Physiology

of Normal and Abnormal

Synovium

By Peter A. Simkin Because the synovial lining is a major target organ of rheumatic diseases, it seems logical to seek understanding of those conditions through study of the normal and abnormal physiology of this specialized organ system. This brief review covers some basic principles and recent progress

T

HE SYNOVIUM is a lining tissue that covers all intraarticular structures other than the contact surfaces of articular cartilage and menisci (Fig l).” It is distinguished by a well-organized, highly fibrillar interstitial matrix, approximately 25 km deep, containing loosely interdigitating synovial cells. It is often said that these cells are “up to three cell layers deep,” but their arrangement is not laminar and they do not share the tight junctions characteristic of epithelial tissues. Further, there is no basement membrane to mark the point of demarcation between the synovial lining and deeper, subsynovial tissues. These may be fibrous, fatty, or areolar depending on their location and their functional role within the articulation. The tissue is served by a rich meshwork of fenestrated microvessels, a complementary system of lymphatics, and a generous allotment of small nerve fibers. These anatomic features are muddied by the cellular infiltration and hyperplasia characteristic of chronic inflammatory disease. Thus, the normal tissues defined by the histologist and evaluated by the physiologist may be quite different from those palpated by the rheumatologist or removed by the orthopedist in a surgical “synovectomy.”

in this area with emphasis on our evolving knowledge of microvascular function. Copyright o 1991 by W.B. Saunders Company INDEX WORDS: Synovium; microvascular; protein concentration; ischemia; pharmacokinetics.

nal pressure. There, the cells move apart from each other and become more stellate in appearance, while the vessels move closer to the synovial surface.’ These changes should substantially reduce the interstitial diffusion barrier between plasma and synovial fluid. The expansile capabilities of synovium impose a severe challenge to the lubricating capabilities of synovial fluid. As the tissue adapts to flexion, extension, and additional ranges of joint motion, it does so in direct apposition to large areas of articular cartilage. Despite this intimate contact, synovial tissue is almost never entrapped and traumatized as the joint goes through its working cycles. This highly effective lubrication of synovium on cartilage may well involve hyaluronate.4 The system is as impressive as the separate and better-known lubrication of cartilage on cartilage, which appears to be predominantly a boundary-layer system involving a specialized glycoprotein and perhaps lipid factors as well.’ Both for synovium on cartilage and for cartilage on cartilage, effective lubrication is provided not by a large pool of interposed lubricant but by a thin film of fluid between the opposing surfaces. Thus, the volume of synovial fluid is small in normal joints. JOINT STABILITY AND INTRAARTICULAR PRESSURE

JOINT MOTION

Fundamentally, synovial joints serve as the bearings in the intricate machine that is the human body. In response to the changing articular geometry of motion, large areas of synovium are normally subjected to repetitive expansion and contraction. The histological implications of motion have not yet been evaluated. It seems likely, however, that synovium stretched by the normal range of motion will show changes analogous to those observed when rabbit joints are distended and fixed under increased interSemmars in Arthritis andRheumat/sm,

The thinness of the film suggests that synovial fluid plays another mechanical role in addition ___ From the Division of Rheumatology, Depariment of Medicine, UniversiQ of Washington, Seattle, WA. Peter A. Simkin, MD: Professor of Medicine. Supported in part by NIH grant AM3281 I. Address reprint requests to PeterA. Simkm, MD, Division of Rheumatology, Department of Medicine RG28, Unrversity of Washington, Seattle, WA 98195. Copyright 0 1991 by W.E. Saunders Cornpan) 0049-0172l9112103-0010$5.00l0

Vol21, No 3 (December), 1991: pp 179-183

179

PETER A. SIMKIN

Fig 1:

A normal interphalangeal

joint. The syno-

vial lining overlies all intraarticular

surfaces ex-

cept for the contact surfaces of atticular cartilage. Synovial recesses above and below the joint

facilitate

the expansion

and contraction

required by the normal range of articular motion. The small articular cavity normally occupied by synovial fluid is somewhat tion of this specimen.

exaggerated

(Reprinted

vised Clinical Slide Collection

by fixa-

from the Re-

In normal articulations the volume of free synovial fluid appears to be minimized by a continuing suction exerted through the interstitial matrix of the investing synovial lining. While it reduces volume this force also lowers the intraarticular pressure to the subatmospheric values routinely seen in normal knees.’ The mechanism driving this apparent suction remains uncertain. Most probably it reflects an osmotic effect exerted by the structured gel of the synovial matrix. It seems likely that the osmotic differential is, in turn, sustained by regular articular motion that pumps the valved draining vessels of both the venous and the lymphatic vascular systems. In effect, the synovial matrix acts as a sponge that is regularly “wrung out” by the moving joint. These systems prove inadequate or fail in inflamed tissues in which articular clearance cannot stay ahead of microvascular leakage, and the end results are synovial edema, joint stiffness, and pathological effusions.

on the Rheumatic

Diseases, copyright 1981. Used by permission of the American College of Rheumatology.)

to that of lubrication. Boundary-layer lubricants are well known to be effective adhesives as well.’ In a seeming paradox, such systems do not resist shearing forces but are highly resistant to distraction. It seems likely that the adhesive properties of synovial fluid play a role in maintaining close apposition both of synovium on cartilage and of cartilage on cartilage. In the latter role, the normal synovial fluid film may contribute significantly both to normal “tracking” as one cartilage slides across its mate and to joint stability. The property is readily demonstrated at the base of an extended index finger. Relaxed tendons and collateral ligaments permit ready deviation in any direction, but distraction is resisted by the synovial fluid bond. The rupture of this bond provides the best explanation for the familiar sound when people “crack their knuckles.” The bond is also lost in the presence of a significant synovial effusion. When effusions are chronic, the lack of normal adhesion can be expected to cause a “sloppy” joint with increased stress on adjacent ligaments and resultant articular instability.

PATHOPHYSIOLOGY

OF EFFUSIONS

Presumably, a small volume of synovial fluid, well mixed by continuing joint use, provides an optimal vehicle for the transport of oxygen, glucose, and other micronutrients from the blood in synovial microvessels to the chondrocytes of avascular articular cartilage. Conversely, the same path carries carbon dioxide, lactate, and other metabolic wastes from the tissues back to the blood stream. In normal joints, this system maintains healthy chondrocytes at remarkably great distances from their nurturing microvasculature. In rheumatoid arthritis, however, the system often fails badly. The protein content of synovial fluid increases toward that of plasma, and the small molecules give evidence of local ischemia manifested by low glucose, low PO,, low pH, high lactate, and high Pco,.~,~ Thus, an altered microvasculature appears to be more permeable to proteins but less effective in transporting smaller molecules. That, in fact, is exactly the case. Plasma proteins continuously escape through the microvascular endothelium and diffuse toward the joint space, from whence they are cleared by lymphatics. The synovial fluid concentration of total protein (or of any individual

181

PHYSIOLOGY OF NORMAL AND ABNORMAL SYNOVIUM

plasma protein) reflects both sides of this balance. Concentrations may increase in response to increased vascular permeability, decreased lymphatic clearance, or a combination of the two. In rheumatoid knee effusions the protein content is higher than in osteoarthritis, but not significantly so. On quantitative kinetic evaluation, however, the rheumatoid microvasculature is twice as permeable to protein as is that of osteoarthritis (Fig 2).“’ This very striking difference in vascular permeability is largely obscured by a corresponding increase in lymphatic drainage from the rheumatoid knee. The point is important for clinicians and scientists interested in evaluating synovial events by measuring the concentrations of individual proteins in synovial fluid. Local production and/or release of any protein can be evaluated only when concentrations are measured in concert with kinetics. The best available evidence indicates that rheumatoid synovial ischemia is real (Fig 3). Those knee effusions having, for instance, low glucose or low pH also have a plasma flow significantly lower than that of rheumatoid effu-

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20

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80

loo

1

40

60

Molecular Radius &I

Fig 2: proteins

Microvascular permeability to five marker in rheumatoid

(0)

and osteoarthritic

(0) knees. Synovial permeance (the decimal fraction of perfusing protein that escapes into the joint space during each microvascular passage) is more than twice as great in the rheumatoid joints over a wide range of molecular sizes. (Reprinted with permission.“‘)

0 0

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32 33 34 35 Synovlal fluid temperature

36 -+ (“C )

Fig 3: Iodide clearance, a measure of effective synovial blood flow, correlates highly with synovial fluid temperature sions. Together between

in rheumatoid

with comparable

perfusion

and synovial

knee effu-

relationships fluid lactate,

pH, and glucose, this finding strongly indicates that local ischemia

causes metabolic

mise in this disease.

(Reprinted

with

compropermis-

sion.“)

sions not showing such changes. Furthermore, and of particular interest to clinicians, the ischemic knees are also colder than their betterperfused counterparts.” This finding implies that temperature may not be a valid index of the severity of inflammation in joints involved by chronic rheumatoid arthritis. Most rheumatologists have seen many rheumatoid patients who suffered progressive destruction of the wrists although these joints were not warm to the touch. From what we know of rheumatoid knees, it seems reasonable to suspect that cool wrists with boggy swelling are significantly ischemic. At the University of Washington, Andrew Holman, Peter Dewire, John Bassett, and I are pursuing the hypothesis that rheumatoid ischemia may be exacerbated by therapy with nonsteroidal antiinflammatory drugs (NSAIDs). We suspect that many rheumatoid joints resemble marginal kidneys in that their baseline perfusion has become prostaglandin dependent. When such patients are treated with NSAIDs, inhibition of cyclooxygenase removes the prostaglandin prop, and the hitherto sufficient circulation collapses. When

182

PETER A. SIMKIN

this happens to the kidney, ensuing renal insufficiency makes recognition of the problem easy.” In the joint, however, the resultant decrease in temperature, and perhaps also in swelling and pain, are interpreted as a significant therapeutic achievement. Recent Swedish radiographic studies have established that the most ischemic knee joints suffer the greatest destruction.13 If such changes are potentiated by NSAIDs, we may have to reevaluate the role of this cornerstone of current therapy. INTRASYNOVIAL

PHARMACOKINETICS

A working knowledge of synovial physiology is useful in interpreting the pharmacokinetics of antirheumatic drugs. For most agents used by rheumatologists, data are available on drug concentrations in synovial fluid as well as in plasma or serum.14 With rare exceptions, this information was derived from serial observations in knee effusions of people with rheumatoid disease. Such studies are valuable for the insights they provide on drug availability in distended interstitial spaces. However, one must bear in mind that the rheumatoid knee is not representative of other connective tissues. Its relatively limited blood supply and large fluid volume necessarily imply that the intraarticular concentration will lag well behind changing plasma levels. This will be true during the absorptive phase, when plasma levels increase rapidly with gastrointestinal uptake. It will also be true during the later clearance phase, when tissue (and synovial fluid) levels normally exceed those in plasma. Such patterns can be expected, and have been observed, with virtually all antirheumatic agents. PHYSIOLOGICAL

DIFFERENCES AMONG

NORMAL JOINTS

In considering the structure and function of synovium, it is important to remember that all synovial joints need not be the same. In fact, existing evidence on hydrostatic pressure, oncotic pressure, and total protein concentration of synovial fluids reveals highly significant interarticular differences between, for instance, the wrists and knees of normal dogs (Fig 4).” The importance of such patterns lies in the fact that these findings imply corresponding differences

I

Knee

Fig 4:

I

I

Wrist

Shoulder

The oncotic pressure in canine “wrists”

is consistently

lower than that in “knee” (stifle)

and shoulder joints. Comparable wrist/ knee differences in hydrostatic pressure and in microvascular permeability

confirm a highly significant,

interarticular difference in microvascular physiology. Such physiological differences may be important determinants ity of individual

of resistance or susceptibil-

joints

to specific

rheumatic

diseases. (Reprinted with permission.‘“)

in microvascular physiology.‘6 It would not be surprising if their physiological characteristics made individual joints more, or less, susceptible to specific rheumatic diseases. Every clinician recognizes that each pathological entity tends to affect some joints and spare others. These patterns do not happen by chance, and they cannot result from systemic factors that should involve all joints alike. Further study of normal articular physiology may ultimately provide logical explanations for the fact that rheumatoid arthritis regularly attacks metacarpophalangeal joints and spares the distal interphalangeals, while interphalangeal osteoarthritis exactly reverses this pattern.

PHYSIOLOGY

OF NORMAL AND ABNORMAL

183

SYNOVIUM

CONCLUSIONS Although swollen joints are the rheumatologist’s “stock in trade,” no one really knows why an inflamed joint swells. Recent years have brought a rich harvest of information about the cells involved and about their potential responses to a host of demonstrated mediators. In

the final analysis, some (or all) of these factors interact with each other and with synovial microvessels to produce swelling, redness. and sometimes heat. A further focus on this vascular bed and its response to disease and to therapy seems likely to produce progress in practice as well as in theory.

REFERENCES I. Ghadially FN: Fine structure of joints, in: Solokoff L, ed: The Joints and Synovial Fluid, vol 1. San Diego, CA, Academic, 197X 2. Henderson B. Edwards JCW: The synovial lining in health and disease. London. England, Chapman and Hall, 1987 3. Levick JR, McDonald JN: Synovial capillary distribution in relation to altered pressure and permeability in knees of anaesthetized rabbits. J Physiol 419:477-492, 1989 4. Swann DA. Radin EL, Nazimiec M, et al: Role of hyaluronic acid in joint lubrication. Ann Rheum Dis 33:318326. 1074 5. Swann DA, Silver FH, Slayter HS, et al: The molecular structure and lubricating activity of lubricin isolated from bovine and human synovial fluids. Biochem J 225:195-201, 19x.5 6. Salomon G: The adhesion of liquids to solids, in Houwink S, ed: Adhesion and Adhesives, vol 1. New York, NY. Elsevier, 1965, pp 25-51 7. Levick JR: Joint pressure-volume studies: Their importance. design and interpretation. J Rheumatol 10:353-357, 1983 X. Levick JR: Hypoxia and acidosis in chronic infammatory arthritis: Relation to vascular supply and dynamic effusion pressure. J Rheumatol 17:576-580, 1990 0. Stevens CR, Williams RB, Farrell AJ, et al: Hypoxia

and inflammatory synovitis: Ann Rheum Dis 50:124-132.

Observations 1991

and speculation.

IO. Wallis WJ, Simkin PA, Nelp WB: Protein traffic in human synovial effusions. Arthritis Rheum 3057-63, lY87 Il. Wallis WJ, Simkin PA, Nelp WB: Low synovial clearance of iodide provides evidence of hypoperfusion in chronic rheumatoid synovitis. Arthritis Rheum 28:lOY61104,1985 12. Clive DM, Stoff JF: Renal syndrome associated with non-steroidal anti-inflammatory drugs. N Engl J Med 310: 563-572, 1984 13. Cieborek P, Saxne T, Pettersson H, et al: Synovial fluid acidosis correlates with radiological joint destruction in rheumatoid arthritis knee joints. J Rheumatol 16:468472, 1989 14. Netter P, Bannwarth B, Royer-Morrot M-J: Recent findings on the pharmacokinetics of non-steroidal antiinflammatory drugs in synovial fluid. Clin Pharmacokinet 17:145-162. 1989 IS. Simkin PA, Benedict RS: Hydrostatic and oncotic determinants of microvascular fluid balance in normal canine joints. Arthritis Rheum 33:80-86, 1990 16. Simkin PA, Benedict RS: Iodide and albumin kinetics in normal canine wrists and knees. Arthritis Rheum 33:73-70. 1990

Physiology of normal and abnormal synovium.

Because the synovial lining is a major target organ of rheumatic diseases, it seems logical to seek understanding of those conditions through study of...
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