British Journal of Rheumatology 1996;35(soppL 3): 10-13

THE PATHOPHYSIOLOGY OF CARTILAGE AND SYNOVIUMANTHONY J. FREEMONT

Department of Osteoarticular Pathology, University of Manchester, Manchester

SUMMARYTo interpret joint imaging it is necessary to understand the pathology of the joint. It is not possible to describe the pathology ofevery joint disease, nor is it relevant. In this paper the pathophysiology of the major joint changes, cartilage loss, change insubarticular bone, increase in joint fluid, and thickening of the synovium, that can be visualized by MRI are described anddiscussed.

KEY WORDS: Imaging, Joint disease, Pathophysiology.

THE NORMAL SYNOVTAL JOINTBECAUSE of their unique structure, synovial joints allowvery complex movements between adjacent bones. Theends of the bone are covered by articular cartilage. Thecartilage covered surfaces of the two bones move overone another lubricated by synovial fluid, a product ofthe synovial lining of the joint. A synovial joint is verymobile and therefore inherently unstable. Stability isproduced by the capsule, ligaments and muscles.

NORMAL CARTILAGECartilage consists of two major components: type II

collagen and glycosaminoglycan-rich proteoglycans.The latter are hydrophilic and by absorbing waterexpand, an expansion resisted by the collagen fibres,anchored to the underlying bone. The integrity of theanatomical structure of cartilage is maintained by thecells of cartilage which have the potential to synthesizeand degrade cartilage matrix[l].

NORMAL SYNOVIUMSynovium 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. Thecells are of two types: macrophage-derived phagocytesand mesenchymal connective tissue lineage-derived cellsthat synthesize factors that give synovial fluid itslubricating properties. The synovium contains vesselswhich are the only intra-articular vessels. Below thesynoviocyte layer lies either adipose or fibrous tissue.

NORMAL SYNOVIAL FLUIDSynovium and cartilage share one common property,

namely that although they appear to line a fluid-filledbody cavity there is no complete cellular barrier betweenthe fluid and the more solid tissue, as there is in pleuraor pericardium. Thus the only opposition to freemovement of chemical mediators and cells from onetissue to the next is the physical (and chemical)characteristics of the tissue matrices.

Correspondence to: A. i. Freemont, Department of OsteoarticularPathology, University of Manchester, Manchester

In this context synovial fluid is not a typical bodyfluid but might be best regarded as a relativelyhypocellular avascular tissue. Synovial fluid consists ofa transudate of serum, derived from synovial vessels,supplemented by complex saccharides, such as hyalur-onan, which give it its lubricating properties. Its cells arederived from cartilage and synovium and includechondrocytes, fibroblasts, synoviocytes and 'defence'cells, predominantly macrophages and lymphocytes[2].

THE PATHOLOGY OF SYNOVIAL JOINTSThe pathology of synovial joints can be considered to

be alterations in synovium and cartilage with secondaryeffects on bone, capsule and synovial fluid. Diseases ofjoints fall into two general categories: inflammatory andnon-inflammatory. Neoplastic disorders of synovialjoints are very rare, presumably because the cells ofjoints are either not undergoing frequent mitosis or aretransient.

From the pathophysiological viewpoint, the potentialcellular and matrix responses in synovium and cartilageare limited.

SYNOVIAL CHANGES IN DISEASEIn synovium most of the changes result in an increase

in the volume of synovium. There may be changes in thenumber and distribution of cells normally found insynovium such as synoviocytes, fibroblasts and nerves.There may be an influx of cells from outside thesynovium (Fig 1). Notable amongst these are immunecompetent cells such as lymphocytes and macrophages,but immune mechanisms are not the only drive tocellular accumulation, as evidenced by hyperlipidaemiasand other metabolic disorders.

Changes in the synovial matrix are very common andusually are manifest as fibrosis, oedema, myxoid changeor the accumulation of fibrin, usually on the synovialsurface, which has leaked from synovial vessels ininflammatory states. These changes are a reflection ofaltered synovial cell function. Intra-articular foreignmaterial accumulates in synovium. It may be endo-genous or exogenous, but most commonly the former,including crystals such as monosodium urate andcalcium pyrophosphate and dislodged fragments of

O 19% British Society for Rheumatology

10

Dow

nloaded from https://academ

ic.oup.com/rheum

atology/article/35/suppl_3/10/1782444 by guest on 09 February 2022

FREEMONT: THE PATHOPHYSIOLOGY OF CARTHAGE AND SYNOVIUM 11

Flo. 1.—Synovium thickened by an increase in the number ofsynoviocytes, an inflammatory cell infiltrate and increased matrix.H&E x200.

articular surface. This material frequently induces acellular response with profound changes in the structureand function of the synovium.

The most common synovial change seen in diseasestates is altered vascularity. It is seen in bothinflammatory and non-inflammatory arthropathies asan increase in blood flow, manifest either as dilatationof existing vessels and/or angiogenesis.

CARTILAGE CHANGES IN DISEASEThe possible changes to cartilage are equally limited.

The integrity of cartilage is a function of the balancebetween the amount of glycosaminogrycans and type IIcollagen. Disturb this balance and the structuralintegrity of cartilage is lost. This is seen specifically inthe earliest lesions of osteoarthritis where a failure ofsynthesis of glycosaminoglycans by chondrocytes leadsto a decreased resilience of the cartilage, which, underload, fractures—a process known as fibrillation. Theselesions may be focal initially but propagate laterally togive the characteristic appearance of osteoarthritis. Inosteoarthritis cartilage loss occurs predominantly fromthe surfaces.

Although surface loss of cartilage is most commonlyseen in osteoarthritis (Fig. 2) it is also a feature of other

disorders. In the inflammatory arthropathies it is seenin septic arthritis, where production of neutrophilproteases leads to rapid destruction of the articularcartilage and chondrocyte necrosis.

In rheumatoid disease cartilage is lost from thesurface, periphery, internally and from beneath. Innormal joints, synovium does not grow over cartilagebut in rheumatoid disease the inhibitors of synovialovergrowth of cartilage are overcome and synoviumgrows over, and erodes, articular cartilage. As erosionproceeds, cells in pannus—notably endothelial cells,mast cells and macrophages—induce chondrocytes todestroy their domainal matrix by producing solublemediators, a process known as chondrocytic chon-drolysis.

In very active rheumatoid disease the same chemicalfactors that cause synovium to overgrow and erodecartilage cause a seed change in the bone marrow deepto articular cartilage. This causes a loss of haemopoiesisand organization of the marrow into an erosivemembrane to which cells resembling osteoclasts, butwith the power to erode calcified cartilage, contribute.

KEY CELLULAR EVENTS IN THEPATHOPHYSIOLOGY OF ALL JOINT DISEASESIt is commonly accepted that certain cells participate

more than others in the genesis of joint disease. A hugeeffort has been expended to examine the effects on jointsof infiltrating cells of the body's defence system on jointbiology. In vivo they play only a partial role inintra-orbicular events in the broad spectrum of jointdisease, with others being equally or more important.

Synovial blood vesselsSynovial vessels participate in a number of ways.

Changes in endothelial cell adhesion moleculeexpression promote lymphocyte entry into inflamedsynovium. The vessels in pannus stimulate chondrocyteproduction of metalloproteinases and thus chondro-cytic chondrolysis. Altered vascular permeability leadsto synovial oedema and accumulation of synovial fluid.

Connective tissue cellsLocal connective tissue cells may be abnormally

stimulated or inhibited. In some inflammatorydisorders this propagates the process of joint damage,whereas in others they stimulate matrix synthesis, givingrise, in particular, to synovial fibrosis and new boneformation in subchondral or periarticular bone

'Non-inflammatory inflammationRecent research has shown that inflammation is

becoming increasingly difficult to define. Typical'inflammatory cells—neutrophils, macrophages andlymphocytes—are sometimes seen in synovium andsometimes not. When not seen the synovium may stillappear 'inflamed'. Other cells must therefore beimplicated in the 'inflammatory' process. Studies ofsuch synovium typically show an increase in cytokinesynthesis by synoviocytes, neurones and vascularendothelial cells.

Dow

nloaded from https://academ

ic.oup.com/rheum

atology/article/35/suppl_3/10/1782444 by guest on 09 February 2022

12 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 whichcontrasts with other joints in the vicinity. H&E x30.

Mast cells, although not 'fixed', are important inthe genesis of connective tissue damage. Factorsproduced by mast cells can induce chondrocytes andother connective tissue cells to synthesize enzymesthat degrade connective tissue and alter vascularpermeability.

SynovialfluidThe cell profile of synovial fluid is very different to

that of synovium. In the inflammatory arthropathiesthe synovial fluid is usually rich in polymorphs whilstthe synovium contains a predominantly lymphoplasma-cytic infiltrate. This means that the fluid bathing thesurface of synovium and cartilage contains a highconcentration of polymorph products, particularly ifthe processes controlling removal of polymorphs fromthe joint—apoptosis and cytophagocytosis—are faultyas in rheumatoid disease.

TRAUMA AND JOINT DISEASEThe processes of joint damage are accelerated or

worsened if there is, in addition, joint instability, eitherconsequent upon loss of cartilage or damage to thecapsule. In these circumstances the pathology of traumais added to the other pathologies in operation. Theseprocesses include damage to connective tissue ofcapsule and bone, with attempted repair, typified byaltered matrix synthesis, neovascularization and mastcell activation in capsule and synovium.

THE POSSIBLE ROLE OF SUBARTICULAR BONEAND BONE MARROW

There is much controversy as to the role ofsubchondral bone and adjacent marrow in cartilagedamage. What is certain is that in rheumatoid diseaseprofound changes occur in the sub-articular marrowwith formation of a tissue that is in many ways similarto pannus, incorporating multinucleated cells that erodebone and cartilage. In osteoarthritis there is a greatincrease in bone cell activity, leading to very active boneremodelling with a balance towards bone deposition.Remodelling is mediated by cytokines which arebeing actively synthesized, particularly by osteoblastsimmediately adjacent to the cartilage. The effects ofthese cytokines on cartilage is unknown, but must besignificant.

INVESTIGATION OF THE PROCESSES OF JOINTDISEASE

The processes of synovial and cartilage diseasein different types of arthritis are very variable andmediated by a complex and varied combination ofcellular and molecular events. The general effectsinduced by these mechanisms are, however, remarkablysimilar, at least as far as they affect radiographic imagesof the joint. These effects are thickening and increasedvascularity of the synovium, accumulation of synovialfluid and loss of cartilage, often together with somechange to the subchondral or periarticular bone[3].

One of the great advances in understanding the

Dow

nloaded from https://academ

ic.oup.com/rheum

atology/article/35/suppl_3/10/1782444 by guest on 09 February 2022

FREEMONT: THE PATHOPHYSIOLOGY OF CARTILAGE AND SYNOVIUM 13

pathophysiology of joint diseases has been theapplication of modern cell and molecular biology totheir study. To date, these techniques have been appliedto cell cultures, animal models and latterly diseasedhuman tissue. They have delivered a great deal ofinsight into the molecular mechanisms underlying alljoint diseases, but they suffer from being eitherinappropriate to human disease or 'snapshots' of theprocess. What is really needed is a dynamic system thatworks in live human tissue.

CAN MRI PROVIDE DYNAMIC INFORMATIONON DISEASE PROCESSES?

It is possible to generate water and fat images ofjoints using MRI. Flux of water between compartmentsand vascular imaging are not only possible but routine.MRI is already capable of generating non-invasive dataabout the pathophysiology of joints. Introduction offerromagnetic materials into joints, or cells labelled withthese molecules or their subsequent redistribution, offer

the opportunity for examining cell types and their activeand passive distribution. As new software becomesavailable for analysing components of the MRI signaland newer techniques are developed for interfering withthe signal, so new opportunities will present themselvesthat will, perhaps, offer the opportunity of developingmolecular and cellular imaging. These are exciting timeswith the possibility of expanding imaging from apredominantly diagnostic entity to one at the forefrontof investigating the molecular basis of joint disease.

REFERENCES

1. Gardner DL. Pathological basis of the connective tissuediseases. London: Edward Arnold, 1992.

2. Freemont AJ, Denton J. Atlas of synovial fluidcytopathology. Dordrecht: Kluwei; 1991.

3. Salisbury, JR, Woods, CG, Byers PD. Diseases of bone andjoints, cell biology, mechanisms, pathology. London:Chapman & Hall, 1994.

Dow

nloaded from https://academ

ic.oup.com/rheum

atology/article/35/suppl_3/10/1782444 by guest on 09 February 2022