ACVP 2014
Assessment of OA Severity in Animal Models
Cathy S. Carlson, DVM, PhD, DACVP
Professor, Department of Veterinary Population Medicine
College of Veterinary Medicine
University of Minnesota
Saint Paul, MN 55108
carls099@umn.edu
Osteoarthritis [osteo- + Gr. arthron joint + itis] (OA) is a progressive disorder of the joints occurring chiefly in
older individuals and characterized by degeneration of the articular cartilage, hypertrophy of the bone, and
changes in the synovial membrane. It is accompanied by pain and stiffness, particularly after prolonged activity.
OA is an important and costly health issue, affecting an estimated 27 million individuals in the United
States alone and resulting in a significant economic burden for the nation’s health care industry
(estimated $185 billion annually). In spite of this, the pathogenesis of this disease is poorly understood
and no treatments that effectively influence the disease progression have yet been developed. In fact,
many of the treatments currently under investigation are directed towards alleviating pain, likely due to
the fact that this is a more achievable goal.
There are several major challenges associated with the study of OA in human beings, perhaps the most
important being that, as is true of many orthopaedic diseases, clinical signs/symptoms are not evident
until the disease is in the advanced stages. In addition, there often is a high degree of variability in
activity types and levels, body weight, age, and number and types of concurrent medications among
individuals. Furthermore, although clinical imaging techniques are continuing to evolve and improve in
precision, offering the possibility of identifying earlier changes occurring in the disease, histological
evaluation of the affected tissues is rarely possible except in advanced disease (e.g., at the time of joint
replacement). At these late stages of the disease, the combination of chronic disease and repair
processes make interpretation difficult and determination of the chronology of the changes impossible.
It has long been recognized that many of these issues can be addressed through the study of animal
models and, as a result, many different models have been developed. Disadvantages of using animal
models to study OA include difficulties in modeling pain, gait abnormalities, and disability, which are
present primarily in the advanced stages of the disease and may be better studied in humans.
Differences in body size, anatomical conformation and limb usage (e.g. biped vs. quadruped) also are
challenges when using animal models. Perhaps the greatest advantage posed by the use of animal
models is the ability to evaluate the tissue changes, in detail, allowing one to correlate
anatomic/histological changes with clinical information such as imaging and biomarker data. In general,
the knee/stifle joint has been the focus of study. This joint is chosen for its large size, relevance to
human OA, and to allow comparison with previous studies, the great majority of which focus on the
knee joint. Histopathology has been the gold standard for outcome assessment in animal models of OA.
The purpose of this presentation is to provide some guidelines for the accurate assessment of
histological changes of OA severity in animal models of disease.
Most histological OA grading schemes are based on modifications of the Mankin system, which was
originally designed for evaluation of OA of the femoral head in humans and includes grades for cartilage
structure (0-5), chondrocytes (0-3), safranin O staining (0-5), and tidemarks (0-1). Although the Mankin
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system has been widely used, it is recognized to be imperfect in that it only assesses articular cartilage
pathology and is subject to significant intra- and inter-observer variability. While there is an
acknowledged need to develop grading schemes that are sensitive and accurate across all severities of
OA, there is considerable disagreement among pathologists regarding the approach to doing this. This is
exemplified in the special issue of Osteoarthritis & Cartilage (Volume 18, Suppl 3, 2010), which
represents an initiative by the Osteoarthritis Research Society International (OARSI) to standardize
scoring systems for each of the major species used as animal models of OA. Each group with expertise
in a particular species took at least a somewhat different approach to the project, resulting in a variety of
different schemes that vary considerably by species. Some of these differences are due to anatomical
differences in joint tissues among species, including: 1) variability in articular cartilage thickness and
morphology (e.g., mice have 50-fold thinner articular cartilage than humans, a zone of calcified cartilage
that is equivalent to or thicker than the non-calcified zone, and lack of distinct superficial, middle, and
deep zones); and 2) physical size of the joint (murine and rat are small enough to embed/section intact
whereas the larger species need to be dissected with study focused on specific sites). Another difference
among these schemes involves the decision to evaluate one site, or plane of section through the joint, in
detail (utilizing both semiquantitatie grades and morphometric measurements) vs. using a less detailed
scheme to evaluate multiple sites (typically 3-6) across the joint. Whether or not it is appropriate to add
the grades for different parameters together for a total joint score, or to add scores for individual joint
sites (e.g., medial femoral condyle and lateral femoral condyle), particularly when the range of possible
scores is not the same for each parameter, also is in question.
It is unlikely that a single scheme will be identified that will be suitable for evaluation of all models. In
fact, this probably is not desirable given differences in species and disease induction methods and the
focus on early/mild vs. late/severe disease. It is likely that, with the continued advancement of imaging
techniques that are able to detect morphological changes with increasing clarity in vivo, histological
grading schemes will be most relevant for assessment of early disease. The following guiding principles
regarding assessment of severity in OA models are offered: 1) because OA is a disease primarily
affecting older adults, animal age is an important consideration when modeling the disease; 2) an
appropriate power calculation should be done in advance to determine that the animal numbers needed
to ensure statistical power are used; 3) appropriate controls should be included; 4) surgical techniques
and tissue sampling, handling, processing, sectioning, staining, and evaluation techniques should be
standardized; 5) changes in cartilage, menisci (when present), bone and synovium all should be
assessed; 6) the anatomy of the joint and the site of the most severe lesions (to ensure that it is included
in the evaluations) should be clarified for the model being used; 7) validity of the scheme should be
established through correlation of histological findings with a different outcome measure, such as MRI
or synovial fluid biomarker concentrations; and 8) the individual grading the sections should be blinded
as to the animal status/treatment group.
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