Cytoskeletal Modulation of Bone Cell Mechanosensitivity

Project: Research project

Description

DESCRIPTION (provided by applicant): Bone cells are capable of sensing and
responding to mechanical stimuli, but mechanosensitivity begins to decay soon
after the stimulus is initiated. Under continued stimulation, a mechanosensory
saturated state is reached. As an extension of in vivo work showing that
approximately 8 hours of recovery are required to restore mechanosensitivity to
bone cells, the long term objective of this project is to determine the
cellular and molecular mechanisms involved in bone cell mechanosensory
desensitization and subsequent resensitization. They propose that the
architecture of the actin cytoskeleton plays an important role in the loss and
recovery of mechanosensitivity. The hypothesis is that the shear induced
cytoskeletal reorganization process which occurs in response to mechanical
stimulation results in a rigid cell that is ineffective in transducing
subsequent mechanical signals. Further, stress fiber bundles must be allowed
time to disassemble before another robust response can be generated from the
next mechanical stimulus. To test these proposals, two hypotheses are
presented: (1) Mechanical stimulation causes bone cells to become less
sensitive to further stimulation, and a recovery period (no loading) is
required to regain mechanosensitivity; and (2) mechanically induced
cytoskeletal reorganization into stress fiber bundles causes a decrease in bone
cell mechanosensitivity, and disassembly of stress fibers is required to for
the cell to respond to subsequent mechanical stimuli. The hypotheses will be
tested on cultured osteoblasts and osteocytes using fluid flow induced shear as
a mechanical stimulus. Hypothesis 1 will be evaluated by determining (Aim 1)
flow duration required for maximal stimulation of mechanotransduction markers:
cfos, COX 2, and PGE2; (Aim 2) marker expression during the post flow recovery
period; and (Aim 3) marker expression upon reflow at different recovery time
points. Hypothesis 2 will be evaluated by determining (Aim 1) the post flow
recovery time required for disassembled cytoskeletal architecture; (Aim 2) the
association between mechanosensitivity and cytoskeletal architecture; and (Aim
3) changes in mechanosensitivity with agents that either prematurely
disassemble or prolong flow induced architecture. Insights into the mechanisms
of mechanosensory loss and recovery hold potential in the public health arena
for optimizing the positive effects of loading on bone mass, fragility, and
fracture risk.
StatusFinished
Effective start/end date6/20/025/31/08

Funding

  • National Institutes of Health: $108,702.00
  • National Institutes of Health: $105,336.00
  • National Institutes of Health: $102,099.00
  • National Institutes of Health: $98,256.00
  • National Institutes of Health: $94,587.00

Fingerprint

Bone and Bones
Stress Fibers
Osteocytes
Osteoblasts
Actin Cytoskeleton
Dinoprostone
Public Health

ASJC

  • Medicine(all)