Osteoarthritis and Cartilage 27 (2019) 230e239

Review

Models of osteoarthritis: the good, the bad and the promising

P.J. Cope, K. Ourradi, Y. Li, M. Sharif*
Musculoskeletal Research Unit, Translational Health Sciences, Bristol Medical School, University of Bristol, Learning and Research Building Level 2,
Southmead Hospital, Bristol, BS10 5NB, UK

a r t i c l e i n f o s u m m a r y

Article history: Osteoarthritis (OA) is a chronic degenerative disease of diarthrodial joints most commonly affecting
Received 8 April 2018 people over the age of forty. The causes of OA are still unknown and there is much debate in the literature
Accepted 13 September 2018 as to the exact sequence of events that trigger the onset of the heterogeneous disease we recognise as OA.
There is currently no consensus model for OA that naturally reflects human disease. Existing ex-vivo
Keywords: models do not incorporate the important inter-tissue communication between joint components
Osteochondral plugs
required for disease progression and differences in size, anatomy, histology and biomechanics between
Osteoarthritis
different animal models makes translation to the human model very difficult. This narrative review
ex-vivo model
in-vivo model
highlights the advantages and disadvantages of the current models used to study OA. It discusses the
Animal-model challenges of producing a more reliable OA-model and proposes a direction for the development of a
consensus model that reflects the natural environment of human OA.
We suggest that a human osteochondral plug-based model may overcome many of the fundamental
limitations associated with animal and in-vitro models based on isolated cells. Such a model will also
provide a platform for the development and testing of targeted treatment and validation of novel OA
markers directly on human tissues.
Crown Copyright © 2018 Published by Elsevier Ltd on behalf of Osteoarthritis Research Society
International. This is an open access article under the CC BY license (http://creativecommons.org/
licenses/by/4.0/).

Introduction degradative sequence of events involved in OA pathogenesis very

difficult to dissect3e5.
Osteoarthritis (OA) is a chronic degenerative disease of dia- The initial onset of OA disease is considered due to an imbalance
rthrodial joints, predominantly affecting the spine and peripheral between the cartilage degradation and repair process6,7. The exact
joints of the body, particularly the hands, hips, knees and feet. OA sequence of events that trigger the onset of the disease is however
most commonly affects people over the age of forty, with the risk of widely debated throughout the literature. One hypothesis, suggests
disease increasing with age. OA is a complex heterogeneous disease that secretion of pro-inflammatory cytokines into the synovial joint
with different clinical and biochemical phenotypes. induces matrix metalloproteinases which cause the fragmentation
The cause(s) of OA are unknown, and many studies have sug- and degradation of cartilage extracellular matrix leading to bone
gested that the pathobiology of OA is far more complex than a remodelling and synovitis8e10. Contrary to this theory, some
simple cartilaginous or bone disease. It is now acknowledged that studies suggest that subchondral bone remodelling and synovitis
OA affects many joint structures, including degeneration of carti- precede articular degeneration in the early stages of OA8,11,12. While
lage, abnormal bone remodelling and synovial inflammation1,2. other studies suggest that meniscal degeneration evolving through
Also, studies have shown that there is a complex interplay between fibrillation of tissue and a decrease in the levels of type I and II
the different joint components, making understanding of the collagen within the meniscus, act as a predisposing or contributing
factor to OA progression13,14. In the later stages of OA, formation of
subchondral cysts, subchondral sclerosis and osteophytes occur as a
direct result of bone remodelling, cartilage degradation and
* Address correspondence and reprint requests to: M. Sharif, Musculoskeletal synovitis15e17.
Research Unit, Translational Health Sciences, Bristol Medical School, University of
Treatment of OA is largely symptomatic due to insufficient un-
Bristol, Learning and Research Building level 2, Southmead Hospital, Bristol, BS10
5NB, UK. Tel: 44-117-414-7926.
derstanding of aetiopathogenesis hindering the development of
E-mail addresses: pc14080@my.bristol.ac.uk (P.J. Cope), Khadija.ourradi@bristol. suitable disease-modifying drugs. This makes targeted treatment of
ac.uk (K. Ourradi), Yunfei.Li@bristol.ac.uk (Y. Li), mo.sharif@bristol.ac.uk (M. Sharif).

https://doi.org/10.1016/j.joca.2018.09.016
1063-4584/Crown Copyright © 2018 Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
 P.J. Cope et al. / Osteoarthritis and Cartilage 27 (2019) 230e239 231

Table I
A summary of the advantages and disadvantages of different ex-vivo models used in OA research

Ex-vivo Model Advantages Disadvantages Example of the application of the model in

OA research

Monolayer culture - A large number of cells can be easily produced - Limited for certain tissue types such as - Monolayer cultures can be used to study
from a single sample23 cartilage, whose phenotype changes once in a the effects of cytokine stimulation and
- The configuration of cells cultured in a monolayer culture environment, introducing osmotic pressure23
monolayer layout allows homogenous spread inter-experimental variability25,26 - Synovial cell cultures useful to study the
of nutrients and growth factor from the - Chondrocytes are very sensitive to their role of the synovium in OA
culture medium24 molecular environment and so need to
remain in contact with the extracellular
matrix to ensure that they reflect natural in-
vivo samples23
- Cartilage has low cellularity, therefore, a large
sample of cartilage is required to ensure
sufficient numbers of cells are present to
carry out a reliable experiment23
- Isolating a tissue in culture removes all
systemic influences on that tissue, which
does not reflect natural joint tissue
- Cells in monoculture traditionally grow on a
flat surface in glass or plastic flasks and so
do not allow for growth in all directions, as
seen in the natural 3D in-vivo environment24
Co-culturing cells - Co-culturing cells of different lineages is - Different conditions are required for culturing - Co-culturing cells can be used to study
important to allow for changes in cell-specific each cell type23 the effects of cytokine stimulation and
physiology and cellecell interactions that are - Co-culturing cells can result in alterations of osmotic pressure23
important in regulating cell and tissue phenotype when cells are isolated23 - Osteoblast-chondrocyte co-culture useful
physiology23,27 - Co-cultures traditionally grow on a flat in understanding bone-cartilage cross-
surface in glass or plastic flasks and so do not talk28
allow for growth in all directions, as seen in - Co-culturing chondrocytes and
the natural 3D in-vivo environment24 osteoblasts results in greater cell growth,
matrix production and deposition as well
as reduced glycosaminoglycan deposition
compared to culturing chondrocytes
alone29,30
- Co-culturing sclerotic osteoarthritic
osteoblasts and chondrocytes from
osteoarthritic articular cartilage results in
an increased shift towards chondrocyte
hypertrophy and release of matrix
metalloproteinases and aggrecanases31,32
- Culturing synovium and cartilage
together produce very different results in
terms of the break-down of proteoglycan
and matrix structure compared to when
cultured alone4
- Co-culturing synovium and injured
cartilage produces a protective effect on
synoviocytes21
- Synovium-cartilage cultures useful to
study the role of the synovium in OA
- Co-culture of bone components ensure
balanced bone remodelling5
3D cell culture - 3D cell culture allows for culture of different - The proliferation rate of cells tends to be - 3D cell culture can be used to study the
cell lines and important cellecell interactions slower in 3D cell cultures compared to 2D effects of cytokine stimulation and
- 3D cell cultures grow as aggregates or cultures33 osmotic pressure, as well as the effects of
spheroids in a matrix, allowing growth in all - The structural strength provided to cultured physical injury and loading on tissue23
directions, similar to the natural in-vivo cells depends on the scaffold used23 - A matrix structure of collagens and
environment24 proteoglycans favours phenotypically
- The 3D structure provides structural strength normal cartilage28
to sensitive cells23
Explant based models - Simple, cheap and easy to produce23 - Cell death often occurs at the explant edge - Explant based models can be used to
- Explant models allow for the natural - Only a limited number of cells can be study the effects of cytokine stimulation
processes that occur within the extracellular extracted from a single source and osmotic pressure, as well as the
matrix environment to be observed26 - Limited tissue availability and significant effects of physical injury and
inter-experimental variability23 biomechanical loading on tissue23,28
- Synovial tissue explants useful to study
the role of the synovium in OA

OA a distinct challenge. Human OA tissue samples are usually pathology, particularly early OA, is therefore very difficult to study,
collected for research once end stages of the disease have been and so researchers turn to in-vivo and ex-vivo preclinical animal
reached, for example during joint replacement, by which time models to investigate early pathological changes in OA. These
destructive changes in the joint are well established. This makes models offer unique advantages as well as limitations for studying
studying the early disease process very challenging18. OA human OA. This article will review the different models used for
232 P.J. Cope et al. / Osteoarthritis and Cartilage 27 (2019) 230e239

Table II
A summary of the different animal models used in OA research

Species/ Spontaneous Surgically induced Chemically Induced Examples of the application of the
Model model in OA research

Mouse Naturally occurring OA1,2,34 - Anterior cruciate ligament - Mono-iodoacetate (MIA) intra- - Mouse models widely used for
- Genetic models: transection (ACLT)18,34,41e43 articular injection34,40 toxicology testing.1
PAR2 / , CD4 / , MMP17 / , - Articular groove model34 - Steroids, cytokines34,40 - Mouse models used to study the
Tenascin C /-, Ddr2 / , - Intra-articular tibial plateau - Papain34,40 molecular basis of OA.45
SulPhatase /- 1/2, Syndecan 4 / , fracture, cyclic articular cartilage - Collagenase34,40,41 - Genetically modified mouse
Fgf2 / , Mmp13 / , tibial compression, anterior models used to investigate the
Hif2a+/-, GDF5+/ , Osteopontin, cruciate ligament, rupture via genetic factors and specific genes
Ptges1, Tnfrsf11b+/-, Runx 2+/ , tibial compression overload2 involved in cartilage
ADAMTS-5/4 / , Adamts5 / , - Ovariectomy34 degeneration, bone remodelling
ADAMTS4 / , MMP3 / , ICE /-, IL- - Partial discectomy44 and inflammation2,18,43,45
1b /-, iNOS / 35 - Medial partial meniscectomy34
- Transgenic models2,36 - Destabilisation of medial
Mutations in type II collagen gene1 meniscus, meniscectomy, tibial
Brtl mouse37 overload, fracture models34
Mouse Del1: Short deletion in type - Meniscal destabilisation34,38,40,43
II collagen18 - ACLT and removal of medial/
Col9a1 knockout36 lateral meniscus or transection
STR/ORT + C57/BL6 strains1,2,36,38 of posterior/medial/lateral
e40
collateral ligament34
Rat - Naturally occurring OA - ACLT34,41,46 - Intra-articular injection of - Rat model useful in toxicology
uncommon18,41 - Medial meniscectomy steroids, cytokines40 testing of pharmaceutical
(MMx)34,40,41,46 - Collagenase40,41 compounds1. MMT, medial
- Articular groove model34 - Iodoacetate collateral ligament transection
- Medial meniscal transection injection18,34,40,41,45,48 (MCLT) and iodoacetate induced
(MMT)1,34,41,45 - Papain34,40,41 models used to study pain40,45
- Combination surgery40 - Immunotoxin41 - Rat undergone partial medial
- Ovariectomy34,40,41 meniscectomy are useful in
- Partial medial meniscectomy45 cartilage restoration techniques45
- Immobilization40
- ACL injury47
Syrian - Naturally occurring OA1,34 - Syrian hamster OA models are
hamster - Transgenic models1 naturally occurring, and
transgenic models are used to
study pathogenesis of OA1
Guinea pig - Naturally occurring OA2,34,39 - ACLT40,41 - Immunotoxin, papain, - Transgenic guinea pig models
e41,45,49
- MCLT, osteotomy, patellectomy, collagenase, copper II used to study pathogenesis of
- Transgenic models1 sciatic neurectomy41 bisglycinate, lipopolysaccharide, OA1
- Naturally occurring OA in medial - Meniscal transection1,34 chondromucoprotein41 - Guinea pig models used to study
compartment of knee joint in - Ovariectomy34,41 - MIA34,41 age and BMI associated risk
Dunkin Hartley guinea pigs1,18 - MMx41,50 - Quinolone34 factors in OA49. Dunkin Hartley
- Combination surgery40 guinea pig used in therapeutic
and pathogenic studies of knee
OA51. Guinea pigs induced by
medial meniscal tear and spon-
taneous OA models used to study
slow and rapidly progressive
OA34
Cat - ACLT40 - Useful in pain studies2
Rabbit - Naturally occurring OA2,52 - ACLT, MMx, posterior cruciate - Intra-articular injection of - Rabbit models useful in efficacy
ligament transection (PCLT), steroids and cytokines40 testing of various compounds
patellectomy34,39e41 - Papain34,40,54,55 such as hyaluronic acid45.
- ACL tear45 - Allogeneic cartilage particles56 - Partial meniscectomy models
- Section of medial collateral and - Iodoacetate and collagenase40,41 used in testing
both cruciate ligaments, - Quinolone34 chondroprotective agents1
resection of medial meniscus53 - Chymopapain, trypsin, IL-1b,
- Immobilization40 chondroitinase, vitamin A,
- Combination surgery, impact fibronectin fragments41
loading, cartilage scarification40
- ACLT, ACLT and PCL/MCL34
- Ovariectomy34
- Articular groove34
- Partial and MMx1,34,39,45
- Transarticular mechanical impact
on patellofemoral joint, femoral
condyle impact2
Canine - Naturally occurring OA2,34,41 - Abrasion, valgus osteotomy, - MIA, papain, calcium - MMx model useful in toxicology
pelvic osteotomy, cartilage pyrophosphate crystals34,41 testing and ACLT model used to
defect41 - Allogeneic cartilage particles61 study slow progression of OA and
- Cranial cruciate ligament pathogenesis that mimics
transection57 naturally occurring disease1
- Articular groove34,41,58 - Canine models that naturally
- ACLT1,2,41,45,58,59 develop OA have been used in
- Partial medial and MMx34,41
 P.J. Cope et al. / Osteoarthritis and Cartilage 27 (2019) 230e239 233

Table II (continued )

Species/ Spontaneous Surgically induced Chemically Induced Examples of the application of the
Model model in OA research

- Immobilization1,40 therapeutic intervention

- Impact loading, cartilage preclinical trials2
scarification40 - Transarticular impact models
- ACLT60 were used to identify whether
- Groove model in femoral condyle osteoarthritic changes originate
- Transarticular impact to stifle34,58 from cartilage or subchondral
bone changes34 and to study early
changes in OA in articular carti-
lage due to joint impact trauma34
- ACLT induced model have been
used in identification of OA
biomarkers45
Caprine -Naturally occurring OA41 - MCLT, ACLT41 - Goat models used to study
- MMx34,39,41,45,62 cartilage repair45
- Articular groove34
- Unilateral medial MMx, unilateral
MCL, meniscal transection,
cartilage scarification, unilateral
ACLT63
Ovine - Naturally occurring OA2 - Lateral meniscectomy, ACLT, - Ovine models used to study early
MCLT41 OA cartilage changes, meniscus
- Articular groove model34 changes and related treatment
- MMx34,39e41,45,62 techniques45,64
- Bilateral and unilateral Mx,
unilateral ACLT, medial MMx,
unilateral MCLT, unilateral radial
meniscal tear, unilateral caudal
pole hemi-meniscectomy,
unilateral medial
meniscectomy63
- Ovariectomy34,40
Equine - Naturally occurring OA2,45 - Metacarpophalangeal ligament - Amphotericin, E. coli - Equine models used to study
- Post carpal fracture, exercise- transection41 lipopolysaccharide, IL-1, articular cartilage repair,
induced41 - Osteochondral fragment66 carrageenan41 osteochondral defects and
- Trauma to medial femur and - Articular groove model34 - Monosodium iodoacetate40,41,48 naturally occurring bone
tibia65 - Filipin34,41,67 remodelling2
- Lipopolysaccharide68
- Amphotericin69
- Polyvinyl alcohol foam
particles41,70
- Papain40
- Intra-articular injection of
steroids, collagenase, cytokines40
Zebrafish - Genetic knockout e.g. COL10A171 - Zebrafish model useful in
studying gene related pathology
of OA71
Porcine - Post-fracture72 - ACLT, ovariectomy, ACL - Porcine model used to study
reconstruction, articular groove repair and regeneration of focal
model34 cartilage defects73
- Arthroscopy
- Cartilage resurfacing
Surgically in miniature pigs:
- ACLT and ACL reconstruction41
Bovine - Naturally occurring OA in - ACLT34
patella74,75
Non- - Naturally occurring OA1,34,76 - Meniscectomy34,40 - Collagenase induced in - Naturally occurring and
human - Naturally occurring OA in - Ovariectomy in macaques40,77,79 cynomolgus monkeys80 transgenic models of non-human
primates macaques34,40,77,78 - Ovariectomy in cynomolgus primates used to study general
- Transgenic models1 monkeys34 features of OA1

investigation of OA, discuss their advantages and disadvantages, that no single model provides the opportunity to study the disease
and propose development of a gold standard model for OA that as a whole. The different models currently used in OA research are
closely reflects natural human disease. discussed below.

Current models used in OA research Ex-vivo models

OA research models can be categorised into either ex-vivo or in- Ex-vivo models can be categorised into monolayer culture, co-
vivo models. Depending on the research question, different models culture, three-dimensional (3D) culture and explant-based cul-
can be used to address different aspects of OA development and ture. Each model has its advantages and disadvantages and so can
progression. Each model has its advantages, yet it has become clear be used to answer different questions in OA research.
234 P.J. Cope et al. / Osteoarthritis and Cartilage 27 (2019) 230e239

Table III
A summary of the advantages and disadvantages of different animal models used in OA research

Animal Model Advantages Disadvantages

Mouse - Mice have a short life span (generally one or 2 years) and so develop OA - Huge variation in results observed between different strains
fairly rapidly, making mice an easy model to study the whole disease of mice18
process18,43 - Disease severity varies with age, with older mice more
- Small animal size means the whole joint can be histologically sectioned81 representative of human disease82
- Mice are easily managed, with low maintenance cost, demonstrate rapid - Difficult to ascertain skeletal maturity as growth plates often
disease onset and their complete genome is available for study40 do not close completely82
- Genetically modified mouse models are easy to produce and are useful to - Mice are anatomically and histologically different to humans,
investigate the genetic factors involved in OA pathogenesis, specifically for example, mice have a thicker layer of calcified cartilage, do
genes involved in cartilage degeneration, bone remodelling and not have three distinct chondrocyte layers and have a cartilage
inflammation18,45 seventy times thinner than humans45
- Mouse models can be used in toxicology testing and to establish the - Macroscopic lesions and degrees of damage are difficult to
molecular basis of OA1,45 identify due to the small anatomical size of mice81
- The progression and process of disease is faster in mice than
in humans (weeks rather than decades)36
- The small size of mice makes surgically inducing OA more
challenging40
- Postoperative management of mice is difficult in surgically
induced models40,45
Rat - Rat cartilage is thicker than that of mice, so it is possible to induce partial - Naturally occurring OA is uncommon in rats, variation in
and full-thickness cartilage defects1,45 results is often observed between different strains of rat and
- Rats rarely experience post-operative infection so are useful animal disease severity varies with age, with older rats tending to
models to surgically induce OA1 present with more severe OA18
- Rats are easily managed and require low maintenance costs40,45 - It is difficult to ascertain the skeletal maturity of rats83
- It is easier to perform surgery in rats than in mice due to their larger size40 - Rats have greater volumes of highly vascularised adipose
- The full rat genome is available for study40 tissue and muscle in the medial knee region
- MMT, MCL transection and iodoacetate models useful to study pain40,45 - Post-operative rats immediately resume load-bearing
- Rat models useful in toxicology testing and studying cartilage restoration which accelerates joint degeneration1
techniques1,45 - Genetically engineered rat models are not available and
postoperative management of rats is challenging45
Guinea Pig - The guinea pig model has similar OA histopathology to disease in - The weight of each guinea pig and whether they are housed
humans84 alone or in pairs influences the severity of their OA41,49
- Guinea pigs are large enough that tissue samples can be easily collected - Unlike in humans, guinea pigs resume load bearing post-
for tests and the whole joint can be histologically sectioned49 operatively which accelerates joint degeneration1
- Guinea pigs are easy to manage40 - The time to guinea pig skeletal maturity is fast45
- Naturally occurring guinea pig models are available and the disease
pathogenesis is predictable and similar to that seen in humans1,45
-Hartley guinea pigs can be used to study risk factors for OA such as BMI and
age
- Complete guinea pig genome available85
Cat - Cats are larger in size allowing for tissue and fluid collection40 - Cats are difficult and costly to manage and there are ethical
- The full cat genome is available40 issues surrounding emotional attachment40
- Cats display genetic variability between individuals40
Rabbit - Naturally occurring OA is very common in rabbits52 - Rabbits have a very different gait compared to humans and
- Rabbit model useful in studying the efficacy of compounds45 only rabbits over the age of eight or 9 months can be used to
- Complete rabbit genome available86 guarantee skeletal maturity52
- The cartilage of rabbits is ten times thinner compared to
humans, with a higher chondrocyte density and cartilage
zonal layers that varies highly within the same joint87,88
- The rabbit meniscus is more cellular, has less vascular
penetration and can heal faster than the human menisci89
- Rabbit cartilage can spontaneously heal and regenerate and
there is no complete rabbit genome available for study40
- OA progression varies with the age of the rabbit after
surgical OA induction, with faster progression seen in older rabbits41
Canine - Canines have similar anatomy and disease progression to humans18,90 - Canines have different joint biomechanics and gait compared to
- Canines display a widespread clinical incidence of OA18,83 humans, their skeletal maturity is not reached until 9 to 18 months
- Canines are easy to manage and train postoperatively40,45 of age and their cartilage is half the thickness of human cartilage64
- Surgical lesions develop slowly in canines, similar to the human model1 - There are ethical issues surrounding emotional attachment of dogs
- Canines have similar gastrointestinal physiology to humans45 and management is costly40,45
- The canine model is widely used so comparison across different studies - Canines display genetic variability between individuals40
can be made, the larger size of canines allows for tissue and fluid
collection and the full canine genome is available40
- Naturally occurring OA models are available for intervention preclinical
trials2,41
Caprine - Anatomically the caprine stifle joint is very similar to the human knee64 - Caprine cartilage thickness varies between individuals, the skeletal
- The caprine stifle joint is closest in size to the human knee joint, the larger maturity of a goat is not reached until at least 2 years of age and
size of the animal allows for tissue and fluid collection and goat cartilage cartilage healing capacity varies with a goat's age, with better capacity
thickness is close to that of humans40 in younger animals87,92
- Goats are cheap and easy to use in studies compared to most large animal - Cartilage repair outcomes differ in the short and long term and so
models and they can be used to study cartilage repair45 follow up is required to assess progress83
- Complete goat genome available91 - Naturally occurring OA in goats is uncommon40,45
Ovine - Sheep are cheap and easy to use in studies compared to most large animal - The disadvantages of the sheep model are very similar to the caprine
models. model of OA
- The advantages of the sheep model are similar to the caprine model of OA
 P.J. Cope et al. / Osteoarthritis and Cartilage 27 (2019) 230e239 235

Table III (continued )

Animal Model Advantages Disadvantages

Equine - The large size of horses allows for easy tissue and fluid collection and a full - Horses are difficult and expensive to house and manage due to their
genome is available40 large size40
- Anatomically and histologically the equine stifle joint is similar to the
human knee, the articular cartilage is very similar in thickness and the
cellular structure, biochemical makeup and properties of the cartilage are
most comparable to humans2,92,93
- There are a wide range of imaging and clinical tests that can be performed
on horses, including rehabilitation techniques94
- Naturally occurring OA models are available45
Zebrafish - Zebrafish model is useful to study gene related pathology of OA and - Zebrafish do not have synovial joints71
zebrafish genome available71
Porcine - The porcine stifle joint is anatomically similar to the human knee joint and - The porcine meniscus is wider, and the cruciate ligaments are longer
pigs have similar immune systems and gastrointestinal physiology to than in humans64,95
humans41 - Pig skeletal maturity is reached between 10 and 24 months of age41
- Pigs are most similar to humans in terms of their anatomy, neurobiology,
cardiovasculature, gastrointestinal tract and genome73
- Genetically modified models are available and pigs are a useful model to
study repair and regeneration of focal cartilage defects73
- Pigs have similar joint size, weight-bearing and cartilage thickness to
humans73
Bovine - Bovine cartilage thickness, cellularity and zonal cartilage layers of patella - Bovine lateral tibial plateau cartilage is thinner, more cellular and
is similar to in human femoral condyles75,88 varies in zonal cartilage thickness compared to the human75,88
- Bovine meniscus is biomechanically similar to the human meniscus95
- Complete bovine genome available96
Non-human - Non-human primates have similar anatomy, genetics, biology, behaviour - Non-human primates are expensive and ethically difficult to keep, for
primates and physiology to humans2 example chimpanzees display depression and post-traumatic stress
- The pathology of OA and the relationship between age and disease disorder on a similar scale to that of humans97
severity is very similar to in humans18,76,77 - Non-human primates have a long-life span and so a long disease
- The larger size of non-human primates allows for tissue and fluid pathogenesis time scale which is both time consuming and costly2
collection and the full primate genome is available for some species40 - There are difficulties in obtaining adequate subject numbers for
studies1
- Housing and management of non-human primates is challenging40

Ex-vivo models such as monolayer culture and co-culture are remodelling. Animal models used in OA research (see Table II) can
easier and cheaper to produce than 3D cell cultures and explant- be categorised into either induced or spontaneous models. Induced
based models. Monolayer cultures are also easy to produce on a models refer to models where OA disease (or OA like features) have
large scale and avoid the challenges associated with culturing been induced either chemically or surgically. On the other hand,
different cell types at different conditions. However, monolayer spontaneous models are subcategorised into naturally occurring
and co-cultures are limited in their use due to the fact that they and genetically modified models that develop OA.
isolate only one or two tissue components at a time. Many studies Smaller animal models of OA such as mice, rats, rabbits and
have shown that there is a strong interplaying network of guinea pigs are much easier, quicker, cheaper and more readily
communication between different joint components that help available than larger animal models such as horses, pigs and
regulate and maintain a healthy joint, and so isolation of specific dogs2,40. Smaller animals can be handled and housed with greater
joint components hinders this communication3,19,20. For example, ease than larger models, but due to their smaller size, tissue samples
healthy articular cartilage is dependent upon the release of solu- extracted are much smaller and therefore tend to differ to a greater
ble factors by subchondral bone, and interactions between extent in their anatomical and histological structure when
chondrocytes and synovial fluid ensures the flow of growth fac- compared to humans18. Larger animal models therefore provide
tors, regulatory peptides and nutrients between them19,20. When many advantages over the use of smaller animal models in terms of
injured cartilage is co-cultured with synovium, a protective effect their greater anatomical similarity to the human model. A dog's
is produced on the synoviocytes21. Similarly, culture of sub- articular cartilage for example is half the thickness of a humans,
chondral bone and cartilage separately results in increased whereas that of a mouse is a minimum of 70 times thinner2,18.
chondrocyte death and cartilage degradation as well as decreased Additionally, a wider range of tests can be performed on larger an-
protein content in culture media compared to when cultured imals, such as repeated synovial fluid collection and imaging. They
together3,19,22. Explant models and 3D cell cultures allow for this also have a longer life span allowing for slower disease progression
inter-tissue communication and so are arguably more useful and time to end stage OA, as seen in humans. Whilst slow progres-
models available to OA researchers to reproduce natural in-vivo sive models most accurately reflect human OA, they are however
environments. Despite this, these models are more difficult to more expensive and time consuming to conduct. There are also
produce in terms of tissue volume and maintaining cell viability greater ethical considerations around the use of larger animal
over extended periods of time. Some of the advantages, disad- models such as non-human primates and canines41. Based on this,
vantages and applications of various ex-vivo models used in OA some animal models are therefore better suited to OA research than
research are summarised in Table I. others, such as the canine, caprine, bovine and porcine models. Some
of the advantages and disadvantages of various animal species used
in OA research are summarised in Table III.
In-vivo models

Many animal models in at least eighteen different species have Challenges presented by current OA models
been developed to study established pathological features of OA At present, there is no gold standard animal model used in OA
such as pain, synovitis, cartilage degeneration and bone research. Differences in size, anatomy, histology (specifically
236 P.J. Cope et al. / Osteoarthritis and Cartilage 27 (2019) 230e239

cartilage thickness) biomechanics and physiology makes trans- cultured in serum-free culture medium such as Dulbecco's Modified
latability between animal models and human disease very diffi- Eagle Medium F-12 (DMEMF-12, Invitrogen, USA) or a-Minimum
cult52,83. Challenges are posed by species-specific differences in Essential Medium (a-MEM, 22,561 Gibco, The Netherlands) for up to
disease pathology and progression, as well as normal joint ho- 57 days with significant cell viability98. Indeed, an early study re-
meostasis, specifically the repair processes that occur within the ported that >99% chondrocyte viability can be maintained in the
joint. Different OA induction methods used in certain animal spe- untraumatized areas at the centre of the osteochondral plugs100.
cies also sometimes results in differences in OA presentation. There The availability of an osteochondral plug-based model, partic-
is therefore a need to reduce experimental variability and increase ularly a human tissue-based one, would be invaluable in screening
the reliability of data interpretation. Furthermore, different animal of new disease-modifying osteoarthritis drugs (DMOADs).
models have been shown to represent different stages of the dis- Currently, there are many DMOADs under different stages of
ease more effectively, making selection of an animal model that development. Early studies of these drugs were in animal models,
completely reflects natural human disease challenging. To add to but the availability of this new model will provide an opportunity
this, it has become clear that there is much dispute as to what to directly test these drugs on human tissues. An osteochondral
defines OA and which molecules are associated with the disease. plug system like this may also be used for discovery of novel
This is in part hindered by the fact that current ex-vivo models do markers for OA.
not allow for the important inter-tissue communication between
different joint components required for natural OA disease pro- Conclusion
cesses to be studied. To gain a better understanding of the mech-
anisms of joint damage in OA, specifically the exact sequence of It is clear that we are limited in our understanding of OA because
events and interactions between different joint components, it has we do not have a suitable model that accurately reflects natural
been suggested that more focus should be placed on developing 3D human OA. Whilst animal models provide crucial information
cell cultures and explant-based models that allow for these about disease mechanisms, none of the current models used in OA
important interactions, providing interesting opportunities for re- research recreate the natural in-vivo environment and allow the
searchers to develop their understanding of OA. whole disease process to be studied. Differences in anatomy and
In the ideal animal model, the disease must be induced reliably, biomechanics also makes translatability to the human model a
with 100% penetrance, and within a suitable time frame, and yet distinct challenge. It is also important to consider the cost and ease
still present with disease characteristics that are comparable to the of management of using animal models in research. Whilst smaller
human condition. Disease progression in the animal model should animal models provide many benefits in terms of availability,
also allow for the examination of all stages of disease to ensure full handling and management, larger animal models such as canines
detection of any therapeutic effects. The animal must be inexpen- and pigs are not only more comparable to humans physiologically
sive, easy to house and manage but also be of large enough size to but also in their progression to disease. Their larger size also allows
allow for a full range of analysis techniques to be performed. The for performance of a broader range of analysis techniques and
animal must also be anatomically, biomechanically and histologi- investigations.
cally similar to humans40. Some animal species, such as the canine, The models currently used in OA research each have their ad-
caprine, bovine and porcine models, are therefore better suited to vantages and disadvantages; however, it has become clear that
OA research than others. there are consistent problems with all of these models that hinders
our ability to understand the pathogenesis of OA. The only way to
A promising model for OA achieve greater understanding of the pathological processes that
OA is a disease of the whole joint and therefore the gold standard underpin OA is to produce a ‘gold standard’ model for OA. Devel-
model for human OA must allow for key communication between opment of a consensus model will provide greater understanding of
different tissues of the joint. An osteochondral (cartilage on bone) the specific stages and interactions involved in OA pathogenesis, as
model may overcome many of the current challenges and limita- well as a model that can be used to compare data findings between
tions of the various models discussed above. The use of osteo- different research groups, test pre-clinical drugs and identify and
chondral plugs provides a model incorporating the key joint tissues test possible biomarker targets directly on OA joint tissue. An
affected in OA, maintaining the important interactions between osteochondral plug-based model could be a “promising” new
these tissues as seen in human disease. There are a few studies that model for OA, able to provide a reliable throughput model for proof
have used osteochondral plugs from bovine, equine and human of concept and mechanistic studies, aiding the discovery of targeted
samples as ex-vivo models of OA98e100. These osteochondral plug- OA therapy. The model would also provide an opportunity to
based models appear very promising and so further studies reduce the financial, ethical and time restraints associated with
should be encouraged as the basis for developing a gold standard using animals in research, shifting OA research to embody the
model for OA. In the model design, cytokines such as interleukin-1 principle of the 3Rs; replacement, reduction and refinement of
beta (IL-1b) and tumour necrosis factor alpha (TNF-a) may be used animal use in research.
as the best method for inducing OA (cartilage damage) and tissue
responses that closely replicate the natural disease, as these cyto-
Author's contributions
kines are known to contribute to the inflammatory effect of the
Conception and design: MS, KO, YL.
synovium in the model. However, OA is a complex disease and many
Drafting of the article: PC, MS, KO.
cytokines and chemokines have been shown to be expressed in OA
Provision of study materials: PC, YL.
synovium and detected in synovial fluid. Therefore, in the model
Final approval of the article: MS.
design, investigators should consider using synovial tissue and/or
synovial fluid from patients with active disease to induce OA in the
osteochondral plugs. Osteochondral plugs can be harvested from Competing interest statement
joint surfaces, such as the femoral condyle, tibial plateau and patella. The authors declare that they have no competing interests.
Methods of plug extraction available for use include different sizes
of graft harvester, biopsy punch, mosaicplasty osteotome, diamond Funding
tipped cylindrical cutter or surgical trephine burr. Plugs can be Not applicable.
 P.J. Cope et al. / Osteoarthritis and Cartilage 27 (2019) 230e239 237

Acknowledgements 20. Sophia Fox AJ, Bedi A, Rodeo SA. The basic science of articular
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BMC Muscoskel Disord 2013;14(1):54.
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