The Role of Mechanobiology in the Attachment of Tendon to Bone - Structural Interfaces and Attachments in Biology - page 229

has also been implicated in mechanotransduction pathways independent of
interactions with Ihh [ 87 ]. In this study, when tendon insertion sites were unloaded
by tail suspension or tendon transection, there was a significant decrease in PTHrP
expression. This decrease was more dramatic in the transection group compared to
the suspension group. Based on this, it is suggested that PTHrP might play a role in
the migration of tendon insertion sites in order to accommodate increases in bone
length during development. In support of this, there is increased osteoclastic
activity at the leading edge of the insertion site, while more osteoblasts are observed
at the trailing edge to allow bone growth.
Type X collagen is a well-described marker of chondrocyte maturation and of
the early stages of mineralization in endochondral bone formation [ 88 ]. Expression
of collagen X is limited to hypertrophic chondrocytes. This molecule is a
response to mechanical loading. In one study, collagen X mRNA was upregulated
after tensile stretch was applied to chondrocytes [ 89 ]. Other reports indicated
that collagen X expression and protein levels were reduced by compressive loading
in growth plate chondrocytes [ 90 , 91 ]. These results are consistent with the idea
that tensile loading of developing bone increases mineralization, which leads to
longitudinal bone growth, while compressive loads have an arresting effect
on growth.
Scleraxis (Scx) is a transcription factor noted for its role in tendon development
[ 92 - 95 ]. Scx null mice have several defects in force transmitting tendons of the
limbs and have severely compromised movement [ 95 ]. Furthermore, this mutation
results in structural changes: increased disorder and decreased amounts of tendon
ECM likely contribute to the noted functional losses. Recently, several studies have
indicated a role for Scx in mechanotransduction. In vitro loading modulates Scx
expression in tenocyte cultures [ 96 ]. More specifically, in tendons, mechanical
force causes release of TGF

b s from the ECM [ 97 ]. This activates the Smad

2 pathway through the TGF receptor leading to upregulation of Scx in response

to mechanical loading. Loss of loading due to tendon transection or botulinum
toxin-induced paralysis results in decreased Scx expression, as demonstrated using
a ScxGFP reporter. In addition, Mendias et al . found that treadmill exercise
upregulates Scx expression [ 98 ].
Finally, connexins are a class of gap junction forming proteins that are important
to cellular mechanotransduction. Connexin 43 has been identified in bone [ 99 , 100 ],
cartilage, and tendon [ 16 ]. Connexin expression is upregulated in tendon fibroblasts
subjected to cyclic loading [ 101 , 102 ]. Connexin proteins assemble in the cell
membrane to form hemichannels or gap junctions to enable direct cell-cell commu-
nication. Selective loss of connexin 43 from bone cells results in a loss of the
mechanoresponsiveness of bone to both loading-induced bone formation and mus-
cle paralysis-induced bone loss [ 103 - 106 ]. The mechanoresponsiveness of
connexins and other molecules involved in direct cell-cell communication
underlines the importance of cell-cell communication in the response to mechanical
stimuli. The combined effect of the mechanotransduction mechanisms described
above is to regulate ECM synthesis and degradation, ultimately affecting tissue
function and development.

b