British Journal of Rheumatology 1996;35(soppL 3): 10-13
THE PATHOPHYSIOLOGY OF CARTILAGE AND SYNOVIUM
ANTHONY J. FREEMONT
Department of Osteoarticular Pathology, University of Manchester, Manchester
SUMMARY
To interpret joint imaging it is necessary to understand the pathology of the joint. It is not possible to describe the pathology of
every joint disease, nor is itrelevant.In this paper the pathophysiology of the major joint changes, cartilage loss, change in
subarticular bone, increase in joint fluid, and thickening of the synovium, that can be visualized by MRI are described and
discussed.
KEY WORDS: Imaging, Joint disease, Pathophysiology.
THE NORMAL SYNOVTAL JOINT
of their unique structure, synovial joints allow
very complex movements between adjacent bones. The
ends of the bone are covered by articular cartilage. The
cartilage covered surfaces of the two bones move over
one another lubricated by synovial fluid, a product of
the synovial lining of the joint. A synovial joint is very
mobile and therefore inherently unstable. Stability is
produced by the capsule, ligaments and muscles.
In this context synovial fluid is not a typical body
fluid but might be best regarded as a relatively
hypocellular avascular tissue. Synovial fluid consists of
a transudate of serum, derived from synovial vessels,
supplemented by complex saccharides, such as hyaluronan, which give it its lubricating properties. Its cells are
derived from cartilage and synovium and include
chondrocytes, fibroblasts, synoviocytes and 'defence'
cells, predominantly macrophages and lymphocytes[2].
NORMAL CARTILAGE
Cartilage consists of two major components: type II
collagen and glycosaminoglycan-rich proteoglycans.
The latter are hydrophilic and by absorbing water
expand, an expansion resisted by the collagen fibres,
anchored to the underlying bone. The integrity of the
anatomical structure of cartilage is maintained by the
cells of cartilage which have the potential to synthesize
and degrade cartilage matrix[l].
THE PATHOLOGY OF SYNOVIAL JOINTS
The pathology of synovial joints can be considered to
be alterations in synovium and cartilage with secondary
effects on bone, capsule and synovial fluid. Diseases of
joints fall into two general categories: inflammatory and
non-inflammatory. Neoplastic disorders of synovial
joints are very rare, presumably because the cells of
joints are either not undergoing frequent mitosis or are
transient.
From the pathophysiological viewpoint, the potential
cellular and matrix responses in synovium and cartilage
are limited.
BECAUSE
NORMAL SYNOVIUM
Synovium lines all of the inside of the joint other
than that lined by cartilage. It consists, in normal joints,
of an incomplete layer of cells called synoviocytes. The
cells are of two types: macrophage-derived phagocytes
and mesenchymal connective tissue lineage-derived cells
that synthesize factors that give synovial fluid its
lubricating properties. The synovium contains vessels
which are the only intra-articular vessels. Below the
synoviocyte layer lies either adipose or fibrous tissue.
SYNOVIAL CHANGES IN DISEASE
In synovium most of the changes result in an increase
in the volume of synovium. There may be changes in the
number and distribution of cells normally found in
synovium such as synoviocytes, fibroblasts and nerves.
There may be an influx of cells from outside the
synovium (Fig 1). Notable amongst these are immune
competent cells such as lymphocytes and macrophages,
but immune mechanisms are not the only drive to
cellular accumulation, as evidenced by hyperlipidaemias
and other metabolic disorders.
Changes in the synovial matrix are very common and
usually are manifest asfibrosis,oedema, myxoid change
or the accumulation of fibrin, usually on the synovial
surface, which has leaked from synovial vessels in
inflammatory states. These changes are a reflection of
altered synovial cell function. Intra-articular foreign
material accumulates in synovium. It may be endogenous or exogenous, but most commonly the former,
including crystals such as monosodium urate and
calcium pyrophosphate and dislodged fragments of
NORMAL SYNOVIAL FLUID
Synovium and cartilage share one common property,
namely that although they appear to line a fluid-filled
body cavity there is no complete cellular barrier between
the fluid and the more solid tissue, as there is in pleura
or pericardium. Thus the only opposition to free
movement of chemical mediators and cells from one
tissue to the next is the physical (and chemical)
characteristics of the tissue matrices.
Correspondence to: A. i. Freemont, Department of Osteoarticular
Pathology, University of Manchester, Manchester
O 19% British Society for Rheumatology
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FREEMONT: THE PATHOPHYSIOLOGY OF CARTHAGE AND SYNOVIUM
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disorders. In the inflammatory arthropathies it is seen
in septic arthritis, where production of neutrophil
proteases leads to rapid destruction of the articular
cartilage and chondrocyte necrosis.
In rheumatoid disease cartilage is lost from the
surface, periphery, internally and from beneath. In
normal joints, synovium does not grow over cartilage
but in rheumatoid disease the inhibitors of synovial
overgrowth of cartilage are overcome and synovium
grows over, and erodes, articular cartilage. As erosion
proceeds, cells in pannus—notably endothelial cells,
mast cells and macrophages—induce chondrocytes to
destroy their domainal matrix by producing soluble
mediators, a process known as chondrocytic chondrolysis.
In very active rheumatoid disease the same chemical
factors that cause synovium to overgrow and erode
cartilage cause a seed change in the bone marrow deep
to articular cartilage. This causes a loss of haemopoiesis
and organization of the marrow into an erosive
membrane to which cells resembling osteoclasts, but
with the power to erode calcified cartilage, contribute.
Flo. 1.—Synovium thickened by an increase in the number of
synoviocytes, an inflammatory cell infiltrate and increased matrix.
H&E x200.
articular surface. This material frequently induces a
cellular response with profound changes in the structure
and function of the synovium.
The most common synovial change seen in disease
states is altered vascularity. It is seen in both
inflammatory and non-inflammatory arthropathies as
an increase in blood flow, manifest either as dilatation
of existing vessels and/or angiogenesis.
CARTILAGE CHANGES IN DISEASE
The possible changes to cartilage are equally limited.
The integrity of cartilage is a function of the balance
between the amount of glycosaminogrycans and type II
collagen. Disturb this balance and the structural
integrity of cartilage is lost. This is seen specifically in
the earliest lesions of osteoarthritis where a failure of
synthesis of glycosaminoglycans by chondrocytes leads
to a decreased resilience of the cartilage, which, under
load, fractures—a process known as fibrillation. These
lesions may be focal initially but propagate laterally to
give the characteristic appearance of osteoarthritis. In
osteoarthritis cartilage loss occurs predominantly from
the surfaces.
Although surface loss of cartilage is most commonly
seen in osteoarthritis (Fig. 2) it is also a feature of other
KEY CELLULAR EVENTS IN THE
PATHOPHYSIOLOGY OF ALL JOINT DISEASES
It is commonly accepted that certain cells participate
more than others in the genesis of joint disease. A huge
effort has been expended to examine the effects on joints
of infiltrating cells of the body's defence system on joint
biology. In vivo they play only a partial role in
intra-orbicular events in the broad spectrum of joint
disease, with others being equally or more important.
Synovial blood vessels
Synovial vessels participate in a number of ways.
Changes in endothelial cell adhesion molecule
expression promote lymphocyte entry into inflamed
synovium. The vessels in pannus stimulate chondrocyte
production of metalloproteinases and thus chondrocytic chondrolysis. Altered vascular permeability leads
to synovial oedema and accumulation of synovial fluid.
Connective tissue cells
Local connective tissue cells may be abnormally
stimulated or inhibited. In some inflammatory
disorders this propagates the process of joint damage,
whereas in others they stimulate matrix synthesis, giving
rise, in particular, to synovial fibrosis and new bone
formation in subchondral or periarticular bone
'Non-inflammatory inflammation
Recent research has shown that inflammation is
becoming increasingly difficult to define. Typical'
inflammatory cells—neutrophils, macrophages and
lymphocytes—are sometimes seen in synovium and
sometimes not. When not seen the synovium may still
appear 'inflamed'. Other cells must therefore be
implicated in the 'inflammatory' process. Studies of
such synovium typically show an increase in cytokine
synthesis by synoviocytes, neurones and vascular
endothelial cells.
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MRI IN THE ASSESSMENT OF RA
Fio. 2.—Histologies! section of part of the wrist. The articular surface between the trapezium and the first metacarpal has lost all its cartilage which
contrasts with other joints in the vicinity. H&E x30.
Mast cells, although not 'fixed', are important in
the genesis of connective tissue damage. Factors
produced by mast cells can induce chondrocytes and
other connective tissue cells to synthesize enzymes
that degrade connective tissue and alter vascular
permeability.
Synovialfluid
The cell profile of synovial fluid is very different to
that of synovium. In the inflammatory arthropathies
the synovial fluid is usually rich in polymorphs whilst
the synovium contains a predominantly lymphoplasmacytic infiltrate. This means that the fluid bathing the
surface of synovium and cartilage contains a high
concentration of polymorph products, particularly if
the processes controlling removal of polymorphs from
the joint—apoptosis and cytophagocytosis—are faulty
as in rheumatoid disease.
TRAUMA AND JOINT DISEASE
The processes of joint damage are accelerated or
worsened if there is, in addition, joint instability, either
consequent upon loss of cartilage or damage to the
capsule. In these circumstances the pathology of trauma
is added to the other pathologies in operation. These
processes include damage to connective tissue of
capsule and bone, with attempted repair, typified by
altered matrix synthesis, neovascularization and mast
cell activation in capsule and synovium.
THE POSSIBLE ROLE OF SUBARTICULAR BONE
AND BONE MARROW
There is much controversy as to the role of
subchondral bone and adjacent marrow in cartilage
damage. What is certain is that in rheumatoid disease
profound changes occur in the sub-articular marrow
with formation of a tissue that is in many ways similar
to pannus, incorporating multinucleated cells that erode
bone and cartilage. In osteoarthritis there is a great
increase in bone cell activity, leading to very active bone
remodelling with a balance towards bone deposition.
Remodelling is mediated by cytokines which are
being actively synthesized, particularly by osteoblasts
immediately adjacent to the cartilage. The effects of
these cytokines on cartilage is unknown, but must be
significant.
INVESTIGATION OF THE PROCESSES OF JOINT
DISEASE
The processes of synovial and cartilage disease
in different types of arthritis are very variable and
mediated by a complex and varied combination of
cellular and molecular events. The general effects
induced by these mechanisms are, however, remarkably
similar, at least as far as they affect radiographic images
of the joint. These effects are thickening and increased
vascularity of the synovium, accumulation of synovial
fluid and loss of cartilage, often together with some
change to the subchondral or periarticular bone[3].
One of the great advances in understanding the
FREEMONT: THE PATHOPHYSIOLOGY OF CARTILAGE AND SYNOVIUM
pathophysiology of joint diseases has been the
application of modern cell and molecular biology to
their study. To date, these techniques have been applied
to cell cultures, animal models and latterly diseased
human tissue. They have delivered a great deal of
insight into the molecular mechanisms underlying all
joint diseases, but they suffer from being either
inappropriate to human disease or 'snapshots' of the
process. What is really needed is a dynamic system that
works in live human tissue.
CAN MRI PROVIDE DYNAMIC INFORMATION
ON DISEASE PROCESSES?
It is possible to generate water and fat images of
joints using MRI. Flux of water between compartments
and vascular imaging are not only possible but routine.
MRI is already capable of generating non-invasive data
about the pathophysiology of joints. Introduction of
ferromagnetic materials into joints, or cells labelled with
these molecules or their subsequent redistribution, offer
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the opportunity for examining cell types and their active
and passive distribution. As new software becomes
available for analysing components of the MRI signal
and newer techniques are developed for interfering with
the signal, so new opportunities will present themselves
that will, perhaps, offer the opportunity of developing
molecular and cellular imaging. These are exciting times
with the possibility of expanding imaging from a
predominantly diagnostic entity to one at the forefront
of investigating the molecular basis of joint disease.
REFERENCES
1. Gardner DL. Pathological basis of the connective tissue
diseases. London: Edward Arnold, 1992.
2. Freemont AJ, Denton J. Atlas of synovial fluid
cytopathology. Dordrecht: Kluwei; 1991.
3. Salisbury, JR, Woods, CG, Byers PD. Diseases of bone and
joints, cell biology, mechanisms, pathology. London:
Chapman & Hall, 1994.