Medical Therapy for Stifle Osteoarthritis 337cartilage repair processes by promoting protein
synthesis, collagen formation, and increasing
GAG and hyaluronan concentration (Glade
1990). PSGAGs also maintain chondrocyte
viability and stimulate chondrocyte division,
thereby slowing the process of extracellular
matrix degradation (Glade 1990; Sevallaet al.
2000). Since PSGAGs are a heparin analog, their
use in dogs with coagulopathies or concurrent
administration of NSAIDs, particularly those
with strong COX-1 (anti-thromboxane) activity,
is contraindicated. Limited clinical data that
supports the use of PSGAG in dogs with OA
are available (Lustet al. 1992; McNamaraet al.
1997; Fujikiet al. 2007).
Hyaluronic acid
Hyaluronic acid (HA) is a linear, non-sulfated
GAG that is the primary constituent of synovial
fluid. HA interacts with aggrecan monomer
through non-covalent association to link
proteins to produce the large aggregating
polyglycosaminoglycans of articular cartilage
(McNamaraet al. 1997). Administered HA is
speculated to increase synovial viscosity by
viscosupplementation. A variety of clinical and
experimental trials are available evaluating the
efficacy of HA for the treatment of cruciate liga-
ment rupture. However, these studies yield con-
flicting data on HA’s ability to ameliorate the
progression of stifle OA (Schiavinatoet al. 1989;
Marshallet al. 2000; Smithet al. 2001; Hellstrom ̈
et al. 2003; Canappet al. 2005; Smithet al. 2005;
Franklin & Cook 2013).
Dietary supplements
Omega-3 fatty acids
Nutritional supplementation with omega-3
(n-3) fatty acids has been proposed as an
adjunctive therapy for the management of OA.
The most prevalent of the polyunsaturated fatty
acids (PUFAs) comprising the cell membrane
are omega-6 (n-6) fatty acid and arachadonic
acid (AA). When the cell membrane, and there-
fore AA, is metabolized by the COX enzyme,
pro-inflammatory and vasoactive mediators of
2- and 4-series prostaglandins, thromboxanes,
and leukotrienes are produced. During the
process of OA, there is an increase in serum,
cartilage and synovial fluid concentrations of
n-6 PUFAs that propagate an inflammatory
reaction. The incorporation of n-3 PUFAs, eicos-
apentaenoic acid (EPA), into the cell membrane
will compete with AA for COX metabolism.
This results in the production of 3- and 5-
series prostaglandins, thromboxanes, and
leukotrienes that are significantly less inflam-
matory and vasoactive, curtailing the inflam-
matory response (Bauer 2007). There are several
n-3 fatty acids available, including EPA, docosa-
hexainoid acid (DHA) and alpha-linolenic acid
(ALA), although EPA is the only n-3 PUFA with
selectivity for the chondrocyte cell membrane.
Several studies clinically support diet supple-
mentation, including complete diets of high
dietary n-3 fatty acids, in the management of
OA (Miller 1992; Bartgeset al. 2001; Roushet al.
2010; Hielm-Bjorkman ̈ et al. 2012; Moreauet al.
2013; Riallandet al. 2013; Mehleret al. 2016).Glucosamine and chondroitin sulfate
Glucosamine and chondroitin sulfate formula-
tions encompass the majority of nutritional sup-
plements available on the current market for the
management of OA. Glucosamine is an amino-
monosaccharide used in the synthesis of the dis-
accharide units of glycoasaminoglycan (McNa-
maraet al. 1997; Neilet al. 2005). It can then
be incorporated into the large aggregating and
small-non-aggregating proteoglycans of articu-
lar cartilage, or as part of the disaccharide units
of hyaluronan. Chondroitin sulfate is a long-
chain polymer of repeating disaccharide units
of galactosamine sulfate and glucuronic acid
that constitutes the majority of glucosaminogly-
cans within articular cartilage (McNamaraet al.
1997; Neilet al. 2005).
The mechanisms of action of chondroitin sul-
fate are synergistic with that of glucosamine,
and can stimulate the synthesis of endogenous
glycosaminoglycans and inhibit the synthe-
sis of degradative enzymes, including MMPs.
Additionally, chondroitin sulfate inhibits both
IL-1-induced type II collagen degeneration,
histamine-induced inflammation, and has the
unique ability to improve synovial fluid vis-
cosity by increasing hyaluronan concentration