Chapter 3 Musculoskeletal Structure and Physiology 49Muscle contractility is robust throughout the
latter half of gestation, and the mechanical
forces produced by developing muscle are
essential to the appropriate development of
all other musculoskeletal structures.
With the exception of the craniofacial
skeleton, which is largely of neural crest ori
gin, bones originate as condensations of mes
enchymal cells that initially differentiate into
chondrocytes to form a cartilaginous model
of the developing skeleton. As the chondro
cytes undergo interstitial growth, hypoxia
develops within the central region of the
avascular cartilaginous precursor. This trig
gers hypertrophy of chondrocytes, and stim
ulates production of angiogenic growth
factors and vascular invasion of the cartilage
model. Vascularization marks the onset of
endochondral ossification as the cartilage
model becomes populated with osteoprogen
itors and as chondroid matrix is resorbed
and replaced with osteoid. Endochondral
ossification continues throughout postnatal
growth, primarily within the physes of the
long bones. This process of developmental
endochondral ossification is recapitulated
with remarkable fidelity during indirect
fracture healing (see later).
The initial mesenchymal condensation
that precedes appendicular bone formation is
initially continuous along the length of the
elongating limb bud. As chondrogenic differ
entiation occurs, this mesenchymal column
undergoes a process of segmentation marked
by the appearance of discrete interzones that
mark the sites of future diarthrodial joints.
Apoptosis of cells within the interzone leads
to the formation of a fluid‐filled joint space, a
process termed cavitation (Khan et al., 2007).
Wnt14 is a key morphogen expressed at these
interzones (Archer et al., 2003). Separation of
the articular surfaces and development of a
fully mobile synovial joint requires continuous
mobilization of the nascent joint by contrac
tion of associated developing musculature, as
well as distention of the joint cavity with hya
luronic acid. The hyaluronic acid within the
interzone is initially secreted by cells of the
articular surfaces and later by the developing
synovium. Mechanical strain of joint tissues
stimulates production of hyaluronic acid
through upregulation of some isoforms of
hyaluronic acid synthase, an effect that persists
through adulthood (Itano & Kimata, 2002;
Momberger et al., 2005).
Tendon and ligament primordia arise as con
densations of mesenchymal cells that initially
reside immediately subjacent to the basal lam
ina of the developing dermis (Benjamin &
Ralphs, 1995). These cells initially organize into
parallel longitudinal rows and subsequently
become separated as they elaborate collagen‐
rich ECM. During differentiation, they develop
long cytoplasmic processes by which cell‐to‐
cell contact is maintained despite deposition of
large quantities of intercellular ECM. The bony
prominences that form attachment sites for
tendons and ligaments are defined during
formation of the cartilaginous anlage of a bone;
however, full maturation of both the bony
tuberosities at which tendons and ligaments
insert, as well as their enthesial architecture,
is dependent upon traction forces exerted on
these sites by developing muscles. In the
proximal portion of the limbs, connections with
bone are established during the early stages of
tendon differentiation. In contrast, distal
tendons initially lack connection with bone but
establish insertions later in development
through fusion with enthesial outgrowths of a
target bone.
During development, all musculoskeletal tis
sues are populated with small but significant
numbers of undifferentiated progenitor cells, or
mesenchymal stem cells (Figure 3.4). These
cells include osteoblasts of bone, satellite cells
of skeletal muscle, and stem cells of tendon,
ligament, and cartilage. Mesenchymal stem
cells are multipotent, capable of undergoing
osteogenic, chondrogenic, adipogenic, or neu
rogenic differentiation in response to appropri
ate signals. They also are capable of self‐renewal
through asymmetric cell division. They are
activated by injury or conditioning stimuli, and
play important roles in the healing and func
tional adaptation of tissues (Wu et al., 2007; Fan
et al., 2009; Tapp et al., 2009; Lim et al., 2010;
Reich et al., 2012). Stem cell therapy involving
harvest and orthotopic implantation of autolo
gous mesenchymal stem cells is an area of
active orthopedic research and has become an
accepted treatment for progressive osteoarthro
sis in the dog (Black et al., 2007, 2008; Guercio
et al., 2012) (see Chapter 16).