ACVP 2014
Biology of Osteoarthritis
Richard F. Loeser, Jr., MD
The Herman and Louise Smith Distinguished Professor
Division of Rheumatology, Allergy, and Immunology
Director of Basic and Translational Research
The University of North Carolina School of Medicine
Chapel Hill, NC 27599
richard_loeser@med.unc.edu
Osteoarthritis is by far the most common form of arthritis affecting both man and the majority of animal
species that have been studied. Currently, there are no known treatments proven to slow or stop
progression of the disease. Therefore, research in the field has focused on elucidating the basic
mechanisms of the disease with the hope that new therapeutic targets will be discovered. Our
understanding of osteoarthritis (OA) has progressed from the old view that it is a non-inflammatory
form of degenerative joint disease resulting from excessive wear and tear on the joints, to the current
concept of excessive remodeling of joint tissues in response to abnormal joint mechanics, systemic
factors, and genetics and driven by localized inflammatory mediators 1-3. Rather than just due to
cartilage breakdown and loss, it is clear that OA is a condition affecting the joint as an organ4 (Fig.1).
The destruction of the articular cartilage is a key
feature and certainly contributes to a loss in normal
joint function but, since cartilage is aneural, cartilage
destruction does not directly result in pain. Other
joint structures affected in OA include the synovium,
bone, menisci (knee), ligaments, joint capsule, bursa,
and local muscle and tendons. These structures are
all potential sources of pain and are probably
affected to a variable extent in each individual
person (or animal). Recent MRI studies in humans
have suggested that synovitis and bone marrow
lesions may be key sources of pain5. The variability in
how the joint tissues are affected is likely the result
of the multifactorial nature of OA.
Synovitis is often present in people with OA but the severity ranges from mild to severe. In a study of
patients with OA severe enough to require joint replacement6, one third had little or no synovitis, one
third moderate synovitis, and one third severe synovitis, suggesting there may be subgroups of people
with OA where synovial inflammation plays a key role. The synovium can be a source of inflammatory
mediators that contributes to the destruction of other joint tissues and progression of disease7 as well as
an important source of pain. A host of inflammatory mediators have been identified in the synovial fluid
of humans with OA including members of the complement family and several cytokines and chemokines
including IL-6, VEGF, MCP-1, IP-10, and MIG 8. The finding of multiple members of the complement
family in human synovial fluid led investigators to study the role of complement in mouse models of OA
where they found evidence that the complement pathway is activated in the OA process and promotes
disease progression9. Future therapies may target the inflammatory mediators produced by the
1
synovium in the subsets of people (or animals) where synovitis is more severe but at the present time a
master regulator of inflammation (such as the apparent role of TNFα in rheumatoid arthritis) has not
been identified in OA.
The bone is commonly affected in OA and involvement ranges from the common findings of osteophytes
and subchondral sclerosis to bone marrow lesions detected on MRI that represent areas of active
localized bone remodeling. Pathologically these lesions show evidence of focal necrosis and fibrosis;
however, as detected by MRI they can be reversible. The location of the bone marrow lesions is
associated with areas of increased biomechanical stress such that varus malalignment that results in
increased medial joint loads is associated with medial lesions while valgus malalignment that results in
increased lateral joint loads is associated with lateral lesions. In humans, these lesions are associated
with pain and disease progression10, 11. There is evidence from animal model studies that the changes in
bone may drive the destruction of the overlying cartilage although this does not hold true in all model
systems with some showing a disconnect between changes in bone and cartilage3, 4. There may be a
subset of people (or animals) with OA where the bone changes are driving disease progression making
bone a potential therapeutic target. But if the bone lesions are only the result of abnormal mechanics
and by themselves do not affect disease progression, then targeting bone without changing the
mechanics will likely be futile.
In the human knee, MRI research studies have found that the menisci are often affected, even in people
without a history of known knee injury, with some type of meniscal change almost always present in
symptomatic knee OA 12-14. Meniscal injury can be a risk factor for the development of OA and as OA
develops from other causes, the meniscus, like the cartilage, appears to be a very vulnerable tissue.
Damage to the meniscus can not only promote OA through changes in joint mechanics with increased
contact stress in areas of meniscus loss but also through the release of inflammatory mediators that are
produced by meniscal cells15, 16.There is no evidence that current surgical techniques used to repair a
damaged or degenerative meniscus are of any benefit in slowing the development of OA. Future
interventions will likely include meniscal replacements using tissue engineering approaches. Likewise,
damage to ligaments, notably the ACL in the knee, is very common in older adults with knee OA. Similar
to the findings of meniscal lesions, many of those with torn or severely degenerated ACLs did not have a
history of trauma17. It appears that degenerative changes in the menisci and ligaments occurs commonly
during the development of OA and their loss of function in turn contribute to the further progression of
OA by altering normal joint mechanics.
The cartilage is still the tissue in the joint that receives the most attention in terms of basic research
studies and is still considered to be an important target for therapy. Cartilage destruction is a key
feature of OA. Often thought to be the shock absorber of the joint (which it is not, it merely distributes
load) articular cartilage is mostly responsible for the normal smooth gliding motion of the joint.
Hyaluronic acid is not the substance responsible for reducing friction on the joint surface but rather a
large mucinous protein called lubricin (also known as superficial zone protein or PRG4), made by the
superficial zone chondrocytes and the synovium, appears to be much more important18. Recombinant
lubricin that can be injected into the joint has been developed and tested in rats19. Trials in humans are
likely to be seen soon and hopefully will show more benefit that HA injections.
The basic mechanisms mediating cartilage destruction in OA can be activated by abnormal forces acting
on normal cartilage or normal forces acting on abnormal cartilage. Abnormal cartilage can result from
either genetic mutations that affect a specific cartilage matrix protein (such as collagen mutations),
metabolic abnormalities (such as hemochromatosis or ochrinosis) or aging changes in the matrix (such
as the accumulation of advanced glycation end-products, matrix fragments and mineral). It is well
2
accepted that the chondrocyte (the one cell type in cartilage) is responsible for the destruction of its
own matrix through the release of matrix degrading enzymes that include several matrix
metalloproteinases, aggrecanases, and cysteine and serine proteases. Evidence is accumulating that the
production of these enzymes is driven by a host of inflammatory mediators including multiple cytokines
(IL-1, IL-6, IL-7, IL-8, IL-17, TNFα, and so on), chemokines (MCP-1, GRO, LIF and others), several
prostaglandins and leukotrienes, as well as reactive oxygen species 4, 20, 21. Aging contributes to the
development of OA in part due to the presence of increased levels of reactive oxygen species resulting
from age-related oxidative stress and due to a decline in autophagy 22-24. Aging chondrocytes become
less responsive to growth factors but maintain their response to cytokines and cartilage matrix
fragments contributing to the imbalance in anabolic and catabolic activity in cartilage and resulting in
cartilage matrix destruction and loss.
Animal models, both spontaneous and injury induced, have been widely used to study OA. Each model
has its advantages and disadvantages and a discussion of the various models is beyond the scope of this
presentation. In order to be able to take advantage of the numerous transgenic and knock-out animals,
much recent attention has been placed on using mouse models with the most commonly accepted
model currently being the destabilized medial meniscus (DMM) model first described by Sonya
Glasson25, 26. In this model, the medial meniscotibial ligament is transected resulting in biomechanical
changes in the joint that lead to progressive pathology that is similar to the pathology seen in human
OA. We have characterized the pathology in this model and examined changes in gene expression using
RNA extracted from joint tissue and microarrays27-30. An important finding from these studies has been
that the age of the animals at the time OA is induced surgically influences both the severity of the
disease and the pattern of gene expression. Mice that were 12 months-old at the time of surgery had
almost twice as severe lesions 8 weeks later when compared to mice that were 12 weeks-old when
DMM surgery was performed28. Importantly, there were striking differences in gene expression changes
with only 55 genes showing a similar expression pattern in young and older adult mice while 493 genes
showed differential expression with many more up-regulated genes in the older mice. Most
investigators using the DMM model use mice between 6-10 weeks of age. Given the differences noted in
our study, and the fact mice that are 6-10 weeks old are equivalent to very young teenaged humans
where OA is extremely rare, investigators need to reconsider the age of animals being used to try and
model human OA.
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