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Tuesday,
September 8, 2009 CUNY Graduate Center, Room C197, 7:00 PM Click here for directions to the CUNY Graduate Center Speaker: Oran Kennedy, PhD, Postdoctoral Research Fellow, Department of Biomedical Engineering, CCNY Host: Mitch Schaffler, CCNY Topic: Changes in Bone Remodeling: Effects on Tissue Properties and Damage MechanicsAbstract: Bone remodeling is the mechanism by which small regions of tissue are replaced in order to remove damaged/functionally impaired material, thus maintaining a balance of healthy bone in the skeleton. Under normal circumstances, the rate of bone remodeling is sufficiently rapid to prevent matrix degradation due to hyper-mineralization or microdamage accumulation, without causing appreciable reduction in mechanical performance. However in diseases such as osteoporosis, the removal of small amounts of bone via resorption is not balanced by sufficient bone formation and can thus have serious deleterious effects, beyond those predicted by the loss of bone volume. This effect is exacerbated by the increase in bone remodeling that is characteristic of this disease. We carried out a number of studies to investigate the effects of increased bone turnover on the mechanical performance of bone. Fluorochrome bone labels provide a useful way of marking sites of bone turnover in vivo. We used 5 such labels in an OVX ovine animal model to study the effects of increased bone turnover on mechanical properties. Studies of compact bone tissue showed that intracortical turnover and microarchitecture were altered by OVX and resulted in increased porosity and reduced strength. Studies of lumbar vertebrae were also carried out and included analyses of both cortical and trabecular bone compartments. While microarchitectural parameters were unchanged bone turnover was increased in both. However, strength and stiffness were reduced in the OVX group and this group also displayed less plastic strain and more strain due to damage. Studies were also carried out on the interaction between fatigue-induced microdamage and areas of increased remodeling. While crack density was higher in OVX, crack surface density was higher in the controls, due to the presence of more long microcracks. It was also observed that long cracks (>300μm) tended to arrest at new (labeled) osteons whereas they tended to penetrate or deflect around older (unlabeled) osteons. These studies showed that increased bone turnover has a direct effect on the mechanical properties of bone tissue at different structural levels. Further characterization of the local effects of excessive remodeling activity will help to characterize certain aspects of diseases such as osteoporosis and may help in designing novel treatment strategies. Tuesday, October 13, 2009 Speaker: F. Patrick Ross, PhD, Hospital for Special Surgery Host: Mitch Schaffler, CCNY Topic: Molecular Mechanisms of Osteoclast Function Abstract: Osteoclasts, the sole cells capable of resorbing bone, arise from hematopoietic precursors by a combination of proliferation and differentiation, two processes controlled by multiple cytokines, of which M-CSF (macrophage colony stimulating factor) and RANKL (receptor activator of NFkB ligand) are the most crucial. Local or systemic inflammation, as typified by absence of estrogen or rheumatoid arthritis, aggravates bone erosion and in this instance a major causative molecule is TNF (tumor necrosis factor). Initiation and maintenance of bone degradation requires osteoclast activation and polarization, events involving re-organization of the cellular cytoskeleton. We have explored the molecular mechanisms by which a range cytokines stimulate intracellular signals responsible for osteoclast generation and function and I will review recent advances in these areas, focusing on synaptotagmins and selected members of the small GTPase family. In all instances we have adopted an approach that involves genetic deletion of molecules of potential interest, either globally or by tissue-specific recombination. Our studies reveal non-overlapping roles for closely-related members of the same family of molecules, suggesting the possibility of developing effective therapeutic approaches for regulating diseases in which bone loss is an important pathogenic component.
Tuesday, November 10, 2009 Abstract:
"Revolution 9" played an
important part in the infamous "Paul is dead" hoax. Most notably, the
repeated "number nine" played backwards can be heard as "Turn me on,
dead man" (http://en.wikipedia.org/wiki/Revolution_9). What
better segue than this for a discourse on the evolutionary history of
hard tissue rhythms and bone/body size, which, from a short 6-day
rhythm in our putative ape-like ancestors, lengthened to the modern
human average of 9-days. What do these numbers mean?
Mammalian enamel formation is periodic, including fluctuations
attributable to the daily biological clock, but as well including
longer period oscillations that correlate enigmatically with body
mass. Lamellar bone is also an incremental tissue, each increment
being a distinct layer, or lamella. From vital labeling
experiments in which two successive labels are given some time apart,
we have ascertained that lamellae are laid down in the time period
represented by the number of days observed between successive striae of
Retzius in enamel, called the repeat interval, which in modern humans
is 9 days (in contrast, that of modern chimpanzees is 6 days, of early
hominids 7 days, and early Homo
8 days). It follows from these experiments that the length
of a striae of Retzius repeat interval should relate to speed of
body development, insofar as the development of bone mass—as reflected
by the addition of lamellae to bones—must be scaled to carry the load
of body mass. Faster speeds of lamellar development should
characterize species with relatively short repeat intervals and brief
periods of development, resulting in small body mass, while longer
repeat intervals should associate with species having slower speeds of
development and larger body mass. Variations in striae of Retzius
repeat intervals thus represent variations in a long-period biological
rhythm, which, when statistically evaluated, reveal a significant
relationship between body size and striae of Retzius repeat intervals
in apes and early fossil humans. “Insular dwarfism” is an extreme
example of body size reduction that occurs on islands and to which for
understanding the phenomenon we can apply our newfound tools of hard
tissue biology. Preliminary work on the long period rhythms of
insular dwarfs indicates that developmental rate is accelerated, which
results in an early cessation of growth and small body size at
adulthood. We now have the basis for informed speculation
concerning how and why “Hobbits," the diminutive fossil human species Homo floresiensis on Flores Island,
Indonesia, attained such small size.
CUNY Graduate Center, Room 9206, 7:00 PM Click here for directions to the CUNY Graduate Center Speaker: Daniel Kelly, PhD, Trinity Centre for Bioengineering, Trinity College, Dublin Host: Chris Jacobs,
Columbia University Abstract: During fracture healing and microfracture treatment of cartilage defects, mesenchymal stem cells (MSCs) from the bone marrow and other surrounding soft tissues infiltrate the wound site, proliferate extensively and differentiate along a chondrogenic or an osteogenic lineage in response to local environmental cues such as growth factors and cytokines. The mechanical environment is also known to regulate the mechanisms of repair following bone fracture. When there is excess motion at the site of injury the predominant mechanism of bone regeneration is through endochondral ossification. Conversely, when motion is minimized, healing primarily occurs through intramembranous ossification. A number of different hypotheses have been proposed to explain how the mechanical environment regulates endochondral ossification during fracture healing. MSCs may be able to directly sense their mechanical environment within a regenerating tissue and differentiate based on the local magnitude of shear strain, hydrostatic pressure, tensile strain, compressive strain and/or fluid flow they experience. In conjunction, or perhaps alternatively, the mechanical environment could also act indirectly to regulate MSC differentiation by inhibiting angiogenesis and hence the supply of oxygen and other factors to the wound site. This talk will begin by explaining how computational models have been used to investigate the mechanobiology of MSCs. Next, the speaker will reinterpret his own work on MSC-based cartilage tissue engineering, exploring if such in vitro models can provide greater insight into how environmental factors regulate endochondral ossification during normal regenerative events such as fracture healing and osteochondral defect repair.
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