The Role of Mechanobiology in the Attachment of Tendon to Bone - Structural Interfaces and Attachments in Biology - page 230

11.4 Mechanobiology in the Development
of the Tendon-to-Bone Insertion
Muscle loading is necessary for the development of a functionally graded tendon-
to-bone insertion. This complex tissue has features of bone, ossifying cartilage, and
tendon and is typically subjected to a combination of compressive and tensile
stresses. As described in the previous section, mechanical signals are capable of
influencing the synthesis rate and composition of the ECM as well as cell fate in
developing musculoskeletal tissues. It is likely that biological factors involved in
mechanotransduction pathways in other orthopaedic tissues also impact enthesis
development. In order to achieve the complex graded microstructure and morpho-
logical characteristics of the insertion, it follows that there must also be spatial and
temporal interplay between gene expression and synthesis of ECM molecules.
These expression patterns are controlled by both genetic and biophysical cues
from the environment (i.e., muscle loading) and produce the complex gradients
found at the mature insertion.
While neo-tendon and bone are established early in fetal development, the
enthesis transitional tissue is often not evident until postnatal stages [ 107 - 110 ].
In an animal model, the supraspinatus neo-tendon was evident adjacent to develop-
ing humeral head bone at 15.5 days post-conception (dpc) [ 6 ]. In contrast, the
mature insertion, defined by the appearance of fibrocartilaginous transitional tissue,
was not identified until after birth. In mouse shoulders, an insertion region between
the supraspinatus tendon and bone begins to appear 1 week after birth and mature
fibrocartilage is not in evidence until 3 weeks after birth [ 108 ]. During this period,
the shoulder experiences large increases in limb loading as body weight and muscle
mass increase along with activity levels. It follows that large muscle forces are
likely necessary to drive the development of transitional tissues in the enthesis.
The insertion develops adjacent to the mineralizing epiphyseal cartilage of the
humeral head. Mineralization of the humeral head occurs through endochondral
ossification, a process that proceeds by mineralization of a cartilage template
followed by vascular invasion and remodeling of the mineralized cartilage template
by osteoclasts and osteoblasts [ 20 , 111 ]. Chondrocytes from the cartilage anlage are
induced by biological and chemical factors to proliferate, resulting in an increase in
size or length of the cartilage template. Cells then enter a terminal differentiation
process beginning with hypertrophy, followed by mineralization of the cartilage
matrix, and finally cell death and matrix resorption and remodeling by recruitment
of angiogenic factors. This bone formation process is characteristic of the growth
plate region of long bones during fetal development that continues into postnatal
development.
In one example, Blitz et al . described the development of the deltoid tendon-
humeral tuberosity attachment (Fig. 11.5 )[ 111 ]. It was observed that the deltoid
tuberosity formed via endochondral ossification in a two-phase process: initiation
was regulated by a signal from the tendons, whereas the subsequent growth phase
was muscle (i.e., load)-dependent. Specifically, Scx regulated BMP-4 production in