Front Matter

Chapter 3 Musculoskeletal Structure and Physiology 47

of  which is an amino sugar (hexosamine)
(Table  3.1). The sugars within most GAGs are
sulfated, which renders the polysaccharide
chains highly negatively charged. Glycosa­
minoglycans are covalently linked to serine
residues within a core protein. Hyaluronic acid
(HA), a ubiquitous component of ECMs
throughout the body, is unique within the
family of GAGs since it is neither sulfated nor
covalently linked to proteins.
Several classes of PGs are recognized, the
most thoroughly characterized of which are
the  interstitial PGs. This class includes
the aggregating PGs and the small leucine‐rich
PGs (SLRPs; Hardingham & Fosang, 1992). The
aggregating proteoglycans include aggrecan,
versican, brevican, and neurocan. These PG
species are massive macromolecular complexes
in which many individual proteoglycan mole­
cules are assembled in a brush‐like array along
a backbone of hyaluronic acid (see Figure 3.2).
Due to their extreme negative charge, aggregat­
ing PGs have a high affinity for water.
Aggregating PGs are immobilized within a
given tissue through association with collagen
fibrils. Their high degree of hydration underlies
the turgidity and resistance to compression of
several musculoskeletal tissues such as hyaline
articular cartilage, meniscal fibrocartilage, and
the nucleus pulposus of the intervertebral disc.
The SLRPs are a structurally diverse group
of PGs with variable degrees of GAG conjuga­
tion and that are expressed in tissue‐specific
patterns. SLRPs associate with fibrillar ele­
ments of the ECM such as collagen and elastin
and have many functions, including modula­
tion of the assembly and interaction of collagen
and elastin fibers, modulation of ion transport
through the ECM, and regulation of growth
factor effects on connective tissue cells
(Schaefer & Iozzo, 2008).

Proteoglycan synthesis involves transcrip­

tion and translation of a core protein, GAG con­

jugation of the protein, and secretion of mature

PG into the extracellular environment. In com­

parison to the fibrillar components of the ECM,

PGs undergo rapid turnover. Existing PGs are

degraded by a variety of proteases and polysac­

charidases. In turn, PG biosynthesis is a highly

regulated anabolic process that can be triggered

by exposure of cells to a variety of biological

mediators as well as some pharmacological

agents. The ability to alter the types and con­

centrations of PGs within the ECM in response

to specific stimuli allows resident cells to adjust

many properties of the ECM in accordance with

tissue demand. PG turnover thus represents an

important mechanism of tissue adaptation, and

targeted stimulation of PG production in vivo is

an area of great clinical therapeutic interest.

Musculoskeletal ontogeny

Regeneration is the re‐establishment of the orig­

inal form and function of a tissue after injury or

loss. Within the musculoskeletal system, bone

and muscle are capable of regeneration, while

the healing of tendon, ligament, and cartilage

results in mechanically inferior tissues.

Currently, there is great interest in clinical strat­

egies, including rehabilitative programs,

designed to promote or accelerate regenerative

healing (Ambrosio et al., 2010). Tissue regenera­

tion often involves a close recapitulation of

developmental morphogenesis; thus, an under­

standing of basic developmental processes is

relevant to physical rehabilitation. A thorough

review of musculoskeletal development is

beyond the scope of this chapter; however, sev­

eral key concepts are outlined as they relate to

rehabilitation, especially of the canine athlete.

Table 3.1 Chemical composition of major glycosaminoglycans

Glycosaminoglycan Hexose/hexuronic acid Hexosamine

Chondroitin sulfate (2‐sulfo‐) glucuronic acid (4/6‐sulfo‐) N‐acetyl‐glucosamine

Dermatan sulfate Glucuronic acid, or (2‐sulfo‐) iduronic acid (4/6‐sulfo‐) N‐acetyl‐glucosamine

Heparan sulfate Glucuronic acid, or (2‐sulfo‐) iduronic acid (6‐sulfo‐) N‐acetyl‐glucosamine, or

(6‐sulfo‐) N‐sulfo‐glucosamine

Keratan sulfate (6‐sulfo‐) galactose (6‐sulfo‐) N‐acetyl‐glucosamine

Hyaluronic acid Glucuronic acid N‐acetyl‐glucosamine