Bone Cell Mechanoresponsiveness - Skeletal Aging and Osteoporosis: Biomechanics and Mechanobiology - page 179

influence of donor cell age in an earlier study [ 48 ], wherein they reported that
pulsatile shear stress-induced PGE2 and PGI2 release increased with donor
cell age.
In summary, these limited data suggest that there is little intrinsic influence of
aging or disease state upon the ability of in vitro osteoblastic cells to perceive or
respond to mechanical stresses. Whether the same occurs in vivo is unknown, but
this instead suggests that additional factors, which influence bone cell function and
which change with aging, may exert potent influences upon load-induced bone
formation. Nonetheless, there remains doubt as to whether these questions have
been studied sufficiently; perhaps the effect of age is on the mechanical regulation
of mesenchymal stem cells or osteoprogenitors, a topic even less studied.
4 Sex Steroids and Mechanotransduction
The tissue-level and intracellular processes involved in mechanotransduction are
influenced not only by local factors produced during the conversion of external
mechanical forces into localized cellular responses, but also by humoral factors
within the circulation. Estrogen has long been postulated as a pivotal mediator of
bone cell mechanoresponsiveness. Frost proposed that estrogen may reduce the
minimum effective strain required for an anabolic response to load. This would
enable strains magnitudes that were previously sub-threshold and therefore
insufficient to cause bone formation, to initiate a bone-forming response [ 28 ].
Estrogen influences skeletal homeostasis through such avenues as progenitor
recruitment, proliferation, differentiation and apoptosis [ 80 ]. Thus, the loss of
estrogen production, as occurs during menopause, is thought to be a causative
factor in age-associated bone loss, and this is supported by bone loss in ovariec-
tomized mice [ 14 ]. Yet, whereas ample in vivo data support the hypothesis that the
loss of estrogen influences skeletal homeostasis and adaptation, there is, again,
little in vitro evidence for an effect upon mechanotransduction. Whereas certain
studies, described below, have examined the influence of exogenous estrogen upon
the response of bone cells to shear stresses in vitro, this does not address the in
vivo phenomenon wherein estrogen is no longer produced.
Mechanistically, estrogen (as well as progesterone and testosterone, other ste-
roids) initiate cellular responses via two general mechanisms, the classical genomic
pathway, or the non-genomic pathway. Canonical estrogen signaling involves ligand
diffusion across the plasmalemma to the nucleus, binding to estrogen receptors, and
induction of gene transcription [ 1 ]. Over the past decade, accumulating evidence
indicates a role for rapid, non-genomic action of estrogen, the effects of which
include microtubule polymerization, second messenger formation, and kinase acti-
vation (for elaboration, the reader is directed to such works as [ 50 , 58 , 106 ]).
Early ex vivo evidence of a role for estrogen in mechanostransduction came
from the work of Lanyon and associates. Using ulnar explants from rats, they
observed a synergistic influence of 10 nM estrogen and cyclical loading (-1300 le