2nd
Bone Fluid Flow Workshop
The
City College of New York 9/20/00
Summary
A Second Bone Fluid Flow Workshop with the objective of summarizing
the state of the research on bone fluid flow and its role in the bone tissue
mechanosensory system was held on September 20th, 2000 at the City College
of New York (CCNY). The workshop was sponsored by City College’s New York
Center for Biomedical Engineering and was organized by Steve Cowin, Shelly
Weinbaum, and Susannah Fritton. The program, with abstracts, the list of
attendees and other information is located here.
There were 80 attendees, 40 from New York State, 28 from out of state including
4 from the west coast and 12 from outside the country (Austria, Bulgaria,
Germany, Japan, the Netherlands, Scotland and Switzerland). The greatest
measure of success of this workshop, after the high number of attendees,
was the fact that others have volunteered to hold the third and fourth
bone fluid flow workshops. John Frangos from UCSD will organize the third
workshop before the ASBMR meeting in Phoenix in 2001 and Jenneke Klein-Nulend
and Theo Smit will organize the fourth workshop in Amsterdam in 2002 to
honor Professor Elisabeth Burger of the Oral Cell Biology Department at
Vrije Universiteit upon her retirement.
The workshop speakers were Mitch Schaffler (Mount Sinai, New York),
Melissa Knothe Tate (ETH-Zurich, AO Research Institute-Davos & Mount
Sinai, New York), Mark Otter (SUNY Stony Brook), Elizabeth Burger (Vrije
Universiteit, Amsterdam), Theo Smit (Vrije Universiteit, Amsterdam), John
Frangos (UCSD), Hank Donahue (Penn State University), Yi-Xian Qin (SUNY
Stony Brook), Roland Steck (ETH-Zurich, AO Research Institute-Davos), Nikola
Petrov (Bulgarian Academy of Sciences), Shelly Weinbaum (CCNY), Liyun Wang
(CCNY), and Lidan You (CCNY).
The contents of the presentations of the thirteen speakers are summarized
below. In addition, the contents of four short communications are
described. The four short communications were given by Chris Jacobs
(Penn State University), Colby Swan (University of Iowa), David Denhardt
(Rutgers University)& Masaki Noda (Tokyo Medical & Dental University),
and Laura McCabe (Michigan State University).
Bone
Fatigue and Remodeling in the Development of Stress Fractures
The first technical presentation entitled “Bone fatigue and remodeling
in the development of stress fractures” was given by Mitch Schaffler (Mount
Sinai, New York). Schaffler began by noting that stress fractures result
from repetitive loading. As such they have often been regarded as a mechanical
fatigue-driven process. However, while bone readily sustains fatigue
microdamage during the course of repeated loading at the stresses or strains
encountered in normal activities, it does not progress to fracture in the
time course seen for the development of stress fracture. This suggests
that other mechanisms drive the development of stress fractures.
Histopathological data from humans and racehorses suggest that increased
remodeling is a prominent early feature of stress fracture. Early increases
in intracortical remodeling were observed experimentally in the rabbit
tibial stress fracture model developed in their laboratory. Together these
studies suggest a central role for increased intracortical remodeling in
the pathogenesis of stress fractures. Schaffler proposed that the
model that best explains the development of stress fracture is that of
a biologically (remodeling)-driven damage accumulation system. In
this model, stress fracture occurs as a positive feedback mechanism, wherein
increased mechanical usage stimulates bone turnover, which results in focally
increased bone remodeling space (porosity) and decreased bone mass.
There is a wide range of factors (low level bone fatigue, altered mechanical
loading, injury, cytokines, vascular alterations) that potentially can
activate local bone remodeling; all of these can occur in the development
of stress fracture. With continued loading of this focally, transiently
osteopenic bone, local stresses would be markedly elevated, leading to
accelerated matrix damage and failure. Fracture is the result of
continued repetitive loading superimposed on the decreased bone mass caused
by more, and larger, resorption spaces.
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The
Role of Interstitial Fluid Flow in the Remodeling Response to Fatigue and
Disuse
The second technical presentation entitled “The role of interstitial
fluid flow in the remodeling response to fatigue and disuse” was given
by Melissa L. Knothe Tate (ETH-Zurich, AO Research Institute-Davos &
Mount Sinai, New York). Knothe Tate noted that the ability of bone to regenerate
itself in response to dynamic metabolic and structural demands is necessary
for the survival of vertebrates. Hence, the structure of mature bone represents
a patchwork; the initial construct, resulting from modeling events during
growth and development, is interwoven with bone laid down by osteoblasts
in areas carved out by osteoclasts during periods of remodeling. The osteocytes,
which are located within the mineralized matrix of bone, are presumed to
play an important role in “sensing” the mechanical and chemical environment
within the tissue. Remodeling events appear to be highly “choreographed,”
but the signaling and timing of interactions between osteocytes, osteoclasts
and osteoblasts are not clear. Osteotropic agents are likely to mediate
remodeling processes; the concentration and distribution of such agents
are a function of tissue perfusion as well as diffusive and convective
transport conditions prevailing in the tissue. Knothe Tate and her colleagues
hypothesize that loss of fluid flow and ensuing compromise to molecular
transport and exchange is a mechanism causing loss of cell viability and
triggering the remodeling response. Microdamage due to fatigue loading
alters interstitial fluid flow and mass transport within bone, reducing
the concentration and distribution of osteotropic agents to osteocytes
“downstream” from the damage. In the case of disuse, the lack of fluid
flow and subsequent deficiency in transport through the tissue causes the
osteocytes to fall into a state of deprivation, ultimately resulting in
a loss of viability. The hypothesis was discussed in light of ongoing work
involving theoretical and experimental models as well as changes in osteocyte
integrity observed in association with bone resorption following disuse.
A model for mechanochemical transduction in bone was introduced.
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Does Bone
Perfusion/Reperfusion Initiate Bone Remodeling and the Stress Fracture
Syndrome?
In his talk, Mark Otter (SUNY Stony Brook) addressed the question “Does
bone perfusion/reperfusion initiate bone remodeling and the stress fracture
syndrome?” Otter noted that stress fractures have been proposed to arise
from repetitive activity of training, inducing an accumulation of microfractures
in locations of peak strain. However, stress fractures most often occur
long before accumulation of material damage could occur; they occur in
cortical locations of low, not high, strain; and intracortical osteopenia
precedes any evidence of microcracks. Otter proposed that this lesion arises
from a focal remodeling response to site-specific changes in bone perfusion
during redundant axial loading of appendicular bones. Intramedullary pressures
significantly exceeding peak arterial pressure are generated by strenuous
exercise and if the exercise is maintained, the bone tissue can suffer
from ischemia caused by reduced blood flow into the medullary canal and
hence to the inner two-thirds of the cortex. Site specificity is caused
by the lack, in certain regions of the cortex, of compensating matrix-consolidation-driven
fluid flow, which brings nutrients from the periosteal surface to portions
of the cortex. Upon cessation of the exercise, re-flow of fresh blood into
the vasculature leads to reperfusion injury, causing an extended no-flow
or reduced flow to that portion of the bone most strongly denied perfusion
during the exercise. This leads to a cell-stress initiated remodeling which
ultimately weakens the bone, predisposing it to fracture.
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Cellular
Aspects of Mechanotransduction and Bone Remodeling
Elisabeth Burger (Vrije Universiteit, The Netherlands) spoke on “Cellular
aspects of mechanotransduction and bone remodeling.” Burger began by noting
that the capacity of bone tissue to alter its mass and structure in response
to mechanical demands has long been recognized, but the cellular mechanisms
remain poorly understood. She noted that several lines of evidence currently
emphasize the role of osteocytes as the professional mechanosensors of
bone, and the lacunar-canalicular porosity as the structure that mediates
osteocyte mechanosensing. Strain-derived flow of interstitial fluid through
this porosity is thought to mechanically activate the osteocytes. The narrowness
of the canalicular annulus ensures that even the minute physiological bulk
strains in bone produce considerable fluid shear stress over the osteocyte
cell “finger.” Extracellular and/or intracellular signaling between activated
osteocytes and the osteoclasts/osteoblasts at the bone surface provides
a mechanism for strain-regulated modulation of bone mass. However, to fully
explain mechanical adaptation, a cellular mechanism must exist whereby
not only the density of bone tissue is regulated, but also the alignment
of the trabeculae and osteons along the dominant loading directions. This
asks for a mechanism that guides the direction in which osteoclastic resorption
proceeds during the process of bone remodeling. Finite element analysis
of remodeling bone at the microscopic, supracellular scale showed opposite
strain levels around the cutting- and closing cone of a (hemi-)osteon loaded
in the longitudinal (i.e. dominant) direction. A region of decreased strain
appeared in front of the cutting cone of the osteonic tunnel, where osteoclasts
are activated to continue resorption. Likewise in a trabecula, the presence
of a Howship’s lacuna induced the appearance of decreased strain fields
along the trabecular surface in the direction of loading. Around the closing
cone of the osteonic tunnel however, where osteoblasts are recruited to
refill the gap, elevated strains appeared in the tunnel wall. Elevated
strains also appeared at the bottom of the Howship’s lacuna. These results
suggest that in remodeling bone, osteocytes, informed by locally reduced
strain fields, may guide the osteoclasts to resorb bone in the right direction,
thereby ensuring correct alignment of the new (hemi-)osteon. They also
may determine, based on locally elevated strain fields, the amount of subsequent
bone formation by osteoblasts, and thereby the final density of the remodeled
piece of bone. Local regulation of bone metabolism by mechanically informed
osteocytes provides therefore a mechanism that explains both aspects of
mechanical adaptation, correct bone density and correct bone alignment.
As each remodeling cycle is also an adapting cycle, adaptation occurs throughout
life.
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Fluid Flow
During Osteonic Tunnelling
Theo Smit (Vrije Universiteit, The Netherlands) expanded on the modeling
work introduced by Elisabeth Burger with a talk entitled “Fluid flow during
osteonic tunneling – a biphasic finite element analysis.” Smit began by
noting that he and his colleagues have recently found evidence that BMU-coupling
during bone remodeling may be regulated by deformation of the bone matrix
under mechanical loading. Further, it is generally assumed that mechanosensing
by osteocytes is related to extracellular canalicular fluid flow, which
is generated by deformation of the bone matrix under mechanical loading.
In an attempt to relate the theory of canalicular fluid flow to BMU coupling,
they determined the pattern of fluid flow around a tunneling osteon under
axial loading. They approached the problem with Biot’s theory of
poroelasticity and the finite element (FE) method. The tunneling osteon
was modeled axisymmetrically as a cylindrical gap with a spherical end,
and the bone matrix was described as an isotropic material with a fully
saturated lacunar-canalicular porosity of 5.0%. They derived the material
properties of the mineralized bone matrix from the isotropic description
of cortical bone by Cowin & Sadegh (1976) and the equations for porous
materials by Christensen (1979). The bulk modulus of the bone fluid was
that of water. An important parameter in the model is the hydraulic permeability
k, which varies over several orders of magnitude in the literature. They
derived its value from the equation for relaxation time by Rice and Cleary
(1976) and the experiments by Otter et al. (1992). Their value of 1.2e-7
was two orders of magnitude smaller than the one derived by Zhang et al.
(1998). The value of this parameter was discussed in some detail, and a
parameter study was presented. The FE analysis showed that during
a walking cycle (4 km/h) a different fluid flow pattern exists near the
cutting cone as compared to the closing cone. Or in other words: the findings
of this study suggest that the osteocytes within the bone matrix sense
different patterns of mechanical stimulation near sites of osteoclastic
and osteoblastic activity. This is compatible with the hypothesis that
local patterns of bone fluid flow regulate BMU-coupling.
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All Bone
Cells are Mechanosensory Cells
John Frangos (UCSD) spoke to the thesis “All bone cells are mechanosensory
cells.” Frangos began by observing that it has been proposed that osteocytes
are the single mechanosensory cell type because they are ideally situated
to sense mechanical stimulation, such as strain or interstitial fluid flow,
as a result of mechanical loading. He noted that while there is little
argument that osteocytes are subject to fluid flow, they are by no means
the only bone cell type to experience hydrodynamic forces. Osteoblasts
and bone lining cells are subject to intercellular fluid flow, as are osteoclasts
and their precursors. Consistent with this view, all bone cell types
investigated respond to fluid shear stress. The significant distance
between most osteocytes from the appositional and resorption surfaces of
bone further suggest that they do not have the dominant role in load-induced
remodeling.
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Gap Junctions
and Biophysical Regulation of Bone Cell Differentiation
Hank Donahue (Penn State University) addressed the topic “Gap junctions
and biophysical regulation of bone cell differentiation.” Donahue began
by noting that physical signals, in particular mechanical loading, are
clearly important regulators of bone turnover. Indeed, the structural
success of the skeleton is due in large part to the bone's capacity to
recognize some aspect of its functional environment as a stimulus for achievement
and retention of a structurally adequate morphology. However, while
the skeleton's ability to respond to its mechanical environment is widely
accepted, identification of a reasonable mechanism through which a mechanical
“load” could be transformed to a signal relevant to the bone cell population
has been elusive. In addition, the downstream response of bone cells
to load-induced signals is unclear. Evidence suggesting that gap
junctional intercellular communication (GJIC) contributes to mechanotransduction
in bone and, in so doing, contributes to the regulation of bone cell differentiation
by biophysical signals was reviewed. In that context, mechanotransduction
is defined as transduction of a load-induced biophysical signal, such as
fluid flow, substrate deformation, or electrokinetic effects, to a cell
and ultimately throughout a cellular network. Thus, mechanotransduction
would include interactions of extracellular signals with cellular membranes,
generation of intracellular second messengers, and the propagation of these
messengers, or signals they induce, through a cellular network. Donahue
proposed that gap junctions contribute largely to the propagation of intracellular
signals.
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The Relationship
between Bone Fluid Flow and Adaptation as Stimulated by Intramedullary
Hydraulic Loading
Yi-Xian Qin (SUNY Stony Brook) presented a talk entitled “The relationship
between bone fluid flow and adaptation as stimulated by intramedullary
hydraulic loading.” Qin began by noting that the motion of intracortical
fluid flow, which arises under mechanical loading, has been proposed to
be an important mediator for regulating bone mass and morphology. However,
mechanical deformation-generated stimulation may only partially examine
the mechanism of flow-induced adaptation, because loading of bone results
in not only intracortical fluid flow by the sources of matrix deformation
and intramedullary (IM) pressure, but also the matrix strain which has
been proposed as a key for the remodeling process. Because it has been
demonstrated that bone fluid flow and its associated streaming potential
product can be significantly influenced by the dynamic IM pressure that
can be controlled quantitatively, the hypothesis of fluid-induced bone
adaptation was evaluated in an avian ulna model using IM hydraulic loading
in the absence of bone matrix strain. The fluid pathways in bone during
the loading were discussed. The left ulnae of adult male turkeys were functionally
isolated via transverse epiphyseal osteotomies. A specially designed fluid-loading
device was firmly attached on bone via a 5-mm hole allowing IM pressure
oscillation in the cavity. A sinusoidal fluid pressure was applied to the
ulna with the magnitude of 50 mm Hg, 20 Hz, 10 min/day for 4 weeks. With
IM pressure generating a spatial fluid pressure gradient distribution through
the cortex, fluid loading (n=4) resulted in significant new surface bone
formation (12.2±4.2%). In the animal group subject to sham disuse
alone (n=4), the cortex showed a decrease in cross-sectional area with
6.1±3.0% reduction compared to the contralateral control.
The results show that low magnitude IM pressure can initiate a spatial
fluid flow in bone and thus stimulate a bone adaptive response. This suggests
that oscillation of IM pressures may influence the perfusion of bone tissue
in many ways, e.g., altering blood supply and enhancing pressure gradients
in a variety of fluid channels. IM pressure loading can increase and improve
this perfusion process. Moreover, it assumes that there is a fluid pathway
directly connected between the marrow cavity and intracortical porous space,
e.g., Haversian canal and lacunae-canaliculi, which may play a role in
regulating fluid transportation and perfusion in bone. These experiments
may yield new insights into the mechanisms, at least at the tissue level,
by which bone fluid flow initiates and controls bone morphology.
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Implications
of Load-Induced Fluid Flow for Functional Adaptation: a Combined
Theoretical and Experimental Modeling Approach
Roland Steck (ETH-Zurich) described the “Implications of load-induced
fluid flow for functional adaptation: a combined theoretical and experimental
modeling approach.” Steck and his colleagues hypothesize that load-induced
fluid flow through bone enhances transport of substances (i.e. nutrients
and osteotropic substances such as signal molecules, molecular factors
and hormones) that modulate cellular activities associated with growth,
adaptation and repair, thereby providing a mechanochemical transduction
mechanism for functional adaptation. In order to start to understand the
implications of fluid flow for processes associated with remodeling, they
have developed a macroscopic continuum model of the rat tibia in parallel
with carrying out molecular tracer experiments using an established four-point-bending
model of the rat tibia. They used a two step finite element (FE) approach
to calculate different fluid flow parameters on a macroscopic scale. In
a first step, bone was modeled as a poroelastic continuum for the calculation
of fluid velocities and displacements resulting from the loading schemes
of the experimental models. In a second step, these fluid velocities were
used in a mass transfer analysis to demonstrate the positive effect of
this additional convective flux on the distribution of a simulated tracer
within bone cross-sections. The purpose of this presentation was to introduce
the theoretical model and to interpret the predictions of the model in
light of experimental data from the molecular tracer experiments as well
as from parallel experiments in which a functional adaptation response
was elicited in response to the hyperphysiological-loading regime.
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An Anatomical
Model of Stress Induced Fluid Flow in Osteons
Nikola Petrov (Bulgarian Academy of Sciences) presented “An anatomical
model of stress-induced fluid flow in osteons.” Petrov presented a new
model for stress-induced fluid flow in bone based upon a triple porosity
model. In this model fluid exchange occurs among the Haversian canal, the
lacunar-canalicular system and the matrix microporosity. The model represents
an extension of the earliest models of Pollack et al. (1984) and Kufahl
and Saha (1990) and is an alternative to the Weinbaum et al. (1994) model.
The model incorporates a porous boundary in the lacunar-canalicular system,
thereby permitting flow between the lacunar-canalicular system and the
microporosity. Results for flow in an osteon were presented and used to
describe streaming potential data from various authors. Outstanding fit
to both "live" and "dead" bone data is achieved along with the explanation
of the long standing observation of two time constants.
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Thinking
and Feeling Like an Osteocyte in its Mechanical Environment
Shelly Weinbaum (CCNY) spoke to the topic “Thinking and feeling like
an osteocyte in its mechanical environment.” Weinbaum began by noting that
it is very difficult for people to imagine how an osteocyte senses and
responds to its mechanical environment largely because people are unaccustomed
to the forces and length scales of the microenvironment in which the osteocyte
lives. This is particularly true of the cytoskeletal structure of the osteocyte,
its pericellular matrix and the permeability properties of the lacunar-canalicular
and mineralized matrix porosities. New insights into the relationship between
cellular structure and function were deduced from important new findings
with other cells that have structures in common with osteocytes. In particular,
Weinbaum addressed the following questions:
1. Why does an osteocyte need a pericellular matrix (glycocalyx)? What
are its functions?
a. structural
b. hydrodynamic
c. molecular sieving
Why does bone not need a lymphatic system?
2. How does this matrix differ from the endothelial glycocalyx in structure
and function?
3. Does water pass through the canalicular wall? Will the mineralized
matrix porosity allow for water movement if there is a small amount of
free water?
4. How does one account for the short and long SGP relaxation times
in Pienkowski (1982) and Otter et al. (1992) if there is no fluid interchange
between the lacunar-canalicular and mineralized matrix porosities?
5. What changes occur in the lacunar-canalicular porosity when a cell
dies and how does this affect SGP relaxation time?
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A Lacunar
Mixing Mechanism for Solute Transport in Cyclically Loaded Bone
Liyun Wang (CCNY) described “A lacunar mixing mechanism for solute
transport in cyclically loaded bone.” Wang began by noting that a fundamental
conundrum in mechanically loaded bone is how, during cyclic loading, there
can be net solute (e.g., nutrient, tracer) transport via the lacunar-canalicular
porosity when there is no net fluid movement in the canaliculi over a loading
cycle. She and her colleagues propose a lacunar mixing mechanism where
the fluid space in an osteocytic lacuna facilitates a nearly instantaneous
mixing process of bone fluid that creates a difference in tracer concentration
between the inward and outward canalicular flow and thus ensures net tracer
transport to the osteocytes during cyclic loading, as has been shown experimentally.
The sequential spread of the tracer from the osteonal canal to the lacunae
is investigated for an osteon experiencing sinusoidal loading.
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A Potential
Mechanism for Mechanotransduction in Bone: Fluid flow Induced Strain Amplification
on Bone Cells
Lidan You (CCNY) presented a talk entitled “A potential mechanism for
mechanotransduction in bone: fluid flow-induced strain amplification on
bone cells.” You began by observing that the cell processes of bone cells
in their canaliculi provide a greatly simplified and heretofore unexploited
model system to explore the effect of fluid drag forces on extracellular
matrix, its coupling to the intracellular actin cytoskeleton (IAC) and
the strain amplification that results from this coupling. The model also
provides a resolution to a fundamental paradox in bone physiology, namely,
that the strains applied to whole bone (i.e., tissue level strains) are
much smaller (0.04% to 0.3%) than the strains (1% to 10%) that are necessary
to cause bone signaling in deformed cell cultures. The model of You and
her colleagues shows that (i) it is indeed possible to produce cellular
level strains in bone that are more than 100-fold greater than tissue level
strains and (ii) that the fluid flow-induced drag forces on the fibers
that tether the cell to its surrounding extracellular matrix can be much
greater than the fluid shear forces on the cell membrane, the fluid force
that has been extensively studied until now. In order to examine the hypothesis
of You and her colleagues, a histomorphometric experiment is being carried
out to investigate the detailed structure around the osteocytic process.
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The Importance
of Flow Reversal in the Response of Bone Cells to Fluid Flow
In the first short communication, Chris Jacobs (Penn State University)
addressed the topic “The importance of flow reversal in the response of
bone cells to fluid flow.” Jacobs described that loading-induced fluid
flow in the lacunar-canalicular system is oscillatory in nature due to
the dynamic nature of most physical activities. Thus, it is important the
in vitro investigations of loading-induced fluid flow as a physical signal
regulating bone cell metabolism also be oscillatory and involve a reversal
of flow direction. For example, Jacobs and coworkers have found that GdCl
(a putative stretch-activated channel blocker) had no effect on cytosolic
calcium mobilization and gene expression in response to oscillatory flow,
but does have an effect in the response to steady flow.
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Poroelastic
Modeling of Flow at the Haversian and Lacunar Scales
In the second short communication, Colby Swan (University of Iowa)
spoke on “Poroelastic modeling of flow at the Haversian and lacunar scales.”
Swan described a study in which micromechanical analysis is being used
to quantify load-induced stress fields, strain fields, and fluid flows
in the Haversian system and in the canalicular-lacunar system. He noted
that a significant source of uncertainty in these models is the hydraulic
conductivity associated with the canaliculi. With current best estimates
of canalicular hydraulic conductivities, Swan's models indicate that fluid
flows quite freely in both the Haversian and canalicular-lacunar systems
at physiological frequencies (e.g., frequencies below 100 Hz). The fact
that fluid flows quite freely at physiological frequencies makes it quite
difficult to detect using whole bone viscoelastic spectroscopy.
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Osteopontin
and Bone Remodeling
In the third short communication, “Osteopontin and Bone Remodeling,”
David Denhardt (Rutgers University) summarized some of what is known about
the secreted, phosphorylated sialoglycoprotein, osteopontin, which has
the properties of a cytokine but will also promote cell attachment to mineralized
matrices. The protein is found in bone and body fluids; it interacts with
receptors (integrins, possibly CD44v) to stimulate intracellular signaling
pathways that control gene expression and cell behavior. It is chemotactic
for macrophages and in some situations aids cell survival, likely by inhibiting
apoptosis. Research on OPN-deficient (knock-out) mice has revealed that
OPN is required for cell-mediated immunity and for bone remodeling in response
to stress. Masaki Noda (Tokyo Medical & Dental University) described
some of the studies in his laboratory on the OPN-deficient mice described
by Rittling et al. (JBMR 13:1101, 1998). In contrast to control animals,
ovariectomized OPN-deficient mice retain most of their bone mineral. Additionally,
the knockout mice are resistant to dis-use osteoporosis, and are much less
efficient at resorbing ectopic bone. It appears that in the absence of
OPN osteoclast function is impaired.
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Understanding
the Mechanisms of Simulated Microgravity Effects on Osteoblast Gene Expression
The fourth short communication was from Laura McCabe (Michigan State
University) and was entitled “Understanding the mechanisms of simulated
microgravity effects on osteoblast gene expression.” McCabe described modulation
of osteoblast phenotype in a rotating cell culture system in which fluid
flow is hypothesized to be a component of this responsiveness.
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Steve Cowin and Susannah Fritton, December 20, 2000.