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Steve Cowin
02-07-2003, 06:15 AM
To Bone Researchers in the NYC area:
The NYC Mineralized Tissue Seminar will have its first spring
seminar on Thursday night February 27th. Abstracts for each of the
spring seminars are given below.

THE SPRING 2003 BONE SEMINAR SERIES

The Bone Seminar Series has as its focus the mechanosensory system in
bone. The series sponsors eight seminars a year beginning in
September and continuing until April or May. The seminar program is
regularly posted on www.bonenet.net, a website dedicated to research
on the mechanosensory system in bone.

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THE SPRING 2003 BONE SEMINAR PROGRAM

The seminar series will be held in Room 9204 (on the 9th floor) or
Room C201 (on the concourse level, below the ground floor) at the
CUNY Graduate Center on Thursdays from 7 to 8:30 PM. The CUNY
Graduate Center is in the Altman Building at the corner of 34th
Street and 5th Avenue, catty-corner from the Empire State Building.
There will be some socializing before the seminar in the seminar room
from 5:45 PM. Also, from 5:45 PM until 7 PM there will be food (fruit
plate, vegetable plate, cookies) and drink (coffee and soft drinks)
available in the seminar room. There is also a Graduate Center snack
bar on the first floor; besides the usual snacks and drinks the 365
Express also carries beer and wine.
There are several subway lines nearby and it is less than a
ten-minute walk to either Grand Central Station or Penn Station.
There is money to support parking for graduate students, apply to
Steve Cowin (contact information at the bottom).

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FEBRUARY 27th, 2003 in room 9204 at the CUNY Graduate Center at 7 PM.

Speaker: MITCHELL B. SCHAFFLER, Ph.D., Professor of Orthopaedics,
Cell Biology and Anatomy & Director of Orthopaedic Research,
Department of Orthopaedics, The Mount Sinai School of Medicine and
Co-Director, New York Center for Biomedical Engineering, City College
of New York

Title: MECHANICAL FACTORS AND REMODELING OF COMPACT BONE

Abstract: Skeletal tissues maintain a balance between mechanical wear
and tear (i.e. fatigue) damage and intrinsic, matrix-level repair.
Imbalance in this damage-repair homeostasis, either because of
excessively rapid damage accumulation or because of ineffective,
inadequate or inappropriate biological responses to chronic injury,
leads to pathology and, ultimately, mechanical failure of skeletal
elements. These processes are implicated in a wide range of
conditions, including overuse injuries, tissue fragility in aging,
tendon and ligament failures and degenerative joint disease.
A major function of Haversian (osteonal) remodeling is to
remove and replace regions of compact bone that accumulate
microdamage due to fatigue. However, little is known about the
damage or remodeling responses that occur at the levels of fatigue
expected to result from normal wear and tear. In particular, how
bone-remodeling units "target" microscopically damaged areas of bone
is unknown. Our recent studies of remodeling-repair of microdamage
find that intracortical resorption effectively removes both
linear-type microcracks and diffuse matrix damage. Alterations of
osteocyte and canalicular integrity are observed in microdamaged
areas. Resorption spaces were also seen within areas of cortex in
which no bone matrix damage occurred, but alterations of osteocyte
and canalicular integrity were evident. Recent studies indicate that
these alterations of osteocyte integrity correspond to osteocyte
apoptosis, or programmed cell death. Thus, osteocyte death or damage
may provide a key stimulus for this signaling or targeting the
remodeling process in bone.

RESEARCH INTERESTS OF MITCH SCHAFFLER: Major research efforts in bone
biomechanics and tissue physiology, with emphasis on understanding
mechanical wear and tear (fatigue) processes in skeletal tissues, and
the cellular/molecular mechanisms used in the detection and repair of
connective tissue matrix injury. Related areas of interest extend to
aging and skeletal fragility, including osteoporosis, and the healing
and regeneration of bone.

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MARCH 20th, 2003 in room C201 at the CUNY Graduate Center at 7 PM.

Speaker: NICOLA C. PARTRIDGE, Ph.D., Professor and Chairman,
Department of Physiology & Biophysics, UMDNJ-Robert Wood Johnson
Medical School, Piscataway, NJ 08854.

Title: PARATHYROID HORMONE REGULATION OF GENE EXPRESSION IN THE OSTEOBLAST

Abstract: Parathyroid hormone (PTH) plays a central role in
regulation of calcium metabolism but also appears to have a role as
an anabolic hormone for bone. The hormone has multiple actions,
including many direct changes in the functions of the osteoblast. To
date, all of its skeletal effects appear to be mediated by binding to
a single receptor on osteoblasts. In this process, PTH causes a
change in osteoblastic gene expression and function. Apart from
producing osteoclast-activating factors such as RANKL and interleukin
-6 (IL-6) in response to PTH, the osteoblast appears to also have a
direct role in matrix degradation in response to this hormone. For
instance, PTH induces collagenase-3 gene transcription in
osteoblastic cells through a cAMP-dependent pathway requiring de novo
protein synthesis. Thus, this is a secondary effect that involves the
induction and activation of specific transcription factors acting on
this gene. We identified the PTH-response elements as being the
activator protein-1 (AP-1) and the core binding factor a1 (Cbfa1)
binding sites in the collagenase-3 promoter. We have demonstrated a
PTH-dependent cooperative interaction between the sites and the
proteins binding to them. By gel shift analysis, we have shown
enhanced binding of c-Fos and c-Jun proteins at the AP-1 site upon
treatment with PTH but no significant change in the level of Cbfa1
binding to its site. Supporting our earlier work, the PKA pathway was
shown to be the only pathway regulating the collagenase-3 promoter as
a mediator of PTH action. The importance of this pathway was
demonstrated by the fact that PTH stimulates the transactivation of
activation domain-3 in Cbfa1 through its PKA site. PTH regulates both
transcription factors through this pathway, either by increasing
their expression or altering their phosphorylation. Our hypothesis of
the functions of these proteins is that they interact physically in a
nucleosomal structure, recruiting other proteins such as
co-activators, modifiers of the nucleosome and the general
transcription factors. If there is time, I will talk about some of
our new work on PTH regulation of novel genes in osteoblasts.

RESEARCH INTERESTS OF NICOLA PARTRIDGE: We have shown that
parathyroid hormone (PTH) induces the transcription of collagenase-3
in osteoblastic cells. This involves the protein kinase A pathway
and induction of activator protein-1 transcription factors as well as
phosphorylation of another transcription factor, core binding factor
a1. Thus, PTH regulates both transcription factors through this
pathway, either by increasing their expression or altering their
phosphorylation. Our hypothesis of the functions of these proteins is
that they interact physically in a nucleosomal structure, recruiting
other proteins such as co-activators, modifiers of the nucleosome and
the general transcription factors. In another project, we are
investigating the signal transduction pathways whereby PTH induces
anabolic effects on bone and determining novel genes regulated by
this hormone. In two other projects we have shown that extracellular
concentrations of collagenase-3 are regulated by the existence of a
specific receptor that binds the enzyme. Subsequent internalization
and degradation of collagenase-3 require transfer to the endocytotic
receptor, the low-density lipoprotein receptor-related protein. We
have recently purified and identified the specific receptor as a
170-kDa protein. We are now further characterizing the collagenase-3
removal process in osteoblasts, fibroblasts as well as chondrocytes
from patients with osteoarthritis. The latter work could lead to new
treatments for this disease.

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APRIL 10th, 2003 in room C201 at the CUNY Graduate Center at 7 PM.

Speaker: HELEN H. LU, PhD, Department of Biomedical Engineering,
Columbia University in the City of New York.

Title: DESIGN CONSIDERATIONS IN ORTHOPEDIC TISSUE ENGINEERING OF
BONE, SOFT TISSUE, AND INTERFACES

Abstract: Optimal treatment modalities in orthopedics are needed to
meet the demands of an aging yet still active population. Due to
limitations associated with existing biological and synthetic grafts,
tissue engineering has emerged as an alternative approach in
orthopedic repair and regeneration. An area of recent interest is
the design of interfaces to facilitate the integration of bone with
tissues such as muscle, cartilage, ligaments, and tendon. The nature
of the tissue-tissue interface is important in the fixation of
existing implants to bone, and in the integration of a variety of
tissues formed in vitro using tissue engineering approaches.
Development of a bone-soft tissue interface is a highly complex
problem, involving the engineering of both soft and hard tissue, as
well as the interfacial region. This talk will first describe our
research efforts in bone tissue engineering utilizing a composite
scaffold of biodegradable polymers and bioactive ceramics seeded with
bone-forming cells, as well as the use of bone morphogenetic proteins
in promoting mineralization by varied cell sources. Next, results
from our work in tissue engineering of the anterior cruciate ligament
using a three-dimensional, porous, biodegradable, and braided
construct will be presented. The design, in vitro and in vivo
characterizations, and optimization of both soft and hard tissue
engineering constructs will be discussed. Finally, current efforts
in the integration of soft and hard tissues will be described, and
new research directions will be proposed.
RESEARCH INTERESTS OF HELEN LU: Dr. Lu's research focuses on the
regeneration of a functional interface between bone and
ligaments/tendons, as well as the interface connecting bone and
cartilage. Providing a mechanically functional interface between the
biomaterial and bone tissue, and between bone and soft tissue will
significantly improve the long-term stability of the implant. Dr.
Lu's research group at the Biomaterials and Interface Tissue
Engineering Laboratory at Columbia University are developing in vitro
culturing systems to mimic the formation of the interface between
bone and soft tissue (cartilage and ligament) in vivo. These systems
are used to examine the effect of co-culturing on the growth and
differentiation of osteoblasts, chondrocytes and ligament
fibroblasts. Results from these studies are being utilized to design
3-D, tissue engineered scaffold systems that can be applied in the
treatment of osteoarthritis and anterior cruciate ligament injuries.

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MAY 8th, 2003 in room C201 at the CUNY Graduate Center at 7 PM.

Speaker: STEPHEN C. COWIN, PhD. Distinguished Professor of Biomedical
and Mechanical Engineering, Director of the New York Center for
Biomedical Engineering, The City College of New York

Title: BONES HAVE EARS

Abstract: The structural adaptations of living require a cell-based
mechanosensing system with a sensor cell that perceives the
mechanical deformation of the mineralized matrix in which the cell
resides, a cell-based mechanosensing system not unlike that in the
ear. One of the most perplexing features of this mechanosensory
system in bone is the very low strain level that a whole bone
experiences in vivo compared to that needed to produce a response in
cells. The amplitudes of the in vivo strains generally fall in the
range 0.04 to 0.3 percent for animal locomotion and seldom exceed 0.1
percent. These strains are nearly two orders of magnitude less than
those needed (1% to 10%) to elicit biochemical signals necessary for
communication of the sensing cells with the cells that deposit and
resorb bone tissue. There is a paradox in the bone mechanosensing
system in that the strains that activate the bone cells are at least
an order of magnitude larger than the strains to which the whole bone
organ is subjected. A hierarchical model ranging over length scales
that differ by 9 orders of magnitude, from the subcellular level to
the whole bone level, is used to resolve this paradox. Using this
extended model, it is possible to explain how the fluid flow around a
bone cell process can lead to strains on the cell process structure
that are two orders of magnitude greater than the ambient strains in
the mineralized matrix in which the cell resides. This bone
mechanosensory system has many features in common with the auditory
system.

RESEARCH INTERESTS OF STEVE COWIN: His principal research interest is
the mechanics of materials, particularly in determining the influence
of microstructure on the gross mechanical behavior of granular,
composite, and biological materials. He concentrated on bone
mechanics for many years and has been interested in tissue building
process in skeletal tissues in recent years.

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ORGANIZATION OF THE SEMINAR SERIES

The Interinstitutional Steering Committee (ISC) will make decisions
concerning the seminar series, including the selection of speakers.
Interesting, high quality seminar speakers are sought. Seminar
attendees are asked to help in the identification of investigators
with new results relative to the bone research, questions of current
interest and distinguished bone researchers visiting New York City
who might be persuaded to present a seminar. Presentations by
advanced graduate students and post-docs are encouraged.
The members of the Interinstitutional Steering Committee (ISC) are
Adele Boskey (Head of the Mineralized Tissue Section at the Hospital
for Special Surgery and Professor of Biochemistry at the Weill
Medical College of Cornell University), Timothy Bromage (Director of
the Hard Tissue Research Unit and Professor of Anthropology at Hunter
College of CUNY), Stephen C. Cowin (Director of the New York Center
for Biomedical Engineering (NYCBE) and Professor of Biomedical and
Mechanical Engineering at the City College of the City University of
New York (CUNY)), Susannah P. Fritton (Director of the Tissue
Mechanics Laboratory, New York Center for Biomedical Engineering and
Associate Professor of Biomedical Engineering at the City College of
CUNY), X. Edward Guo (Director of the Bone Bioengineering Laboratory
and Assistant Professor of Bioengineering at Columbia University),
Clinton T. Rubin (Professor and Chair of the Department of Biomedical
Engineering, and Director of the Center for Advanced Technology in
Medical Biotechnology at SUNY Stony Brook) and Mitchell B. Schaffler
(Director of Orthopaedic Research and Professor of Orthopedics, Cell
Biology and Anatomy at the Mount Sinai School of Medicine). Each of
these people represents a community consisting of senior bone
research people, graduate students and, in most cases, undergraduate
students.

PLEASE DIRECT YOUR QUESTIONS AND FEEDBACK TO

Stephen C. Cowin
Director, New York Center for Biomedical Engineering
School of Engineering
The City College
138th Street and Convent Avenue
New York, NY 10031-9198, U. S. A.

Phone (212) 799-7970 (Office at Home)
Fax (212) 799-7970 (Office at Home)
Phone (212) 650-5208 (Work)
Email

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PREFERRED MAILING ADDRESS
Stephen C. Cowin
2166 Broadway
Apartment 12D
New York, NY 10024

Phone (212) 799-7970 (Office at Home)
Fax (212) 799-7970 (Office at Home)
Phone (212) 650-5208 (Work)
Fax (212) 650-6727 (Work)
Email

WORK ADDRESS:
Stephen C. Cowin
Director, New York Center for Biomedical Engineering
School of Engineering
The City College
138th Street and Convent Avenue
New York, NY 10031-9198, U. S. A.
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For information about the New York Center for Biomedical
Engineering visit
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