN, he would like to understand how it functions in such apparently diverse processes as bone remodeling and autoimmune disease.
Abstract
Osteopontin (OPN) is a phosphorylated, glycosylated protein found not only extracellularly in all body fluids and in mineralized matrices but also intracellularly at the cytoskeletal/plasma membrane interface. The extracellular form is capable of engaging some half-dozen integrins and at least two CD44 variants. OPN signaling regulates gene expression (e.g., iNOS expression induced by endotoxin) and cell motility, stimulating a chemotactic response. It enhances the survival of cells exposed to various stresses by inhibiting apoptosis. OPN can stimulate tumor cell metastasis and the progression of autoimmune disease: Mice lacking OPN are less susceptible to arthritis induced by anti-type II collagen antibodies (Noda) and to experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein peptides (Steinman, Cantor). They are also unable to remodel bone in response to various stresses (ovariectomy, hind-limb suspension), possibly in part because OPN is required for normal osteoclast function (Hruska, Noda, Sodek).
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___October 2004___
Speaker: Timothy G. Bromage PhD, Department of Biomaterials and Biomimetics, New York University College of Dentistry, New York, NY
Topic: LUCY FALLS FROM SKY AND RETURNS LOST DIAMONDS!
Confocal Circularly Polarized Light Microscopy of the Early Hominid Skeleton
Dr. Bromage’s Research Interests: Comparative hard tissue biology and microanatomy in relation to functional, life history, and environmental reconstruction; human evolution; development of practical solutions to technical problems of mineralized tissue specimen preparation and imaging.
Above: Dr. Bromage views the Taung Child through his portable confocal microscope at Witwatersrand University, Department of Anatomy, Paleoanthropology Research Unit. The Taung Child is an Australopithecus africanus hominid approximately 2.5-3.0 million years old. The field of paleoanthropology is commonly considered to have its modern beginnings with Raymond Dart’s 1925 discovery of this specimen.
Below: Dr. Bromage; cross section of Lucy’s femur.
Abstract
Skeletal microanatomy is typically investigated by some form of light microscopy on specially prepared samples, such as histological thin sections, or by scanning electron microscopy (SEM) of bulk specimens. However, unique African early hominid remains from Pliocene localities some 2-4 million years old are not readily available for histological sectioning, and bulk examination by SEM is restricted to first surfaces. A practical alternative is confocal scanning optical microscopy (CSOM). This permits “optical sectioning” upon and below the intact surfaces of opaque materials, which generates excellent reflection images and provides basic details of bone and tooth histological microanatomy equal to that produced by conventional research microscopes.
This is all very well, but African early hominid repositories do not have available CSOM technologies, requiring that we bring such an instrument to the fossils. This has prompted development of the first portable CSOM, the prototype of which has recently been taken to Ethiopia, Kenya, and South Africa for its first glimpse of the hard tissue microanatomy of Australopithecus, Paranthropus, and early Homo species. CSOM imaging of the dentition is demonstrating species-specific variations of enamel structure related to functional and life history adaptations. Further, because the portable CSOM is configured to generate reflected circularly polarized light images, we are able to study and analyze preferential collagen fiber orientations in bone tissue and thus skeletal function in our fossil ancestors.
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___November 2004___
Speaker: Janet Rubin MD, Professor of Medicine, Division of Endocrinology and Metabolism, Emory University School of Medicine and the Atlanta Veterans Affairs Medical Center, Atlanta, GA
Topic: Turning Mechanical Signals into Biological Effects
Dr. Rubin’s Research Interests: Mechanical and hormonal control of bone remodeling, gene therapy systems, tumor metastases in bone.
Abstract
Biophysical input generated during normal physiologic loading is a major determinant of bone mass and morphology. Our laboratory’s interest is in how bone cells sense and transduce signals generated during loading and how this cellular response leads to skeletal adaptation to its mechanical environment. We have shown that substrate strain regulates gene expression in bone stromal cells, decreasing expression of RANKL and increasing expression of eNOS/nitric oxide. These changes generate a local environment that is inhibitory for osteoclast recruitment. The ability of mechanical strain to induce this functional response requires activation of the ERK1/2 MAP-kinase pathway. The proximal signaling cascade leading to ERK1/2 activation is stunningly specific, and suggests that the putative mechanotransducer occupies a discrete membrane location. Our most recent work suggests that the mechanical signal arises from events occurring within a lipid raft. Distal to ERK1/2 activation, we will also consider possible mechanisms by which strain may inhibit RANKL gene transcription through altering chromatin interactions with the RANKL promoter. By defining the mechanisms involved in strain regulation of osteoclast formation we hope to generate new paradigms for understanding how cells convert mechanical information into biological effects.
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___December 2004___
Speaker: Peter Bullough MD, Director of Laboratory Medicine, Hospital for Special Surgery, New York, NY; Professor of Pathology, Cornell Medical School, New York, NY
Topic: Bone and Subchondral Bone Involvement in the Etiology of Arthritis
Dr. Bullough’s Research Interests: “I have had a long-time interest in the question ‘Why do people get arthritis?’ The study material has been the joints resected in joint replacement, which account for around 30% of all orthopaedic procedures where I work.”
Abstract
Focal degenerative changes occur in some joints very early in life. These changes in the articular cartilage appear to occur on the unloaded, rather than loaded, areas of the joint. Just as unused bone and unused muscle atrophy, so may unused cartilage. If these unloaded structures were never subjected to mechanical stress, degeneration at these sites perhaps would not be important. However, bones, including their articular ends, are in a constant state of change through the process of remodeling, which continues throughout life. Joint surfaces are not, in general, spherical, and therefore must be incongruent during most of their arc of movement. In the young person, this incongruity maintains physiologic loading and joint nutrition. Studies have shown age-related changes in the remodeling process that lead to increasing joint congruity in old age. These age-related increases in congruity may result in a redistribution of load in the joint such that there is an increased stress on formerly unloaded atrophic cartilage. Arthritis always results in a change in joint shape. It is suggested that a change in shape caused by a disturbance in the remodeling process may itself be an important contributing cause of osteoarthritis.
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