Biomedical Engineering Reference
In-Depth Information
Scx is a transcription factor localized to mature tendon that is necessary for
tenogenesis and is found in tendon progenitor cells [
92
-
95
]. This molecule is a
critical mediator of enthesis development. In a recent study, Blitz et al. demonstrated
that Scx is necessary for initiation of development of the deltoid tuberosity, the
attachment site of the deltoid tendon on the humerus [
111
]. This insertion forms by
endochondral ossification and is necessary to create a stable attachment point for the
deltoid tendon. Scx expression in the tendon cells mediated BMP4 expression in
cells near the insertion. Subsequent growth of the insertion was dependent on muscle
loading. Sox9 is a marker of a stable chondrocyte phenotype with important roles in
endochondral bone formation [
84
,
85
]. Sox9 has additional roles in embryonic
development, and together with Scx helps determine chondrogenic vs. tenogenic
cell lineage [
114
].
11.4.3 Mechanical Factors are Required for Insertion
Development
In order to probe the effects of muscle loading on the postnatal development of the
tendon-to-bone attachment, it is useful to employ an animal model that can be
combined with biological and genetic manipulations. By injecting botulinum toxin
into the rotator cuff muscles of mice throughout postnatal development, effectively
paralyzing the shoulder and eliminating muscle forces, it is possible to isolate the
effects of loading on the development of the supraspinatus insertion. Using mice
enables this model to be combined with genetic manipulation to investigate the role of
specific biological molecules implicated in mechanotransduction pathways. Botuli-
num toxin injections are routinely used to induce localized and reversible muscle
paralysis. Botulinum toxin chemically blocks the transmission of nerve impulses
through neuromuscular junctions. To study the role of muscle loading on enthesis
development, mice received botulinum toxin injections in one shoulder and saline
injections in the contralateral shoulder beginning within 24 h of birth [
115
-
117
]. The
saline group provided an internal control for paired statistical comparisons. A third
group of normal age matched mice was used as fully mobile controls.
This animal model displayed a similar phenotype to the human condition
neonatal brachial plexus palsy. In order to ensure that there was no effect of
botulinum toxin on shoulder development that wasn't the direct result of muscle
paralysis, a group of animals received a neurotomy of the upper trunk of the
brachial plexus [
118
]. The phenotype of the neurotomy group closely mimicked
the botulinum toxin-injected group. Both groups showed a substantial decrease in
muscle volume compared to controls. Decreases in muscle volume and mass
correlated to decreases in muscle force generation in botulinum toxin-injected
shoulders compared to saline controls after 4 and 8 weeks of paralysis [
117
].
The shoulder muscle paralysis induced in this animal model resulted in striking
changes to tendon-to-bone insertion development (Fig.
11.8
). Unloading caused
severe mineralization defects in the humeral head, including reduced overall volume
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