Biomedical Engineering Reference
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Eliminating embryonic muscle forces also leads to defects in tendon and cartilage.
Tendon development is initiated, but tendon precursors are not maintained, in the
absence of muscle forces [ 65 , 70 ]. Chondrocyte proliferation is decreased, altering
bone growth rates and contributing to the observed bone defects [ 71 ]. Furthermore,
the lack of joint cavitation results in the complete loss of articular cartilage surfaces
[ 72 ]. Compositional changes occur in developing cartilage as a result of immobili-
zation that lead to altered mechanical properties [ 73 ].
The importance of mechanical loading for development increases after birth.
At this point, the effects of joint contact forces due to body weight are added to the
effects of increasing muscle forces. Bone growth in postnatal chicks is significantly
arrested by adding only 10% of body weight using an external harness [ 74 , 75 ]. The
reduction in bone length is reversed by removing the weight, but the resulting bones
have impaired structural and mechanical behavior.
The rate of long bone growth by endochondral ossification is sensitive to the
mechanical environment. Compression maintains the cartilage phenotype and slows
bone growth, while tensile loads along the long axis of the bone increase elongation
[ 76 , 77 ]. Stokes and coworkers used three different animal models to demonstrate a
linear relationship between the applied axial stress and the bone growth rate using
externally applied loading plates pinned to the bones [ 76 , 77 ]. This relationship held
for both tensile and compressive loading of proximal tibial growth plates and vertebral
bodies. The bone growth rate depends on the combined rates of cell division in the
proliferative zone, cell volume increases in the hypertrophic zone, and the rate of
chondrocyte maturation leading to mineralization [ 21 ]. The biological mechanisms
that enable cells to transduce forces into cell fates, and the matrix production processes
that control rates of bone growth are less well understood. It is likely that the
mechanisms described above that influence endochondral ossification also drive the
development of the unique transitional tissue at the enthesis.
11.3.3 Biological Molecules Critical to Skeletal
Mechanotransduction
Members of many distinct families of molecules have been implicated in
mechanotransduction pathways, all of which likely play roles in enthesis develop-
ment. These include, but are not limited to, ECM proteins (collagens, proteoglycans,
and glycosaminoglycans), growth factors (TGF
s, BMPs, FGFs), cytokines (IL1,
IL6), hedgehog family members (Ihh), matrix metalloproteinases (MMP-1, MMP-
13), and angiogenic factors (VEGF) [ 78 ]. Several mechanisms of cellular
mechanotransduction have been identified. Strains in the ECM are coupled to
cytoskeletal rearrangements through integrins in the cell membrane, which provide
a direct structural connection between the ECM and the cytoskeleton [ 79 ]. Other
cellular mediators of mechanotransduction include cell surface G-protein coupled
receptors, receptor tyrosine kinases, and stretch activated ion channels [ 80 ].
b
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