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Equine osteoarthritis: a brief review of the disease and its causes

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Abstract

Degenerative joint diseases, such as osteoarthritis, adversely impact the health of the equine athlete as well as the economics of the equine industry. Our understanding of the aetiology of osteoarthritis, although not nearly exhaustive, has increased substantially in recent years. Molecules, including cytokines, inflammatory mediators, and metalloproteinases, have been identified and associated with the progression of joint disease. Several factors, including trauma to the joint, immobilization, conformation, shoeing, and ageing, have been linked with osteoarthritis. Our continued efforts into elucidating critical biological mediators and risk factors, coupled with better chondroprotective therapies and diagnostic tools, should facilitate our ability to maintain the skeletal health of the equine athlete
Equine osteoarthritis: a brief review
of the disease and its causes
Angela E Schlueter and Michael W Orth*
Department of Animal Science, Michigan State University, 2209F Anthony Hall,
East Lansing, MI 48824, USA
*Corresponding author: orthm@msu.edu
Submitted 20 October 2003: Accepted 17 June 2004 Review Article
Abstract
Degenerative joint diseases, such as osteoarthritis, adversely impact the health of the equine athlete as well as the
economics of the equine industry. Our understanding of the aetiology of osteoarthritis, although not nearly
exhaustive, has increased substantially in recent years. Molecules, including cytokines, inflammatory mediators,
and metalloproteinases, have been identified and associated with the progression of joint disease. Several factors,
including trauma to the joint, immobilization, conformation, shoeing, and ageing, have been linked with osteo-
arthritis. Our continued efforts into elucidating critical biological mediators and risk factors, coupled with
better chondroprotective therapies and diagnostic tools, should facilitate our ability to maintain the skeletal
health of the equine athlete
Keywords: cytokines; metalloproteinases; joint disease; risk factors
Impact of osteoarthritis in the equine
industry
The equine industry is a growing industry that encom-
passes diverse disciplines ranging from sport horse to
work horse, and has a sizeable share in the US econ-
omy. The American Horse Council Foundation
(Barents Group LLC, 1996) reported that there were
6.9 million horses in the USA in 1996; 725 000
horses were involved in racing, 1 974 000 in showing,
2 970 000 in recreation and 1 262 000 in other activi-
ties. In addition, the equine industry directly provided
338 500 full-time jobs. The report also determined that
in 1996 the equine industry produced goods and ser-
vices valued at $25.3 billion, and the total contribution
to the US gross domestic product was $112.1 billion.
Lameness is a major cause of wastage in horses and
adversely affects the horse industry because one of the
main factors determining a horse’s value is soundness,
especially in athletic horses
1–3
. Jeffcott and Kold
assessed the wastage in Thoroughbred racehorses
from conception to 4 years of age, and determined
that lameness was the most significant factor respon-
sible for failure to race, outweighing respiratory
problems, colic or limited racing ability
3
. Their
study also indicated that, among 140 Thoroughbred
two-year-olds evaluated, only 34 (24%) did not show
any signs of lameness. Similar results were found in a
study determining the wastage of racehorses between
1982 and 1983
1
. The greatest number of days lost to
training was caused by lameness (68%); among 314
horses examined, 53% were lame at some period
during the racing season.
Osteoarthritis (OA) is one of the most common
causes of lameness, and is of particular concern in
horses because their value is closely tied to their
soundness. Lameness that results from OA is a
major cause of poor performance and early retire-
ment of equine athletes
4,5
. A survey performed at a
veterinary school found that 33% of all equine
patients had intra-articular lesions related to OA
6
.
Tew and Hackett
7
randomly evaluated 72 equine
joints at necropsy and discovered that 35% of them
had evidence of grossly visible cartilage damage.
Not only is this degenerative disease found in dom-
estic horses, but it also occurs naturally in the
joints of wild horses
8
. Despite the huge economic
importance of joint disease and OA in horses, our
understanding of the pathophysiological mechanisms
involved in joint degeneration in this species is lim-
ited
9
. Whether OA is a single disease or is caused
by several disorders with a similar final common
pathway remains unclear
10
.
Equine and Comparative Exercise Physiology 1(4); 221 231 DOI: 10.1079/ECEP200428
qCAB International 2004
Aetiology of OA
OA, often referred to as degenerative joint disease
(DJD) in the horse, is characterized by deterioration
of articular cartilage, accompanied by changes in the
bone and soft tissues of the joint. The end stage of
OA results in a net loss of articular cartilage, causing
pain, deformity, loss of motion, and decreased func-
tion. Horses have naturally occurring OA, which is
similar to that of humans, and are often used as
models to investigate the pathogenesis and treatment
of OA.
Synovial joints are the joints usually associated with
lameness in the horse. These joints have two major
functions: to enable movement and to transfer load.
Synovial joints consist of the articulating surfaces of
bone, covered by articular cartilage, secured by a
joint capsule and ligaments, and have a cavity contain-
ing synovial fluid. Articular cartilage is an avascular
tissue, which serves as a shock absorber for bone
and has a frictionless surface bathed in synovial fluid.
This tissue consists of sparsely scattered chondrocytes
(cartilage cells). The extracellular matrix (ECM) pro-
vides cartilage with its compressive strength and is pri-
marily composed of type II collagen and proteoglycans
(PGs). Collagen forms a fibrous network giving carti-
lage its tensile strength. Large aggregating PGs (aggre-
cans), composed of a protein core with several
glycosaminoglycan (GAG) side-chains attached to it,
hydrate the collagen network and provide the tissue
with viscoelastic properties and the ability to resist
mechanical compression
11
. When the joint capsule is
disrupted, proteolytic enzymes are secreted into the
synovial fluid and can facilitate PG and collagen degra-
dation
12,13
. In an attempt to repair structural changes
in the ECM, chondrocytes proliferate and stimulate
synthesis of these components. However, over time,
the metabolic activity of chondrocytes shifts towards
a state where the breakdown of matrix constituents
outweighs new matrix synthesis
10,14
, beginning the
gradual process of ECM degeneration and thus the
loss of articular cartilage.
Subchondral bone, the bone underlying the articular
cartilage, can also be affected by OA. Because it remo-
dels rapidly, subchondral bone is responsible for chan-
ging the shape and congruity of the joint. Mechanical
stimulation of subchondral bone often leads to
micro-damage, which may result in (1) normal remo-
delling; (2) excessive remodelling, leading to bone
sclerosis; or (3) accumulation of micro-damage, leading
to gross fracture
15
. Subchondral bone thickening is a
normal response in exercising horses. However, an
increase in the degree of subchondral bone sclerosis
corresponds to greater degrees of generalized OA in
joints (i.e. fetlock)
16
. Sclerosis of the subchondral
bone can lead to the development of chip fractures,
focal lesions of traumatic osteochondritis dissecans
and slab fractures. Articular cartilage covering sites of
subchondral bone sclerosis is predisposed to the devel-
opment of OA
15
.
Soft tissues of the joint include the intra-articular liga-
ments, joint capsule, menisci and synovial membrane.
Damage to intra-articular ligaments, which provide sup-
port for the joints and distribute normal surface stresses,
can stimulate an inflammatory response and change the
loading characteristics of the joint surface. An example
of this phenomenon is shown by mechanical instability
of the joint after transection of the cranial cruciate
ligament. This surgical procedure produces joint laxity,
loss of joint congruency, and abnormal cartilage
weight-bearing forces and trauma that can directly and
indirectly induce abnormal cartilage wear
17 – 20
. Degen-
erative joint disease often develops in humans following
meniscal injury
18
. Increased stress across the knee joint
induced by performing surgical meniscectomy stimu-
lates OA in humans, rabbits and guinea pigs
18,21 – 23
.
Chronic disease of the equine joint capsule, capsulitis,
can lead to the formation of scar tissue and increased
stiffness, leading to instability of the joint by changing
its surface stresses
15
. Acute synovitis and capsulitis
may cause significant clinical compromise of the joint,
and also contribute to the degenerative process by the
release of cytokines, inflammatory mediators and
enzymes
24
. While the cause of acute primary synovitis
has never been determined, the development of an
acutely inflamed joint is prevalent in trained Thorough-
breds and Standardbreds
25
.
Molecules associated with OA
Cytokines
Interleukin (IL)-1 induces and augments the pathologi-
cal processes involved in inflammatory joint disease.
Morris et al. were the first to identify IL-1 in the
equine osteoarthritic joint, and found that equine IL-1
has many of the characteristics of IL-1 isolated from
other species
26
. IL-1 stimulates chondrocytes and syno-
vial cells to release enhanced amounts of prostaglandin
E
2
(PGE
2
), PGs and matrix metalloproteinases (MMPs)
such as collagenases and stromelysin, and increases
nitric oxide (NO) production
27,28
. Stimulation by IL-1
creates an inflammatory response that is similar to natu-
rally occurring OA. As a result, IL-1 is often used to
stimulate an inflammatory response in chondrocytes.
Equine explants stimulated with IL-1 have demon-
strated an increase in the release of GAGs from the
ECM
29 – 32
. Decreased PG synthesis and increased
MMP-3 activity have been reported in equine explants
following stimulation with IL-1
33
, while recombinant
human interleukin-1b(rhIL-1b) induces the expression
of MMP-13 in equine chondrocytes in monolayer
culture and explants
34,35
. IL-1 also induces IL-6
AE Schlueter and MW Orth222
synthesis in human cartilage from normal controls,
patients with OA and patients with rheumatoid arthri-
tis
36
. Increased PGE
2
and IL-6 concentrations were
found in the synovial fluid of equine joints injected
with IL-1b
30
. In a subsequent study by Simmons et al.
in which rhIL-1bwas injected into the metacarpopha-
langeal (MCP) joints of horses, an increased concen-
tration of IL-6 was also found
20
. Other interleukins,
such as IL-6, -8, -10 and -18, have been studied in
arthritic cartilage as well, although the link to OA is
not as clear for these cytokines as it is with IL-1.
Tumour necrosis factor-b(TNF-a) exerts many of
the same catabolic effects as IL-1 since it activates simi-
lar cell signalling pathways
37
. As an example, like IL-1
it upregulates both MMP-13 and ADAMTS (a disintegrin
and metalloproteinase with thrombospondin motif)
enzymes
37,38
. In equine chondrocytes, it greatly
increased the gene expression of MMP-1, -3 and -13
while only mildly increasing the expression of tissue
inhibitor of MMP-1 (TIMP-1)
39
. Models of inflammation
in horses demonstrate an increase in TNF-a
4
. However,
TNF-aconcentrations in synovial fluid are not con-
sidered reliable indicators of the severity of joint
damage in horses
40,41
.
PGE
2
and NO
Prostaglandins are widely distributed in the body and
mediate or modulate a variety of physiological and
pathophysiological processes in many organ systems
and tissues, including the haematopoietic, cardiovascu-
lar and reproductive systems. They are believed to
bind to receptors on the sensory nerve endings, pro-
moting the discharge of impulses and consequently
causing an increase in pain
42
.
Prostaglandins (primarily E group) are produced in
inflamed joints and can cause a decrease in the PG
content of the cartilage matrix
10
. Actions of PGE
2
in
joints include vasodilation, enhancement of pain per-
ception, degradation of PGs and inhibition of PG syn-
thesis from cartilage, bone demineralization and
promotion of plasminogen activator secretion.
Cyclooxygenase-2 (COX-2) is one of the rate-limiting
enzymes responsible for the production of PGE
2
from cell membrane phospholipids. IL-1 stimulates
the synthesis of PGE
2
, and increased concentrations
of PGE
2
in affected joints suggest a causal link of this
inflammatory mediator to the pathophysiological
events of OA
43,44
. Equine synovial cells and chondro-
cytes increased PGE
2
production after stimulation
with recombinant equine interleukin-1b(reIL-1b) and
lipopolysaccharide (LPS). Exposure of equine synovial
explants to reIL-1benhanced expression of COX2
45
.
In addition, equine articular cartilage explants incu-
bated with LPS or IL-1 had an increase of PGE
2
released
into the culture medium
34,46,47
. Significantly higher
PGE
2
production has been reported in the medium
of explants originating from horses with moderate
OA, compared with normal joints
48
. The PGE
2
content
in the synovial fluid of equine osteoarthritic joints was
increased relative to levels in asymptomatic joints
49,50
.
The generation of specific COX-2 inhibitors for joint
pain in humans demonstrates the significance of inhi-
biting PGE
2
synthesis.
NO may also be involved in the pathogenesis of OA.
This uncharged free radical is released from various tis-
sues and cells, and is the product of a reaction between
L-arginine and oxygen. NO has one unpaired electron
and readily reacts with oxygen, superoxide radicals
and transition metals, which may generate further
destructive species
51,52
. Stadler et al. first showed
that articular chondrocytes have the ability to generate
large amounts of NO
53
. NO is a major component of the
inflammatory response, and may mediate the suppres-
sion of cartilage matrix synthesis occurring in response
to intra-articular cytokines
54
. NO activates MMPs
55
,
suppresses PG synthesis
56
and induces apoptosis in
human articular chondrocytes
57
. The death of chondro-
cytes from NO occurs under conditions where other
reactive oxygen species are generated
58
.
Although NO is generally thought to be an important
mediator of the inflammatory response, it may have an
anabolic function in inhibiting articular cartilage cata-
bolism. NO inhibited degradation of aggrecan in
equine explant cultures, suggesting that NO has an
anticatabolic role in PG degradation
59
. However, the
majority of research suggests that its overproduction
has negative consequences in horses. Explant cultures
of equine synovial membrane and articular cartilage
released significantly higher amounts of NO when the
explants originated from horses with OA
48
. Simmons
et al. injected rhIL-1bintra-articularly into the MCP
joints of six horses, and measured nitric oxide synthase
(NOS) in the synovial fluid of injected joints 6 h post
treatment
20
. Although the intensity and extent of
inflammation were significantly greater in the IL-1b-
exposed specimens compared with healthy specimens,
no significant increase in the inducible isoform of NOS
(iNOS) was found between the control joints and the
joints exposed to IL-1. However, this might not be
the case if different concentrations of IL-1 are tested.
Increased NO synthesis occurs in chondrocytes and
synoviocytes in response to LPS and IL-1 within a
48 h incubation period. In addition, LPS or IL-1 dramati-
cally increased NO synthesis relative to non-stimulated
controls in equine explants
34,60
. An NOS inhibitor pre-
vented cartilage degeneration in dogs with induced
OA
61
. Thus, inhibiting or minimizing NO production
in the joints of horses would probably be beneficial.
Metalloproteinases
Although all classes of proteinases may be involved in
the degeneration of the ECM, the MMPs may play the
Equine osteoarthritis 223
pivotal role in cartilage destruction. These enzymes are
characterized by a requirement for Zn
2þ
in their active
site. Calcium is also required for the expression of full
activity but does not reside in the active site. Overall,
the MMPs are capable of degrading ECM components
such as collagen, aggrecan, link protein and cartilage
oligomeric protein
62
. This growing family of proteo-
lytic enzymes has been divided into four main classes:
collagenases (MMP-1, -8 and -13), gelatinases (MMP-2
and -9), stromelysins (MMP-3 and -10) and mem-
brane-type (MMP-14, -15 and -17). MMPs are inhibited
by a group of endogenously produced tissue inhibitors
called TIMPs.
MMP activity increases in equine osteoarthritic
joints
63
. Specifically, MMP-2 and MMP-9 have been
found in synovial fluid from diseased equine
joints
40,64,65
. The activity of both of these MMPs was
upregulated in normal equine cartilage and synovial
fluid following stimulation with IL-1b
66
. In fact, MMP-
9 in synovial fluid could potentially be an indicator
of joint damage
40
. Stimulation of cartilage explants
with IL-1 also induced the synthesis of MMP-3 in
young and adult horses
33
. rhIL-1 and LPS stimulated
MMP-13 expression in equine chondrocytes and carti-
lage explants
34,67
. An exciting area of research is the
development of assays to quantify the protein frag-
ments of type II collagen degradation by MMPs such
as MMP-13 in biological fluids
68,69
.
Causes of OA
Cartilage damage due to trauma, impact injuries, abnor-
mal joint loading, excessive wear or as part of an ageing
process can lead to changes in the composition, struc-
ture and material properties of the tissue
10,70,71
. These
changes can compromise cartilage function in the stren-
uous mechanical environment normally found in
weight-bearing joints. Regardless of the specific cause,
the initial injury is usually mechanical in nature, with
an imbalance between the load applied and the tissues’
capacity to withstand that load
72
. Trauma to the joint,
immobilization of the joint, poor conformation, impro-
per shoeing and age are often preliminary factors that
contribute to the onset of OA in the horse.
Trauma
Trauma to the joint is believed to be the primary cause
of OA in the horse. Mackay-Smith
5
referred to use-
trauma, or trauma occurring from normal use of the
joint, as a percurrent factor of OA. Very strenuous
exercise injures articular cartilage by increasing fibrilla-
tion of the cartilage and reducing PG content and qual-
ity. Cartilage no longer responds with improved
biomechanical properties, and overload results from
such factors as extensive and intensive exercise, fati-
gue, speed, and poor conformation or footing
73
. For
example, a racehorse’s pace generates millions of
foot-pounds of force per mile, and the wear and tear
produced on the joints during a race can be severe
5
.
Also, in a rabbit trauma-induced model for studying
OA, regular exercise accelerated subchondral bone
thickening and cartilage damage after injury
73
. This
could be a quite relevant model for the equine athlete.
Most lameness occurs in the forelimbs, because they
carry 60 65% of the horse’s weight and are subjected
to higher load rates than the hind limbs
74 – 76
. The hind
limbs propel the horse, while the forelimbs receive the
shock of landing. However, this may vary among breed
and performance event. Different areas of joints and
joint surfaces in both the forelimb and hind limb are
subjected to different types of loading, such as low-
level constant loading during weight-bearing, intermit-
tent loading during locomotion, and very high and
sudden loading during training or racing
77
. The
carpal, fetlock, proximal interphalangeal and distal
intertarsal/tarsometatarsal joints are most frequently
affected by OA.
The fetlock joint of the foreleg has the largest
number of unique degenerative and traumatic lesions
of any limb joint in racing horses
78
. Brama et al.
79
topo-
graphically mapped contact areas and pressure distri-
butions on the proximal articular surface (PAS) of the
proximal phalanx (P1) under various clinically relevant
loading conditions in the forelimbs of 13 horses. These
authors found that certain areas of the PAS of the P1
are permanently loaded in the standing horse, and as
the load was increased to mimic the walk or trot, the
contact area enlarged in the dorsal, dorsolateral and
dorsomedial directions. The joint pressures in the con-
tinuously loaded central area of the equine fetlock joint
are relatively low in the standing horse, but may
increase up to six-fold when loads are applied that
can be expected during athletic performance.
Articular cartilage degeneration of the dorsal joint
margins of the carpal bones in racehorses may be the
direct result of trauma
78
. Repetitive exercise may
induce the replacement of normal subchondral bone
by sclerotic bone, therefore contributing to the patho-
genesis of OA. Research into the effects of exercise on
PG metabolism in the carpal joints has produced con-
flicting results. Palmer et al.
80
assessed the relevance
of site and the influence of exercise on articular cartilage
PG synthesis and metabolism on third carpal articular
cartilage in 16 horses. PG synthesis was increased
in exercised horses relative to non-exercised horses at
the end of a 6-week period. However, the increase in
newly synthesized PG was not reflected in endogenous
PG within the matrix at different sites on the third
carpal bone. A significant correlation of site on endogen-
ous PG was evident, with a greater concentration of PG
located in the palmar aspect of the radial facet compared
with the sites located on the dorsal aspect of the radial
AE Schlueter and MW Orth224
facet or all sites on the intermediate facet. Total PG con-
tent on sites of the middle carpal joint increased in
untrained Thoroughbreds with short-term exercise
81
.
PG content was greater at palmar sites overall, and
dorsal sites of the high-intensity trained group had 12%
higher PG compared with those of the low-intensity
trained group. A contradictory study to those previously
described evaluated the effect of strenuous versus
moderate exercise on the metabolism of PGs in the
articular cartilage from different weight-bearing regions
in the equine third carpal bone
9
. PG synthesis was
reduced in both exercise groups and greater PG loss
was found in the different joint regions of the strenu-
ously trained animals. No change in PG size or ability
to aggregate in different regions of any articular cartilage
site was found in this study. The differences in the
studies cited could be due to the use or non-use of seden-
tary controls and different exercise programmes. For
example, Palmer et al.
80
trained horses for 6 weeks,
Murray et al.
81
for 19 weeks, and Little et al.
9
for 25
weeks. The fact that the longest exercise programme
had decreased PG synthesis may be significant.
Low-motion joints such as the proximal interphalan-
geal, distal intertarsal and tarsometatarsal are vulner-
able to the development of OA because they have a
relatively smaller area of joint surface that must sustain
the same weight-bearing load for a relatively longer
period of time during joint movement
78
. Both ring-
bone and bone spavin can produce crippling lameness
in horses. Although the aetiology of ring-bone and
bone spavin is undetermined, the cause could be
trauma to the periarticular soft tissues including the
joint capsule insertions and periosteum
82
.
Ring-bone is a term used to describe DJD of the
proximal and distal interphalangeal joint. This disorder
most commonly occurs in horses forced to make quick
turns and abrupt stops, such as Western performance
horses, polo ponies and jumpers
83
. Ellis and Green-
wood
84
evaluated six cases of ring-bone in young Thor-
oughbreds ranging from the age of 3 months to 4
years. All cases except one had other pre-existing or
concurrent bone disease, which could have conse-
quently placed abnormal weight on the interphalan-
geal joint resulting in DJD. Ring-bone was the most
serious cause of wasting in Norwegian Do¨le horses
over 30 years ago
85
.
Bone spavin is the most common cause of hind-limb
lameness of athletic horses, and involves the distal
intertarsal, tarsometatarsal and occasionally the proxi-
mal intertarsal joints
76,86 – 88
. This degenerative dis-
order has been found in a variety of breeds including
Quarter Horses, Thoroughbreds, Standardbreds and
Icelandic horses. Wyn-Jones and May
86
treated 30
horses and ponies for lameness due to bone spavin,
finding that 25 of the 30 horses were lame in both
hind legs and that lameness varied from slight to
severe. Twenty-three per cent of Icelandic horses eval-
uated radiographically (379 total) had signs of bone
spavin, suggesting a predisposition to the disease
89
.
Immobilization
Reduced loading or immobilization, due to lack of
exercise, can lead to atrophy or degeneration of articular
cartilage. While excessive forces may lead to articular
cartilage loss, removal of all mechanical stimulation
leads to atrophy. When cartilage is subjected to high-
pressure loads, PGs are compressed and water is
expressed from the cartilage
72
. Cartilage then expands
as it is rehydrated upon alleviation of pressure. Physio-
logical loading and motion are therefore essential to
maintain the normal nutrition and metabolism of articu-
lar cartilage provided by exchange with synovial fluid.
Although several immobilization studies have been
conducted, few have been done on horses. An early
study investigating changes in the metabolism of PGs
in immobilized limbs of sheep showed a decrease in
GAG content of the non-load-bearing joint
90
. PGs iso-
lated from the immobilized limb were smaller than
those isolated from load-bearing joints. Instability of
the MCP joint was performed surgically in six horses
by transecting the collateral and lateral sesamoidean
ligaments
20
. This procedure induced OA in all
horses, which resulted in lameness, increased joint cir-
cumference, decreased joint range of motion and
increased new synthesis of PG production. Horses
immobilized with fibreglass casts from the proximal
portion of the metacarpus down to the hoof tended
to have lower hexosamine concentrations in articular
cartilage biopsied from their cast joints
91
. The contral-
ateral limbs of each horse served as a mobilized con-
trol, and the control articular cartilage tended to gain
hexosamine during the 30-day trial. These researchers
saw little change in GAG synthesis in the cast joints,
while the largest significant change occurred in the
control. Similar results have been found in the
rabbit
92
. Thus, contralateral limbs are unsuitable for
controls in immobilization studies because of their bio-
logical response to increased weight-bearing. Palmer
et al.
80
found a lower concentration of newly syn-
thesized PGs in non-exercised horses than in exercised
horses. Exercised horses had a noticeable increase in
the early PG peak of newly synthesized PGs, while
this did not occur in the sites of the non-exercised
group. Immobilization studies performed with canine
and rabbit limbs have indicated a depletion of PGs,
defective aggregation of PGs and accumulation of
water in the tissue
92 – 94
. These problems may be
reversed after remobilization.
Conformation
Conformation is defined by the physical appearance
and outline of a horse, which is dictated primarily
Equine osteoarthritis 225
by bone and muscle structures. Certain conformational
traits can predispose the horse to lameness. Confor-
mation defects such as ‘calf knees’, ‘knocked knees’
(carpus valgus), ‘bowed knees’ (carpus varus) and
‘bench knees’ cause the animal to load its carpus
abnormally, and OA can result
95
. In the rear legs,
horses that are extremely straight in angulation of
the stifle and hock, or are obviously sickle- or
cow-hocked, are predisposed to conformationally
induced lameness
96
. Certain breeds’ characteristic con-
formation magnifies their risk of developing OA. For
example, Icelandic horses with sickle hocks had a
prevalence of radiographic signs of bone spavin of
42%, which was significantly higher than that of
horses with straight (20%) or normal (19%) confor-
mation
89
. In addition, the prevalence of bone spavin
was 19% in horses with a light skeletal type, whereas
lesions were identified in 23% of those with intermedi-
ate and in 24% of those with heavy skeletal type. A
more recent study confirmed this finding, and indi-
cated that the prevalence of radiographic signs of
DJD in the distal tarsus of Icelandic horses increased
in horses with a smaller tarsal angle
97
. Upright pas-
terns, base-narrow front limbs and a rectangular-
shaped P1 in the Norwegian Do¨le horse are confor-
mation defects that contributed to the development
of ring-bone
85
. Quarter Horses can be prone to OA
because they have a relatively large body mass,
poor carpal conformation, small feet and short upright
pasterns
98
.
Shoeing
Since the hoof capsule is malleable, the manner in
which it is trimmed and shod can have a marked
effect on the performance and soundness of the
equine athlete. The hoof of the horse must be
balanced to absorb high-impact vibrations when it is
exposed to the repetitive trauma incurred during per-
formance events and normal use. Maximum energy dis-
sipation depends on proper hoof preparation and
shoeing
77
. Good shoeing is an art and maintenance
of the natural angle and balance of the hoof is critical.
Improper shoeing can change the limb configur-
ation of the horse, resulting in a modification of the
forces placed on the joint surfaces
99
. Increased abnor-
mal wear and loading on the joint surface due to
improper shoeing can contribute to degeneration
of articular cartilage. The typical long toe/low heel
conformation commonly seen in Thoroughbred race-
horses can accentuate hyperextension-type injuries in
the fetlock and carpus and cause direct injury to the
foot in the form of OA in the distal interphalangeal
(DIP) joint
100
.
Corrective trimming and shoeing alters the hoof
shape or angle to affect stance or stride and breakover,
in order to help the horse achieve a more normal
movement. Altered foot orientation, which could
result from trimming and shoeing, influences intra-
articular pressure in the articular contact area of the
DIP joint
101
. When a hoof is being actively re-formed,
the change in shape during one trimming may be dra-
matic. Types of shoes and shoeing devices can alter the
traction of the hoof. For instance, sliding plates and
wide web shoes are often used on reining horses.
These types of shoe provide inadequate traction for
the horse, and can result in strained tendons or
sprained ligaments. Traction devices, such as toe
grabs, heel calks and borium, can provide too much
traction. Excess torque on the limb and joints resulting
from using these devices can lead to strain or sprain
and may contribute to the development of OA.
Horses shod with hoof caulks had altered joint
angles, which could change the forces placed on the
joint surfaces or the soft tissue structures in the
lower limb
99
. A study evaluating the effects of shoeing
horses with wedges (angle 3.7 and 58) showed that an
increased elevation of the heel delayed unloading of
the heel and an increased elevation of the toe
advanced unloading
102
. These results suggest that the
horse does not compensate for an acute foot imbalance
by redistributing the load under the foot. Increased
joint pressure has been implicated in the progression
of OA
103
.Anin vitro study evaluating the intra-articu-
lar pressure in the DIP joint showed that elevating the
heels by 58significantly increased DIP pressure
101
.
Age
Advancing age is the most significant risk factor for OA
in humans. In horses, however, OA is known to
develop in animals as young as 2 years of age. Young
performance horses are most likely to develop OA
early in life, because of the emphasis on racing and
showing young horses in futurities and other events.
Training horses at a young age may precipitate
damage to joints unable to withstand the extreme
forces they are subjected to during training and com-
petition
95
. Racing and training may accelerate the
naturally occurring age-related changes. In addition,
some horses may be genetically predisposed to devel-
oping OA due to either age or training, while other
horses may never be prone to the disease
8
.
Pathological and arthroscopic examinations have
shown that OA is commonly observed in the joints
of older horses
8,76,78,104
and in specific locations
within a joint
105
. Naturally occurring OA also becomes
more severe with age in untrained wild horses
8
.
Increased severity of lesions is correlated with sub-
chondral bone sclerosis and ossicles with increasing
age. Age is also a significant cause for the prevalence
of OA in Icelandic horses
89,97
. Many studies have
described surgical treatment of horses diagnosed with
OA ranging from the age of 1 year up to the age of 21.
AE Schlueter and MW Orth226
Similar to humans, as the horse ages, the biochemi-
cal properties of articular cartilage change. Several
recent studies have investigated the effect of age on
the biochemical characteristics of equine articular
cartilage. Variations in biochemical characteristics of
cartilage in relation to site and age showed no
significant change in cartilage collagen between
horses ranging from 4 to 30 years old, but indicated
that non-enzymatic cross-linking was higher in older
horses and was linearly related to age
106
. A steady
increase in pentosidine cross-linking increased with
age from 5 years onward, resulting in a 10-fold increase
up to the age of 30 years. Cross-linking of articular car-
tilage by non-enzymatic glycation is expected to result
in stiffer, more brittle tissue that is more vulnerable to
damage by mechanical loading. Non-enzymatic cross-
linking during ageing may predispose older horses to
development of OA.
The biochemical characteristics of articular cartilage
in mature cartilage differ from those of immature carti-
lage at different sites on the joint surface. No signifi-
cant differences in water content and
hydroxylysylpyridinoline cross-links were found at
two different sites of the MCP joint in neonatal, 5-
month-old and 1-year-old horses. However, differences
in DNA, GAG, collagen and hydroxylysine content
between sites paralleled those shown in the mature
horse
106
. In a more recent study, the same researchers
investigated the influences of age and exercise on the
biochemical characteristics of articular cartilage
107
.
Neonatal foals showed no site-specific biochemical het-
erogeneity, in contrast to mature horses. The process
of formation of site differences was almost completed
in exercised foals at age 5 months, but was delayed in
those deprived of exercise. They concluded that the
functional adaptation of articular cartilage to mechan-
ical loading occurs during the first 5 months postpar-
tum, and that a certain amount of exercise is
required to sustain this adaptation. Joints of horses
less than 2 years of age had significantly higher cell
numbers, total collagen and DNA content, and lower
PG content, relative to mature horses ranging in age
from 2 to 20 years old
108
. No significant difference in
these measurements was found within the mature
age groups. Another study has reported no significant
difference in collagen or GAG content in cartilage
derived from horses aged 2 5 years
109
.
Chondroitin sulphate (CS), the most abundant GAG
in aggrecan, and keratan sulphate (KS), the most
widely distributed GAG in aggrecan, have both been
reported to change with age. The sulphation patterns
in CS chains affect the specific properties and func-
tions of these molecules. Cartilage degeneration in
the MCP joints of racehorses was accompanied by
deposition of CS chains with altered sulphation pat-
terns
110
. Six-sulphation of internal and terminal CS
residues increased with age. The same phenomenon
has been reported in human studies
111
.
High KS concentrations were reported in foals from
1 week after birth to 3 months of age
112
. These values
decreased rapidly from 3 to 5 months, and gradually
reached adult values between the ages of 5 and 18
months. This pattern also has been reported in chil-
dren
113
and puppies
114
. Todhunter et al.
115
had a simi-
lar finding, and reported a significant relationship
between age of foals and plasma KS concentration.
Mean plasma KS concentration peaked when foals
were 10 weeks old. Age affected KS concentration in
the synovial fluid of 32 clinically normal horses. How-
ever, no significant effect of age on plasma KS concen-
tration was seen in normal adult horses with a mean
age of 65 months. An earlier study also reported no
age-related changes in synovial fluid KS concentrations
in mature horses ranging in age from 8 to 30 years
old
116
.
Based on explant studies, ageing equine cartilage is
not as sensitive to stimulation of PG synthesis by link
peptide
117
. In humans, the concentration of osteo-
genic protein-1, a growth factor found in cartilage,
decreases dramatically with age
118
. Thus, although
some gross measurements might stay relatively con-
stant, subtle changes in the metabolism of chondro-
cytes over time may facilitate degenerative changes.
Conclusion
The focus of this brief review was to provide updated
information concerning equine OA and factors associ-
ated with it. Exercise is essential to the horse’s well-
being. Although we do not know unequivocally how
to prevent OA, our molecular understanding of it and
how to monitor it are improving quickly. In the near
future, intensive research efforts should identify
better markers for monitoring cartilage loss and pro-
vide more information regarding how chondrocytes
adapt to stress and ageing. Using relatively non-inva-
sive measures to monitor the effects of training regi-
mens and management on joint health should
facilitate the care of the equine athlete. This strategy
is currently being used to monitor bone health in
horses under various conditions
119 – 122
. Furthermore,
chondroprotective nutraceuticals, diagnostic tools
and therapeutic strategies will improve and expand.
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Equine osteoarthritis 231
... A U.S Department of Agriculture survey performed in horses attributed 60% of lameness to be related to OA which translates to millions of horses being impacted by this performance-limiting musculoskeletal condition (6). OA has a considerable economic impact on the equine industry, with the annual direct and indirect costs amounting to over $1 billion per year in the United States (7,8). There is no cure for OA and treatment primarily revolves around managing symptoms by systemic and local pharmacological therapies including analgesics and non-steroidal anti-inflammatory agents (NSAIDs) (9), surgical approaches such as microfracture and chondroplasty (10)(11)(12)(13), and regenerative medicine strategies using blood derived (ACS, APS, and PRP) (14-17) or cellbased approaches (ACI/MACI) (18)(19)(20)(21)(22). ...
Article
Full-text available
With an intrinsically low ability for self-repair, articular cartilage injuries often progress to cartilage loss and joint degeneration resulting in osteoarthritis (OA). Osteoarthritis and the associated articular cartilage changes can be debilitating, resulting in lameness and functional disability both in human and equine patients. While articular cartilage damage plays a central role in the pathogenesis of OA, the contribution of other joint tissues to the pathogenesis of OA has increasingly been recognized thus prompting a whole organ approach for therapeutic strategies. Gene therapy methods have generated significant interest in OA therapy in recent years. These utilize viral or non-viral vectors to deliver therapeutic molecules directly into the joint space with the goal of reprogramming the cells' machinery to secrete high levels of the target protein at the site of injection. Several viral vector-based approaches have demonstrated successful gene transfer with persistent therapeutic levels of transgene expression in the equine joint. As an experimental model, horses represent the pathology of human OA more accurately compared to other animal models. The anatomical and biomechanical similarities between equine and human joints also allow for the use of similar imaging and diagnostic methods as used in humans. In addition, horses experience naturally occurring OA and undergo similar therapies as human patients and, therefore, are a clinically relevant patient population. Thus, further studies utilizing this equine model would not only help advance the field of human OA therapy but also benefit the clinical equine patients with naturally occurring joint disease. In this review, we discuss the advancements in gene therapeutic approaches for the treatment of OA with the horse as a relevant patient population as well as an effective and commonly utilized species as a translational model.
... Osteoarthritis (OA) in the carpal joint is commonly seen in Thoroughbred and Standardbred racehorses. 1,2 In racehorses, OA is thought to be a stress-related syndrome caused by repetitive overloading of the articular surface of the carpal bones. 3,4 OA is a degenerative joint disease characterized by fibrillation and gradual thinning of the articular cartilage as a consequence of joint inflammation [5][6][7], and measurement of cartilage thickness is therefore potentially a valuable tool for diagnostic and prognostication purposes. ...
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Articular cartilage thinning is an important hallmark of osteoarthritis (OA), and ultrasonography (US) is a clinically accessible tool potentially suitable for repeated evaluation. The aim of the present prospective methods comparison study was to validate US as a tool for measuring cartilage thickness in the carpus of the horse. Eight Standardbred trotters underwent US examination with 9 and 15 MHz linear transducers. Six anatomical locations in the radiocarpal joint (RCJ) and middle carpal joint (MCJ) were examined. The same joints were assessed by ultrahigh field (9.4 Tesla) magnetic resonance imaging (MRI) and histology. Associations between measurements obtained by the different modalities were assessed by ANOVA, Deming regression, Pearson correlation and Bland–Altman plots. Histologically assessed total cartilage thickness (the noncalcified cartilage (NCC) plus the calcified cartilage zone (CCZ)) overestimated thickness compared to MRI (P < 0.01) and US (P < 0.01). US 15 MHz had substantial agreement with MRI and NCC histology, and repeatability was acceptable (coefficient of variation = 8.6–17.9%) when used for assessment of cartilage thickness in the RCJ. In contrast, 9 MHz US showed poorer agreement with MRI and NCC histology, as it overestimated the thickness of thin cartilage and underestimated the thickness of thicker cartilage in the RCJ and MCJ. Moreover, repeatability was suboptimal (coefficient of variation = 10.4–26.3%). A 15 MHz transducer US is recommended for detecting changes in RCJ cartilage thickness or monitoring development over time, and it has the potential for noninvasive assessment of cartilage health in horses.
... The involvement of inflammation produced by synovium and chondrocytes is central to the pathogenesis, with inflammatory cytokines, metalloproteases and other inflammatory mediators being present in synovial fluid of patients with OA (2006). The resulting joint pain manifests as lameness (Schlueter & Orth, 2004) and the joint capsule inflammation causes swelling and fibrosis, resulting in additional pain and decreased range of motion of the affected joint. No curative treatments exist for this disease, but early symptomatic treatment can reduce pain and the cartilage-damaging effects of the inflammatory products, and decrease the progression of cartilage destruction and fibrosis of the joint capsule (Goldring & Otero, 2011). ...
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Intra-articular administration of sustained-release anti-inflammatory drugs is indicated in horses suffering from joint inflammation, but no such drugs are labelled for veterinary use. To obtain initial data on synovial disposition and safety of a new sustained-release formulation of diclofenac (SYN321) in the joints of horses, an experimental interventional study of elimination and side effects of intra-articular administration of SYN321 was conducted. Nine clinically sound horses were included in the study, and SYN321 was administered by the intra-articular route. Dose ranges and sampling intervals were established in a pilot study with two horses, and then applied in a main study involving seven horses treated in the fetlock joint. Diclofenac was detected above lower limit of quantification (LOQ: 0.5 ng/ml) in synovial fluid throughout the study period (14 days), and below LOQ (0.1 ng/ml) in plasma after 4 days and in urine after 14 days. No obvious clinical side effects were detected. Clinical examination and objective lameness evaluation suggested that SYN321 has potential as a local joint NSAID treatment with sustained release in horses, but further studies on synovial fluid exposure, safety and clinical efficacy are warranted.
... Joint insult causes release of the pro-inflammatory cytokines interleukin-1 (IL-1), (IL-6), and tumor necrosis factor-α (TNF-α) by the inflamed synovium (Armstrong and Lees 2002), these cytokines then induce proteoglycan depletion and promote its degradation by stimulating the release of prostaglandin E 2 (PGE 2 ) and matrix metalloproteinases (MMPs) (Trumble et al. 2001). PGE 2 induces vasodilation and heightening of pain perception (Schlueter and Orth 2004), its synthesis depends on the rate limiting cyclooxygenase enzymes (COX-1 and COX-2). COX-1 has a range of physiologic functions, while COX-2 is upregulated only during pro-inflammatory states and is highly expressed in arthritis (Ziegler et al. 2017). ...
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The aim of this study was to explore the diagnostic value of matrix metalloproteinase (MMP)-2 and -9, and cyclooxygenase-2 (COX-2) enzymes in the synovial fluid of horses with different forms of arthritis. Thirty-two horses were involved in this study and based on the clinical, radiographic, and synovial fluid examinations, the horses were divided into three groups: control (group I; n = 12), septic arthritis (group II; n = 5), and aseptic arthritis (group III; n = 15). After routine analysis, synovial fluid was used for assessment of MMP-2 and MMP–9 activities by gelatin zymography, and COX-2 relative gene expression by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Synovial fluid gelatin zymography showed significant gelatinolytic activity for MMP-9 in group II. COX-2 exhibited a 50-fold expression in group II and a 4.5-fold expression in group III compared to group I. In conclusion, the results confirm that MMP-9 and COX-2 detection offers an important diagnostic potential for septic and aseptic arthritis in horses.
... The importance of osteoarthritis (OA) is undeniable in equine medicine, with a high occurrence in the routine, several studies have been carried out to understand the pathophysiology of the disease and to seek more efficient methods of prevention and treatment [1,2]. Among the most frequent approaches in the management of this condition, viscosupplementation (VS) with hyaluronic acid (HA) is widely spread and performed [3]. ...
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Osteoarthritis (OA) is a degenerative joint disease with inadequately understood pathogenesis leading to pain and functional limitations. Extracellular vesicles (EVs) released by synovial joint cells can induce both pro- and anti-OA effects. Hyaluronic acid (HA) lubricates the surfaces of articular cartilage and is one of the bioactive molecules transported by EVs. In humans, altered EV counts and composition can be observed in OA synovial fluid (SF), while EV research is in early stages in the horse—a well-recognized OA model. The aim was to characterize SF EVs and their HA cargo in 19 horses. SF was collected after euthanasia from control, OA, and contralateral metacarpophalangeal joints. The SF HA concentrations and size distribution were determined with a sandwich-type enzyme-linked sorbent assay and size-exclusion chromatography. Ultracentrifugation followed by nanoparticle tracking analysis (NTA) were utilized to quantify small EVs, while confocal laser scanning microscopy (CLSM) and image analysis characterized larger EVs. The number and size distribution of small EVs measured by NTA were unaffected by OA, but these results may be limited by the lack of hyaluronidase pre-treatment of the samples. When visualized by CLSM, the number and proportion of larger HA-containing EVs (HA–EVs) decreased in OA SF (generalized linear model, count: p = 0.024, %: p = 0.028). There was an inverse association between the OA grade and total EV count, HA–EV count, and HA–EV % (rs = – 0.264 to – 0.327, p = 0.012–0.045). The total HA concentrations were also lower in OA (generalized linear model, p = 0.002). To conclude, the present study discovered a potential SF biomarker (HA–EVs) for naturally occurring equine OA. The roles of HA–EVs in the pathogenesis of OA and their potential as a joint disease biomarker and therapeutic target warrant future studies.
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Objective: To identify chondroprotective factors as potential disease-modifying osteoarthritis treatments using an unbiased, bottom-up proteomics approach. Samples: Paired equine cartilage explants and synovial membrane were collected postmortem from 4 horses with no history of lameness and grossly normal joints at necropsy. Procedures: Six groups were established: cartilage, synoviocytes, and cartilage + synoviocytes (coculture), all with or without interleukin (IL)-1β. The catabolic effect of IL-1β was verified by glycosaminoglycan (GAG) released from cartilage into media by 1,9-dimethyl-methylene blue assay and cartilage toluidine blue histochemistry. Conditioned media from cocultures with or with IL-1β were submitted for bottom-up proteomic analysis. Synoviocyte gene expression was evaluated using reverse transcription-quantitative PCR (RT-qPCR) for proteins of interest identified in the proteomics scan. Results: GAG content was retained in cartilage when in cocultures treated with IL-1β. Fourteen proteins of interest were selected from the proteomic analysis. From these 14 proteins, metalloproteinase inhibitor 3 precursor (TIMP3), tumor necrosis factor receptor superfamily member 11B (TNFRSF11B), insulin-like growth factor-binding protein 2 (IGFBP2), and alpha-2 macroglobulin (A2M) were selected for synoviocyte gene expression analysis by RT-qPCR. Gene expression of TIMP3 (P = .02) and TNFRSF11B (P = .04) were significantly increased in synoviocytes from cocultures treated with IL-1β compared to controls. Contrary to expectations based on protein expression, IGFBP2 gene expression (P = .04) was significantly decreased in IL-1β-stimulated coculture synoviocytes compared to control coculture synoviocytes. A2M gene expression in synoviocytes was not different between coculture groups. Clinical relevance: The secretome from synoviocytes could provide a milieu of bioactive factors to restore joint homeostasis in osteoarthritis.
Article
Horses are a widely accepted model for osteoarthritis (OA) research. Synovial tissue sampling is commonly used in studies to evaluate and grade the progress of OA or to assess treatment effects. Synovial explants play an important role in ex-vivo studies, increasingly replacing the use of living animals. To understand histomorphological changes in the process of joint-related diseases such as OA, detailed information about histomorphometric parameters of unaffected synovial villi is necessary. The objective of the present study was to evaluate the mean width of the intimal synovial lining and its cellularity as well as the vascularization of the subintimal layer in juvenile and adult horses not affected by a joint-related disease. One hundred synovial samples from both metacarpophalangeal joints from 25 horses (one day to 24 years old) were collected to evaluate the following parameters on digitalized hematoxylin-eosin stained samples: Width of intimal synovial lining measured by the distance from the inner joint surface to the subintimal layer; density of the cells making up the intimal synovial lining by counting cell nuclei; vascularization of the subintimal layer measured by the number and size of vessels in relation to the subintimal area. The median width of the intimal lining did not differ among juvenile (22.34 µm) and adult (23.34 µm) horses. The cellularity of the intimal lining was significantly lower in juvenile (one cell/143.8 µm²) than in adult (one cell /188.7µm²), (p<0.001) horses as well as the density of blood vessels per mm² within the subintimal layer (juveniles 1/mm² vs. adults 0.05/mm²), (p<0.001). This study provides morphometric data regarding synovial intimal width, intimal cellularity, and vascularization of equine synovial villi of unaffected horses. For future studies, age-related characteristics should be taken into consideration when synovial tissue samples are used for in-vivo and in-vitro studies.
Article
As osteoarthritis is a major cause of lameness in horses in the United States, improving collagen health prior to onset and increasing collagen turnover within affected joints could improve health- and welfare-related outcomes. Through its positive effects on bone mineral content and density and its role in increasing collagen synthesis, silicon (Si) may slow the development and progression of osteoarthritis, thereby reducing lameness. This study evaluated the hypothesis that Si supplementation would increase cartilage turnover through increased collagen degradation and formation markers, as well as bone formation markers, resulting in reduced lameness severity as compared to controls. Ten mature Standardbred geldings were assigned to either a treated (SIL) or control (Con) group and group-housed on pasture for 84 d. Horses were individually fed to ensure no cross-contamination of Si other than what was present in the environment. For the duration of the study, SIL horses received a Si-collagen supplement at the rate of 0.3 g supplement/(100 kg bodyweight∙day). Serum samples were taken weekly for osteocalcin, and plasma samples were taken on d 0, 42, and 84 for plasma minerals. On d 0, 42, and 84, subjective and objective lameness exams were performed, and radiographs and synovial fluid samples were taken from reference and osteoarthritic joints. Plasma minerals were similar in both groups and were lower on d 84 than d 0 (P < 0.05). Silicon supplementation, fed at the manufacturer’s recommended rate, did not improve lameness or radiographs as compared to controls, and supplemented horses did not show greater collagen degradation and/or synthesis markers in synovial fluid than controls, indicating that cartilage turnover remained unaffected. However, a minimum beneficial threshold and range for Si supplementation standardized to bodyweight need to be established.
Article
Radiographic prevalence and correlation of radiographic findings has not been performed in Lusitano Purebred horses. The aim of this study was to (1) evaluate the prevalence of primary osteoarthritis radiographic findings in Lusitano Purebred horses; (2) to assess correlations between radiographic findings in different joints of the same limb and different limbs; and (3) elucidate the effect of age in the radiographic findings. A radiographic protocol of the stifle, tarsi, fetlocks and distal limbs was done in 98 Lusitanos and the classification of the radiographs was performed using a 0-4 scale developed and applied blindly by three veterinarians. The distal interphalangeal, proximal interphalangeal, metacarpophalangeal, metatarsophalangeal, tarsometatarsal, distal intertarsal, proximal intertarsal/, tibiotarsal and femorotibial-patellar joints were evaluated. Most joints presented no abnormal findings or minor abnormal radiographic findings (82.86% grade ≤1). The most affected joint was tarsometatarsal and more severe lesions were found in tarsometatarsal and distal intertarsal. Femorotibial-patellar radiographic changes were rare (2.13%). A strong/moderate correlation was found between contralateral joints with exception hindlimb fetlocks. A moderate correlation was found between fore and hindlimbs for distal limb joints. When analyzing ipsilateral as well as diagonal distal limbs, a strong/moderate correlation was also found. The total score progressed in 0.2 score points per each year of age, revealing that age can be a statistically significant predictor for radiographic changes. Overall, Lusitano horses presented a low prevalence of severe radiographic sings of primary osteoarthritis. Findings in contralateral joints tend to be correlated.
Article
Objective To evaluate the in vivo therapeutic efficacy of N ‐iminoethyl‐L ‐lysine (L‐NIL), a selective inhibitor of inducible nitric oxide synthase, on the progression of structural lesions in the experimental canine model of osteoarthritis (OA), and to explore the effect of L‐NIL on the level of chondrocyte apoptosis and of important proteins involved in the apoptotic phenomenon, i.e., caspase 3 (inducer) and Bcl‐2 (inhibitor). Methods The OA model was created by sectioning the anterior cruciate ligament. Dogs were placed into 4 experimental groups: unoperated dogs that received no treatment (controls), operated (OA) dogs that received placebo treatment, OA dogs that received oral L‐NIL at 10 mg/kg/day, and OA dogs that received oral L‐NIL at 1.0 mg/kg/day. In both L‐NIL groups, treatment started immediately after surgery. The OA dogs were killed at 12 weeks after surgery. Results OA dogs treated with L‐NIL showed a reduction in the size of osteophytes and a significant decrease in the severity of macroscopic and histologic cartilage lesions on both condyles and plateaus, compared with untreated OA dogs. L‐NIL treatment also significantly decreased metalloprotease activity in cartilage. Immunohistochemical analysis revealed that the levels of chondrocyte apoptosis, caspase 3, and Bcl‐2 were markedly increased in OA cartilage (P < 0.0001). A positive correlation between the levels of chondrocyte apoptosis and levels of caspase 3 was found (r = 0.54, P < 0.0001). OA dogs treated with the higher dosage L‐NIL showed significantly reduced levels of chondrocyte apoptosis (P < 0.003) and caspase 3 (P < 0.04), but no effect on the increased level of Bcl‐2 was demonstrated. Conclusion This study shows that L‐NIL reduces the progression of experimental OA. This effect could be related to a reduced level of chondrocyte apoptosis and is likely mediated by a decrease in the level of caspase 3 activity. A sparing effect of L‐NIL on the increased level of Bcl‐2 may also be a contributing factor.
Article
Many lesions of the musculoskeletal system of racing horses are either acute traumatic lesions or are chronic biomechanically induced lesions that become suddenly unstable and provoke acute clinical signs. The latter lesions along with those of DJD are much more common and are of much greater overall economic importance to the racing industry than are the acute traumatic injuries. Chronic biomechanical lesions occur at predictable sites and are the result of an imbalance between repetitive microtrauma sustained in athletic performance and adaptive repair mechanisms of skeletal tissues. The distribution of these lesions in the limbs reflects the patterns of biomechanical forces placed on the skeleton during work at racing speeds and, therefore, reflects the type of racing activity for which the horse was bred. Lesions result when there is a failure of the stressed skeletal structures to adapt to the biomechanical forces placed upon them. Rest or a reduction in the level of training activity permit the healing of many asymptomatic and presumably some symptomatic lesions of the bony tissues. Articular cartilage, tendons, and ligaments have a lower capacity to resolve the damage and return to normal structure and function.
Article
To correlate substance P content of synovial fluid with prostaglandin E2 content, radiographic evidence of joint abnormality, and anatomic location of the joint for normal and osteoarthritic joints of horses. Synovial fluid from 46 normal joints in 21 horses and 16 osteoarthritic joints in 10 horses. Normal and osteoarthritic joints were identified by clinical and radiographic examination, by response to nerve blocks, during scintigraphy or surgery, or by clinicopathologic evaluation. Substance P and prostaglandin E2 contents of synovial fluid were determined by radioimmunoassay. Radio-graphs of joints were assigned a numeric score reflecting severity of lesions. Joints were assigned a numeric score reflecting anatomic location. Median concentrations of substance P and prostaglandin E2 were significantly increased in osteoarthritic joints, compared with normal joints. A significant correlation was found between concentrations of substance P and prostaglandin E2 in synovial fluid, but a correlation was not detected between substance P concentration in synovial fluid and anatomic location of the joint or between radiographic scores of osteoarthritic joints and concentrations of substance P or prostaglandin E2. A correlation existed between concentrations of substance P and prostaglandin E2 in synovial fluid obtained from normal and osteoarthritic joints. However, content of substance P in synovial fluid cannot be predicted by the radiographic appearance of the joint or its anatomic location. Substance P and prostaglandin E2 may share an important and related role in the etiopathogenesis of osteoarthritis, lending credence to the importance of neurogenic inflammation in horses.
Article
Objective —To determine the effects of interleukin- 1β (IL-1β) and tumor necrosis factor-α (TNF-α) on expression and regulation of several matrix-related genes by equine articular chondrocytes. Sample Population —Articular cartilage harvested from grossly normal joints of 8 foals, 6 yearling horses, and 8 adult horses. Procedure —Chondrocytes maintained in suspension cultures were treated with various doses of human recombinant IL-1β or TNF-α. Northern blots of total RNA from untreated and treated chondrocytes were probed with equine complementary DNA (cDNA) probes for cartilage matrix-related genes. Incorporation of ³⁵ S-sulfate, fluorography of ¹⁴ C-proline labeled medium, zymography, and western blotting were used to confirm effects on protein synthesis. Results —IL-1β and TNF-α increased steady-state amounts of mRNA of matrix metalloproteinases 1, 3, and 13 by up to 100-fold. Amount of mRNA of tissue inhibitor of metalloproteinase-1 also increased but to a lesser extent (1.5- to 2-fold). Amounts of mRNA of type-II collagen and link protein were consistently decreased in a dose-dependent manner. Amount of aggrecan mRNA was decreased slightly; amounts of biglycan and decorin mRNA were minimally affected. Conclusions and Clinical Relevance —Treatment of cultured equine chondrocytes with IL-1β or TNF-α resulted in marked alterations in expression of various matrix and matrix-related genes consistent with the implicated involvement of these genes in arthritis. Expression of matrix metalloproteinases was increased far more than expression of their putative endogenous inhibitor. Results support the suggestion that IL-1β and TNF-α play a role in the degradation of articular cartilage in arthritis. ( Am J Vet Res 2000;61: 624–630)