Biomedical Engineering Reference
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relative paucity of in vitro cellular response to in vivo levels of physiologic
strain, may have been underestimated as a biophysical signal. There is increasing
evidence for localized amplification of substrate strain, such that tissue-level
strains may be amplified to the point where they can induce a cellular response
[ 10 , 64 , 78 , 108 , 111 ].
Biophysical signals activate various signaling pathways resulting in both pro-
osteogenic and anti-catabolic outcomes. Rapid responses (0 s-1 min) to such
signals include the generation or liberation of second messengers like Ca 2+ , cAMP,
DAG, and IP 3 . These, in turn, promote the synthesis and secretion of autocrine
paracrine factors (e.g., NO, PGs, and IGFs), kinase activation, cytoskeletal rear-
rangement, transcription factor (NF-jB, b-catenin, ATF4) activity, and changes in
gene transcription and translation. These biochemical signals are communicated
(via gap junctions, integrins, and soluble factors) to effector cells that are
responsible for initiation of tissue-level responses. In the context of skeletal
homeostasis or adaptation, this is the concerted activity of the bone multicellular
unit (BMU) for remodeling, or, in situations of modeling, bone deposition by
osteoblasts or resorption by osteoclasts.
3 Does Aging Influence Mechanotransduction in Bone Cells?
While the pathogenesis of osteoporosis and senescence-related bone loss is mul-
tifactorial, it is thought than one factor may be reduced bone cell mechanosensi-
tivity and/or mechanoresponsiveness [ 63 ]. Surprisingly few studies have directly
examined whether the ability of osteoblastic cells to perceive or to respond to
mechanical stimuli changes with age and, if so, whether that is due to altered
mechanosensitivity or mechanoresponsiveness.
One of the earliest responses of osteoblastic and osteocytic cells to fluid shear
stress is an increase in intracellular calcium levels (Ca 2+ i ) which may require either
release from intracellular stores [ 60 , 110 , 112 ], entry through ion channels from
extracellular fluid [ 79 , 87 ], or both [ 37 ]. This change in Ca 2+ i is observed in MSCs,
osteoblasts, and osteocytes after onset of shear stress. However, there is evidence
that these cells are not equally responsive to a given stimulus: Kamioka et al.
demonstrated that shear stresses of 1.2 or 2.4 Pa (n.b.,1Pa= 10 dynes/cm 2 ) were
less stimulatory to primary osteocytes, in terms of percent of cells responding with
an increase in Ca 2+ i , than were primary osteoblasts [ 44 ]. Despite differences in
sensitivity to applied stresses, those osteocytes which did respond demonstrated no
significant change in the magnitude of the Ca 2+ i response, suggesting that the
difference is in the ability of the cells to perceive, but not respond to, shear stress.
This assumes that the magnitude of the Ca 2+ i response is most important; some
evidence suggests that other parameters, such as the frequency of applied load, is
more important [ 8 , 23 ].
To date, the only study designed to examine whether the Ca 2+ i response of
osteoblastic cells to fluid shear stress was a function of donor age was performed
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