-
STRUCTURE
The synovium is a membranous structure that extends from the
margins of articular cartilage and lines the capsule of
diarthrodial joints, including the temporomandibular joint1 and the
facet joints of vertebral bodies (Fig. 21).2 The healthy synovium
covers intraarticular tendons and ligaments, and fat pads, but not
articular cartilage or meniscal tissue. Synovium also ensheathes
tendons where they pass beneath ligamentous bands. Normally, the
synovial membrane has two componentsthe intima, or lining cells,
and the subintima, otherwise referred to as the sublining or
supportive layer. The intima represents the interface between the
cavity containing synovial fluid and the subintimal layer. There is
no wellformed basement membrane to separate the intima from the
subintima. The subintima is composed of fibrovascular connective
tissue and merges with the densely collagenous fibrous joint
capsule.
SYNOVIAL LINING CELLS
The synovial intimal layer is composed of synovial lining cells
(SLCs), which have an epitheliallike arrangement on the luminal
aspect of the joint cavity. SLCs, termed synoviocytes, are one to
three cells deep, depending on the anatomic location, and they
extend 20 to 40 m beneath the lining layer surface. The major and
minor axes of SLCs measure 8 to 12 m (major axis) and 6 to 8 m
(minor axis). SLCs have poorly defined cell borders and elliptical
nuclei with generally a single small nucleolus.3
Ultrastructure of Synovial Lining Cells
Transmission electron microscopic analysis shows that the
intimal cells form a discontinuous layer, something not appreciated
under transmission light microscopy, so that the subintimal matrix
is in direct contact with the synovial fluid (Fig. 22). The
existence of two distinct cell types, type A and type B
SLCs, originally was described by Barland and associates,4 and
several lines of evidence, including animal models, detailed
ultrastructural studies, and immunohistochemical analysis, indicate
that these cells represent macrophages (type A SLCs) and
fibroblasts (type B SLCs). Studies of the SLC populations in a
variety of species, including humans, have found that macrophages
make up approximately 20% and fibroblastlike cells approximately
80% of the lining cell.5,6 The existence of the two cell types has
been substantiated by similar findings in a wide variety of
species, including hamsters, cats, dogs, guinea pigs, rabbits,
mice, rats, and horses.614
Distinguishing the different cell populations that form the
synovial lining is impossible by hematoxylin and eosin staining
under transmission light microscopy. At an ultrastructural level,
the type A cells are characterized by a conspicuous Golgi
apparatus, large vacuoles, and small vesicles, and contain little
rough endoplasmic reticulum, giving them a macrophagelike phenotype
(Fig. 23A and B). The plasma membrane of type A cells possesses
numerous fine extensions, termed filopodia, which are
characteristic of macrophages. These cells are located for the most
part on the lining surface, where it is more than one cell thick.
Type A cells cluster at the tips of the synovial villi, and this
uneven distribution at least partly explains early reports that
suggested type A cells were the predominant intimal cell
type.4,8
Type B SLCs have prominent cytoplasmic extensions that extend
onto the surface of the synovial lining (Fig. 23C and D).15
Frequent invaginations are seen along the plasma membrane, and a
large indented nucleus relative to the area of the surrounding
cytoplasm is also a feature. Type B cells have abundant rough
endoplasmic reticulum widely distributed in the cytoplasm, and the
Golgi apparatus, vacuoles, and vesicles are generally
inconspicuous, although some cells have small numbers of prominent
vacuoles at their apical aspect. Type B SLCs also are known to
contain longitudinal bundles of differentsized filaments,
supporting their classification as fibroblasts. Desmosomes and
gaplike junctions have been described in rat, mouse, and rabbit
synovium, but the existence of these structures has never been
documented in human SLCs.
Cells exhibiting the ultrastructure of type A and type B SLCs
have been classified as intermediate, or type AB. The existence of
intermediate cells has been refuted on the basis of detailed
electron microscopic studies, and it is now accepted that a
proportion of type B cells have conspicuous vacuoles, and that
rough endoplasmic reticulum appears in activated macrophages.16,17
The putative existence of an intermediate SLC implies that type A
and type B SLCs are part of the same cell lineage. This concept is
contrary to all current evidence, which finds that type A and type
B SLCs are histogenetically and functionally distinct.
2 SynoviumBARRY BRESNIHAN ADRIENNE M. FLANAGAN
KEY POINTS
The synovium provides nutrients to cartilage and produces
lubricants for the joint.
The intimal lining of the synovium introduces macrophage-like
and fibroblast-like synoviocytes.
The sublining contains scattered immune cells, fibroblasts,
blood vessels, and fat cells.
Fibroblast-like synoviocytes in the intimal lining express
specialized proteins that synthesize proteoglycans such as
hyaluronic acid.23
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24 bresnihan | synovium
mImmunohistochemical Profile of Synovial Intimal Cells
Synovial Intimal Macrophages. Synovial macrophages and
fibroblasts express lineagespecific molecules, which can be
detected by immunohistochemistry. Synovial macrophages express
common hematopoietic antigen CD45 (Fig. 24A); monocyte/macrophage
receptors CD163 and CD97; and lysosomal enzymes CD68 (Fig. 24B),
neuronspecific esterase, and cathepsin B, L, and D. Cells
expressing CD14, a molecule that acts as a coreceptor for the
detection of bacterial lipopolysaccharide, and expressed by
circulating monocytes and monocytes newly recruited to tissue, are
rarely seen in the healthy intimal layer, but small numbers are
found close to venules in the subintima.1824
The Fc receptor, FcRIII (CD16), expressed by Kupffer cells of
the liver and type II alveolar macrophages of the lung, also is
expressed on a subpopulation of synovial macrophages.2527 The
synovial macrophage population also expresses the major
histocompatibility complex (MHC) class II molecule which plays an
important role in the immune response. More recently, the
macrophages, which are responsible for the removal of debris,
blood, and particulate material from the joint cavity and possess
antigen processing properties, have been found to express a new
complementrelated protein, Z39Ig, a cell surface receptor and
immunoglobulin superfamily member, which is involved in the
induction of HLADR, and implicated in the regulation of
phagocytosis and antigenmediated immune responses.2830
The expression of the 2 integrin chains, CD18, CD11a, CD11b, and
CD11c, varies; CD11a and CD11c may be absent, or weakly expressed,
on a few lining cells.31,32 Osteoclasts, which are
tartrateresistant, acid phosphatasepositive, and express the v3
vitronectin and calcitonin receptors, do not appear in the normal
synovium.
Synovial Intimal Fibroblasts. Synovial intimal and subintimal
fibroblasts are indistinguishable by light microscopy.
of cell lineage, but because of their different
microenvironments, they do not always share the same phenotype.
They possess prominent synthetic capacity and produce the essential
joint lubricants hyaluronic acid (HA) and lubricin.33 Intimal
fibroblasts express uridine diphosphoglucose dehydrogenase (UDPGD),
an enzyme involved in HA synthesis, which is recognized as a
specific marker for this cell type. UDPGD converts UDPglucose to
UDPglucuronate, one of the two substrates required by HA synthase
for assembly of the HA polymer.34 CD44 expression, the nonintegrin
receptor for HA, is expressed by all SLCs.32,35,36
Synovial fibroblasts also synthesize normal matrix components,
including fibronectin, laminin, collagens, proteoglycans, lubricin,
and other identified and unidentified proteins. They also have the
capacity to produce large amounts of metalloproteinases,
metalloproteinase inhibitors, prostaglandins, and cytokines. This
capacity must provide essential biologic advantages, but the
complex physiologic mechanisms relevant to normal function are
incompletely delineated. The expression of selected adhesion
molecules on synovial fibroblasts probably facilitates the
trafficking of some cell populations, such as neutrophils, into the
synovial fluid, and the retention of others, such as mononuclear
leukocytes, in the synovial tissue. Metalloproteinases, cytokines,
adhesion molecules, and other cell surface molecules are strikingly
upregulated in inflammatory states.
Specialized intimal fibroblasts also express many other
molecules that are not expressed by the intimal macrophage
population, including decayaccelerating factor (CD55), previously
identified by the antibody Mab67; vascular cell adhesion molecule
1; intracellular adhesion molecule33,3740; and cadherin 11.41,42
PGP.95, a neuronal marker, is reported as being specific for type B
synoviocytes in horses.43 Decayaccelerating factor, also expressed
on the cells of other body cavities and cells in bone marrow,
interacts with CD97, a glycoprotein that is present on the surface
of most activated leukocytes, including intimal macrophages, and is
thought to be involved in the signaling processes early after
leukocyte activation.44,45 In contrast, FcRIII is expressed only by
macrophages when they are in close contact with decayaccelerating
factorpositive fibroblasts, or decayaccelerating factorcoated
fibrillin1 microfibrils in the extracellular matrix.26
Cadherins are a class of tissuerestricted transmem
500 m
Figure 2-1 The cartilage-synovium junction. hyaline articular
carti-lageoccupiesthelefthalfofthisimage,andfibrouscapsuleandsyno-vialmembraneoccupytherighthalf.asparse
intimal lining
layerwithafibroussubintimacanbeobservedextendingfromthemarginofthecartilageacross
thecapsular surface toassumeamorecellular
intimalorphologywithareolarsubintima.
2 Microns
Figure 2-2
Transmissionelectronphotomicrographofsynovialintimalcells.Thecellontheleftexhibitsthedendriticappearanceofasynovialintimalfibroblast
(typebcell).otheroverlyingfibroblastdendritescanbeobserved.Thepresenceofintercellulargapsallowsthesynovialfluidtobeindirectcontactwiththesynovialmatrix.They
are generally considered to be closely related in terms brane
proteins that play important roles in homophilic
-
25ParT1 |
sTruCTureanDFunCTionoFbone,JoinTs,anDConneCTiveTissueintercellular
adhesion and are involved in maintaining the integrity of tissue
architecture. Cadherin 11, which was cloned from rheumatoid
arthritis synovial tissue, also is expressed in normal synovial
intimal fibroblasts, but not in intimal macrophages. The finding
that fibroblasts transfected with cadherin 11 are induced to form a
lininglike structure in vitro implicates this molecule in the
architectural organization of the synovial lining.41,42,46 This
suggestion is supported by the observation that cadherindeficient
mice have a hypoplastic synovial lining and are resistant to
1 and 3 integrins are present on all SLCs, forming receptors for
laminin (CD49f and CD49b), collagen types I and IV (CD49b),
vitronectin (CD51), and fibronectin (CD49d and CD49e). In contrast,
the integrin collagen receptors, CD49a, CD54 (a member of the
immunoglobulin superfamily), and CD4 and CD62 (selectin) present on
lymphocytes, and involved in their homing to high endothelial
venules, are not observed on these cells. CD31 (plateletendothelial
cell adhesion molecule), a member of the immunoglobulin superfamily
that is expressed on endothelial cells, platelets,
500 nmA
100 nmB
500 nmC
500 nmD
Figure 2-3
Transmissionelectronphotomicrographsofsynovialintimalmacrophages(typeacells)andfibroblasts(typebcells).A,Low-poweredmagnificationshowingthesurfacefinefilopodia,characteristicofmacrophages,andasmooth-surfacednucleus.B,Theboxed
areainAisshownatahighermagnificationandrevealsnumerousvesiclescharacteristicofmacrophages.Theabsenceofroughendoplasmicreticulumalsoisnoted.C,Theconvolutednucleusalongwiththeprominentroughendoplasmicreticulum(boxed
area)ischaracteristicofasynovialintimalfibroblast(typebcell).D,Theroughendoplasmicreticulumisshownatgreatermagnification.inflammatory
arthritis.47 and monocytes, is only weakly expressed on SLCs.32
-
26 bresnihan | synoviumTurnover of Synovial Lining Cells
Proliferation of SLCs in humans is low, as shown when normal
human synovial explants, exposed to a pulse of 3H thymidine,
resulted in the SLCs having a labeling index of approximately 0.05%
to 0.3%48; this bears a striking contrast with labeling indices of
approximately 50% for bowel crypt epithelium. Similar evidence of
low proliferation has been found in the synovium of rats and
rabbits. The advent of immunohistochemistry saw this observation
substantiated when Revell and others reported that the proportion
of SLCs expressing the proliferation marker Ki67 was between 1 in
2800 and 1 in 30,000.49 It was subsequently shown that the type B
SLCs, the synovial fibroblasts, proliferated in situ,22,50 a
finding consistent with the concept that type A synovial cells are
macrophages. Mitotic activity of SLCs also is low in inflammatory
conditions, such as rheumatoid arthritis, a condition associated
with SLC hyperplasia. Coulton and coworkers51 reported a few
mitotic figures in only 1 of 600 cases of rheumatoid arthritis
synovium samples analyzed.
Apart from the knowledge that synovial fibroblasts proliferate
slowly, little is known about their natural life span, recruitment,
or mode of death. Apoptosis likely is involved in maintaining
synovial homeostasis, but there is little in the literature on this
subject. The dearth of information is likely to be explained by the
lack of normal synovium available for analysis, in addition to the
difficulty encountered when quantifying this process on
histological sections owing to the rapid clearance of apoptotic
bodies.52
Origin of Synovial Lining Cells
There is little doubt that the type A SLC population identified
by Barland and associates4 is bone marrow derived and represents
cells of the mononuclear phagocyte system. The studies conducted by
Edwards53,54 proved informative when they exploited the Beige (bg)
mouse, which harbors a homozygous mutation that confers the
presence of giant lysosomes in macrophages. It was shown that
normal mice,
with bone marrow cells obtained from the bg mouse. Electron
microscopic analysis of the synovium from the recipient animals
revealed that type A SLCs contained the giant lysosomes of the
donor bg mouse, and that these structures were never identified in
type B cells. These findings provided powerful evidence that the
type A SLCs represent macrophages, that they are recruited from the
bone marrow, and that they were unrelated histogenetically to type
B SLCs.
In addition to immunohistochemistry, several other lines of
evidence have added weight to the concept that type A SLCs are
recruited from the bone marrow: (1) The op/op mouse, a
spontaneously occurring mutant that fails to produce macrophage
colonystimulating factor because of a missense mutation in the
csf-1 gene,5557 has low numbers of circulating and resident
macrophage colonystimulating factordependent macrophages, including
those in the synovium. (2) Type A cells in rat synovium do not
occur until after the development of synovial blood vessels.22 (3)
Others have reported that type A SLCs were conspicuous around
vessels in the synovium in neonatal mice.6 (4) When synovial
explants are placed in culture, the reduction in the type A SLCs is
partially explained by their migration into the culture medium, an
observation that reflects the process of migration of macrophages
into the synovial fluid in vivo.1,58 (5) Macrophages are found
around venules in disease states and constitute 80% of the intimal
cells in inflammatory conditions, such as rheumatoid arthritis.
Type B intimal cells represent a resident fibroblast population
in the synovial lining, but little is known about the cells from
which they derive, and how their recruitment is regulated. The
existence of a mesenchymal stem cell in the synovium is a prime
candidate for the origin of the synovial lining fibroblast, but
this has not been substantiated. To date, a transcription factor
directing mesenchymal stem cell differentiation into synovial
fibroblast, similar to the factors required for commitment by this
multipotential population into bone (cbfa-1), cartilage (Sox 9),
and fat (peroxisome proliferatoractivated receptor [PPAR]), has not
been
20 m20 m
20 mA B
Figure 2-4
Transmittedlightphotomicrographsdepictingsynovialintimalmacrophagesbyimmunohistochemistry.AandB,macrophagesaredeco-ratedwithCD45(arrow
in
A)andCD68(B),markersthatidentifyhematopoieticcells(CD45)andmacrophages(CD68).bone
marrow depleted through irradiation, were rescued identified.
-
27ParT1 |
sTruCTureanDFunCTionoFbone,JoinTs,anDConneCTiveTissueSUBINTIMAL
LAYER
SLCs are not separated from the underlying subintima by a
wellformed basement membrane composed of the typical trilaminar
structure that is seen beneath epithelial mucosa elsewhere.
Nevertheless, most components of basement membrane are present in
the extracellular matrix surrounding SLCs. These components include
tenascin X, perlecan (a heparin sulfate proteoglycan), collagen
type 4, laminin, and fibrillin1.59,60 Of note is the absence of
laminin5 and integrin 332, which are components of epithelial
hemidesmosomes.61
The subintima is composed of loose connective tissue of variable
thickness and variable proportions of fibrous/collagenous and
adipose tissue depending on the anatomic site. Under normal healthy
conditions, inflammatory cells are virtually absent from the
subintima apart from a sprinkling of macrophages. A few mast cells
also are present.62 Human synovial tissue also is a rich source of
mesenchymal stem cells, and although it is unknown which
compartment contains this cell population, some cells have the
ability to selfrenew, and differentiate into bone, cartilage, and
fat in vitro, a phenomenon that reflects its ability to regenerate
in vivo.6365
There are three welldefined categories of subintimathe areolar,
fibrous, and fatty/adipose types. Under the light microscope,
areolartype subintima, the most commonly studied, is generally
found in larger joints where there is free movement (Fig. 25A). It
is composed of fronds with a cellular intimal lining and loose
connective tissue in the subintima, with little in the way of dense
collagen fibers, and a rich vasculature. The fibrous subintima is
composed of scant dense fibrous, poorly vascularized connective
tissue and has an attenuated layer of SLCs (Fig. 25B). The adipose
type contains abundant mature fat cells and has a single layer of
SLCs. This is seen more commonly with aging and in intraarticular
fat pads (Fig. 25C).
The subintima contains collagen types I, III, V, and VI;
glycosaminoglycans; proteoglycans; and extracellular matrices
including tenascin and laminins. Integrin receptors for collagens,
laminin, and vitronectin are absent or at best weakly expressed by
the subintimal cells. In contrast, receptors for fibronectin (CD49d
and CD49e) are detected, and CD44, the HA receptor, is strongly
expressed in most subintimal cells. 2 integrins are largely limited
to perivascular areas, particularly in the subintimal zone, as is
CD54.66
50 m50 m 100 m100 m
100 m
A B
CFigure 2-5
Transmittedlightphotomicrographsofdifferentmorphologictypesofsynovialtissue.allphotomicrographsshowanintimallayerofonetotwocellsindepth.A,Theareolarsynoviumiscomposedofvillousfronds.beneaththeintimallininglayer,thereiscellularloosefibrovascularfattysubintima.B,Thefibroussynoviumcomprisesdensecollagenousmaterialinthesubintimallayer.C,Thesubintimallayerofthefattysynovialtissueis
composedoflesscellularmatureadiposetissuewithlittlecollagendeposition.
-
28 bresnihan | synovium
Subintimal Vasculature
The vascular supply to the synovium is provided by many small
vessels and is partly shared by the joint capsule, epiphyseal bone,
and other perisynovial structures. Arteriovenous anastomoses
communicate freely with the vascular supply to periosteum and to
periarticular bone. As large synovial arteries enter the deep
layers of the synovium near the capsule, they branch, and branch
again to form microvascular units in the more superficial
subsynovial layers. Precapillary arterioles probably play a major
role in controlling circulation to the lining layer. The surface
area of the synovial capillary bed is large, and because it runs
only a few cell layers deep to the surface, it has a role in
transsynovial exchange of molecules.
Numerous physical factors influence synovial blood flow. Heat
increases blood flow through synovial capillaries. Exercise also
increases synovial blood flow to normal joints, but may reduce the
clearance rate of small molecules from the joint space. Experiments
have shown a substantial vascular reserve capacity in normal
articulations. Immobilization reduces synovial blood flow, and the
pressure on synovial membrane from joint effusions can act to
tamponade synovial blood supply.
The vascular endothelial lining cells express CD34 and CD31
(Fig. 26A). They also express receptors for the major components of
basement membrane, including laminin and collagen IV, and the
integrin receptors CD49a (laminin and collagen receptors), CD49d
(fibronectin receptor), CD41, CD51 (vitronectin receptor), and
CD61, the 3 integrin subunit. Endothelial cells also express CD44,
the HA receptor, and CD62, Pselectin, which acts as a receptor that
supports binding of leukocytes to activated platelets and
endothelium. They are only weakly positive, however, for expression
of CD54, intercellular adhesion molecule1, an integral membrane
protein of the immunoglobulin superfamily. The endothelial cells of
capillaries in the superficial zone of the subintima are strongly
positive for HLADR expression by immunohistochemistry, whereas
cells in the larger vessels in the deep aspect of the membrane are
negative.32,34
Subintimal Lymphatics
Detailed analysis of the number and distribution of lymphatic
vessels has been made possible with the use of the antibody to the
lymphatic vessel endothelial HA receptor (LYVE1) (Fig. 26B).67 This
antibody is highly specific for lymphatic endothelial cells in
lymphatic vessels and lymph node sinuses and does not react with
endothelial cells of capillaries and other blood vessels that
express CD34 and factor VIIIrelated antigen. The expression of
LYVE1 in lymphatic endothelial cells has been used as a marker to
show that lymphatic vessels are less common in the fibrous synovium
compared with the areolar and adipose variants of human subsynovial
tissue. Detection of this molecule also reveals that lymphatics are
present in the superficial, intermediate, and deeper layers of
synovial membrane from normal, osteoarthritic, and rheumatoid
arthritic joints, although the number in the superficial subintimal
layer is low in normal synovium. Little difference in the
distribution and number is noted between normal and
osteoarthritic
channels are plentiful, however, in the subintimal layer in the
presence of villous edema hypertrophy and chronic inflammation.
Subintimal Nerve Supply
The synovium has a rich network of sympathetic and sensory
nerves. The former, which are myelinated and detected with the
antibody against S100 protein, terminate close to blood vessels,
where they regulate vascular tone (Fig. 26C, D, and E). The sensory
nerves respond to proprioception and pain via large myelinated
nerve fibers, and small (
-
29ParT1 |
sTruCTureanDFunCTionoFbone,JoinTs,anDConneCTiveTissueNonadherence
The second important characteristic of the synovium that
facilitates joint movement is its nonadherence to opposing
surfaces. The intimal cells on the synovial surface adhere to
synovial and cartilage surfaces. The mechanism that preserves
this phenomenon of nonadherence is unknown and may involve the
arrangement of cell surface and tissue matrix molecules, such as
collagen, fibronectin, and HA. Alternatively, nonadherence may
result partially from the
100 m100 m
500 m500 m
200 m
50 m50 m
A B
C D
E
Figure 2-6 Transmission lightphotomicrographsofsynoviumshowing
lymphovascularandnervousstructuresby immunohistochemistry.AandB,
areolar synovium featuring thin-walled vessels are highlightedwith
antibody toCD31 (A), and lymphatic vessels in an inflamed
synoviumarehighlightedwithantibodytoLyve-1(B).C,Deepinthesynovialsubintimaclosetothejointcapsule,therearemedium-sizedneurovascularbundleswiththenerveshighlightedbyantibodytos100.D,Withinthemoresuperficialsynovium,smallnervesdecoratedwiths100alsoareidentified.E,Theboxed
areainDisshownathighermagnification;upper arrowisnerve;lower
arrowisdirectedatasmallvessel.underlying cells and matrix, but do
not adhere to opposing regular movements of the normal synovial
lining.
-
30 bresnihan | synoviumLubrication
The third characteristic of synovium that is essential for joint
motion is an efficient lubrication mechanism to facilitate
cartilage movement on cartilage. The mechanisms of joint
lubrication are complex and are an integral component of synovial
physiology. In an articulating joint, cartilage is subjected to
numerous compressive and frictional forces every day. Friction and
wear can never be eliminated from a functioning joint. Adult
chondrocytes do not normally divide in vivo, and damaged cartilage
has limited capacity for selfrepair. For a joint to maintain its
function throughout a lifetime of use, there must be protective
biologic mechanisms, such as lubrication, which help minimize the
wear and damage that result from normal daily activities.
Boundary lubrication refers to the protective effect of
particular lubricating molecules adsorbing to a surface and
repelling its opposing interface.73 Bearing surfaces must generate
a mutual repulsion to be lubricated in the boundary mode. Boundary
lubricants exert their effects by changing the physicochemical
characteristics of a surface and reduce articular friction and wear
by providing a smooth and slippery coating. Friction is reduced by
an interposed film of protective fluid that allows one surface to
ride freely over another. The cartilage matrix is integral to this
phenomenon because it is fluidfilled and compressible. Loaded
cartilage extrudes lubricant fluid from its surface, and the
expressed fluid contributes to the separation of the two
articulating surfaces. Scanning electron microscopy has shown a
continuous film of fluid, only 100 nm thick, which separates one
surface from the other, preventing direct abrasive contact.74 This
ultrathin coating of lubricant also resists distraction of the two
articulating surfaces, enhancing joint stability. Another essential
advantage of an intraarticular lubrication system is the effective
prevention of pinching of adjacent, wellvascularized synovial
membrane.
Hyaluronic Acid
HA, a highmolecularweight polysaccharide, is a major component
of synovial fluid and cartilage.75 It is produced in large amounts
by mechanosensitive, fibroblastlike synoviocytes.76,77 HA, of which
there are three mammalian forms designated HAS1, HAS2, and HAS3,78
is synthesized by HA synthase at the plasma membrane and extruded
directly into the extracellular compartment. HA synthase activity
and HA secretion are stimulated by proinflammatory cytokines,
including interleukin1 and transforming growth factor.76,79,80 HA
also is synthesized by many other skeletal cells and is an
important component of extracellular matrices. It is simultaneously
a solid phase matrix element of cartilage and other tissues, and a
fluid phase element in the synovial space under normal and abnormal
conditions.
HA has many biologic functions, which include effects on cell
growth, migration, and adhesion.72 The regulatory role of HA is
mediated through HAbinding proteins and receptors, including CD44,
which are present on the cell surfaces of chondrocytes,
lymphocytes, and other mononuclear cell populations. HA plays a
crucial role in morphogenesis and in wound healing. Additionally,
HA is a vital structural component of the synovial lining, and it
has an essential role in the induction of joint cavitation during
embryogene
primarily a joint lubricant, and it is generally accepted that
it plays a major physiologic role in maintaining synovial fluid
viscosity. It is important in normal joint function, not least
through its capacity to provide effective shock absorption. It has
been suggested that HA is a particularly important
viscohydrodynamic lubricant at lowload interfaces, such as
synoviumonsynovium and synoviumoncartilage.81 Synovial fluid HA,
acting in combination with albumin, also has a role in the
attenuation of fluid loss from the joint cavity, particularly
during periods of increased pressure, which can occur during
sustained joint flexion.8284
Lubricin. Compelling evidence suggests that lubricin, first
described in the 1970s,85 is the factor primarily responsible for
boundary lubrication of diarthrodial joints.86 Lubricin, a large
secreted, mucinlike proteoglycan with an apparent molecular weight
of 280 kD, is a product of the gene proteoglycan 4 (PRG4). It is a
major component of synovial fluid and is present at the cartilage
surface. The gene is highly expressed by human synovial fibroblasts
and by superficial zone chondrocytes.87 Lubricin is closely related
to superficial zone protein, megakaryocytestimulating factor, and
hemangiopoietin. Superficial zone protein is expressed by SLCs and
by the superficial zone chondrocytes at the cartilage surface, but
not by intermediate or deep zone chondrocytes.88 It has been
suggested that lubricin may bind to the much longer hyaluronate
polymers, distributing shear stress and stabilizing essential
lubricant molecules.89
In an experimental model, lubricin seemed to have multiple
functions in articulating joints and tendons that included the
protection of cartilage surfaces from protein deposition and cell
adhesion and the inhibition of synovial cell overgrowth.90 Prg4/
mice, consistently normal at birth, showed progressive loss of
superficial zone chondrocytes and increasing synovial cell
hyperplasia (Fig. 27). The essential role of lubricin in
maintaining joint integrity was shown by the identification of
diseasecausing mutations in patients with the autosomal recessive
disorder camptodactylyarthropathycoxa varapericarditis (CACP)
syndrome.91 CACP is a large joint arthropathy associated with the
absence of lubricin from synovial fluid and ineffective boundary
lubrication provided by the synovial fluid (Fig. 28).89,92 In other
studies of lubricin biology and joint integrity, experimental
injury resulted in reduced synovial fluid lubricin concentrations,
decreased boundarylubricating ability, and increased cartilage
matrix degradation, each of which could be attributed to
traumainduced inflammatory processes.87
Others have argued against the primacy of lubricin in joint
lubrication by proposing that surfaceactive phospholipid, also
secreted by intimal fibroblasts, is the essential boundary
lubricant that reduces cartilage friction to remarkably low
levels.93 It was hypothesized that lubricin acts as the carrier of
surfaceactive phospholipid to articular cartilage, but is not the
lubricant per se, a function that is similar to the
wellcharacterized alveolar surfactant binding proteins in the
lung.
FORMATION OF SYNOVIAL FLUID
In health, a constant volume of synovial fluid is important
during joint movement as a cushion for synovial tissue and sis. HA,
produced by synovium, was originally thought to be as a reservoir
of lubricant for cartilage. Many of the soluble
-
31ParT1 |
sTruCTureanDFunCTionoFbone,JoinTs,anDConneCTiveTissuecomponents and
proteins in synovial fluid exit the synovial microcirculation
through pores or fenestrations in the vascular endothelium, then
diffuse through the interstitium before entering the joint space.
Synovial fluid is partially a filtrate of plasma to which
additional components, including HA and lubricin, are added and
removed by the SLCs (Fig. 29).72 The concentrations of electrolytes
and small molecules in synovial fluid are equivalent to those in
plasma. Synovial permeability to most small molecules is determined
by a process of free diffusion through the double barrier of
endothelium and interstitium, limited mainly by the intercellular
space between the SLCs. For most small molecules, synovial
permeability is inversely related to the dimensions of the
molecule.
Experimental evidence suggests that the exchange of small
solutes is determined predominantly by the synovial interstitium,
and that permeability to proteins is mainly determined by the
microvascular endothelium. The synovium should not be regarded as
simply an inert membrane, but as a complex regulatory tissue
system. The small physiologic molecules that traverse the
endothelium of synovial blood vessels and diffuse through the
intercellular spaces of the synovial lining before entering the
synovial fluid include water, glucose, and many other essential
nutrients and waste tissue metabolites. Evidence suggests that the
passage of some solutes across the synovium is facilitated by
specific transport systems providing, possibly, a pump
mechanism
All plasma proteins are capable of crossing the endothelium,
traversing the synovial interstitium, and entering the synovial
fluid. The efficiency of this process is determined by the
molecular size of the protein and the diameter of the endothelial
pores. Smaller proteins, such as albumin, enter easily, whereas
larger molecules, such as fibrinogen, gain access with greater
difficulty. In contrast, the clearance or removal of proteins and
other synovial fluid constituents is unrestricted, and considerably
more efficient, through lymphatic drainage. The synovial fluid
concentration of any protein reflects the dynamic balance between
ingress and egress at a given time. Because egress is more
efficient than ingress, joint space pressure is normally
subatmospheric. The negative intraarticular pressure also is
thought to be important in maintaining joint stability. The
synovial fluidtoserum ratio of plasma proteins is inversely related
to the molecular size of the protein. When the joint becomes
inflamed, greater endothelial permeability permits more profuse
ingress of all proteins, and the most obvious changes are in the
concentrations of larger molecules. Increased synovial fluid volume
also reduces the stability of the joint.
In contrast to hydrophilic molecules, fatsoluble molecules can
diffuse through and between cell membranes, and their passage
across the synovial surface is less restricted. The entire surface
area of the synovium is available to lipophilic molecules that
diffuse in and out of the joint space.
A
t
tah
s
c
f
f
p
t
fib
+/+
+/+
+/+/
/
/
+/+ /
B
C D G H
E F
Figure 2-7
ClinicalappearanceandradiographicchangesinPrg4/mice.AandB,Photographsofthehindpawsof6-month-oldPrg4/(A)andwild-type(B)mice.notethecurveddigitsinthemutantmouseandtheswellingattheanklejoint.CandD,radiographsoftheanklejointof9-month-oldwild-type(C)andPrg4/mice(D).Thestructurescorrespondingtothetibia(t)andtalus(ta)areindicated.notethecalcificationofstructuresadjacenttotheankle(arrows
inD).E,Lateralkneex-rayofa4-month-oldwild-typemouse.Thestructurescorrespondingtothepatella(p),femoralcondyle(f),tibialplateau(t),andfibula(fib)areindicated.F,Lateralkneex-rayofa4-month-oldPrg4/mouse.notetheincreasedjointspacebetweenthepatellaandfemur(arrow),andosteopeniaofthepatella,femoralcondyles,andtibialplateau.G,shoulderx-rayofa4-month-oldwild-typemouse.Thestructurescorrespondingtothehumeralhead(h),glenoidfossaofthescapula(s),andlateralportionoftheclavicle(c)areindicated.H,shoulderx-rayofa4-month-oldPrg4/mouse.notetheincreasedjointspacebetweenthehumerusandscapula(arrow),andtheosteopeniaofthehumeralhead.(From
Rhee DK, Marcelino J, Baker M, et al: The secreted glycoprotein
lubricin protects cartilage surfaces and inhibits synovial cell
overgrowth. J Clin Invest 115: 622-631, 2005.)capable of moving
water out of the joint space. Physiologically, the most important
fatsoluble molecules
-
32 bresnihan | synoviumare the respiratory gasesoxygen and
carbon dioxide. When the joint is inflamed, synovial fluid may
exhibit low partial pressure of oxygen, high partial pressure of
carbon dioxide,
hypoxia and acidosis can have serious implications for the
synovial microcirculation and chondrocyte metabolism.
NUTRITION OF CHONDROCYTES
Another important function of synovium is to facilitate the
nutrition of chondrocytes, which are resident in articular
cartilage (see Chapter 3). Because articular cartilage is
avascular, the delivery of nutrients to chondrocytes and the
removal of metabolic breakdown products from the cartilage are
believed to occur through the synovial fluid and the synovial
tissue arterioles and venules.33 Morphologic, physiologic, and
pathologic studies have confirmed that solutes pass easily from the
synovial fluid into cartilage, and that cartilage does not survive
without synovial fluid contact in vivo. Within the cartilage
matrix, three potential mechanisms for nutrient transfer have been
proposeddiffusion, active transport by chondrocytes, and pumping by
intermittent compression of cartilage matrix. A large proportion of
hyaline cartilage lies within 50 m of a synovial surface and its
rich supply of blood vessels. Chondrocytes are oxygen sensitive and
well adapted to living in hypoxic conditions. Low oxygen tension
promotes the expression of the chondrocyte phenotype and
cartilagespecific matrix formation. Reactive oxygen species also
may play a crucial role in the regulation of some normal
chondrocytic activities, such as cell activation, proliferation,
and
A B
CFigure 2-8
Clinicalfeaturesofcamptodactylyarthropathycoxavarapericarditis(CaCP)syndrome.A,Thecharacteristicdeformityofthehandsisshown.B,Chestx-rayshowsanenlargedcardiacoutlinecausedbypericarditis.C,X-rayofthepelvishighlightscoxavarainaboywithCaCP.(BandCcourtesy
of Ronald Laxer, MD, Hospital for Sick Children, Toronto.)
Hydrophillic molecules: water, electrolytes, glucose,
proteins
Blood vessel
Synovium
Sublining Lining
Lymphatic
Egress of SF components unrestricted
Synovial fluid Cartilage
Lipophilic molecules:O2, CO2Lubricants Hyaluronan Lubricin
Superficial zone chondrocytes
Matrix
Figure 2-9
schematicrepresentationoftheformationofsynovialfluid.manyofthesolublecomponentsandproteinsinsynovialfluidexitthesynovial
subintimalmicrocirculation through pores or fenestrations
inthevascularendothelium,thendiffusethroughthe
interstitiumbeforeenteringthejointspace.synovialpermeabilitytomostsmallmoleculesis
determined by a process of free diffusion through the double
bar-rierofendotheliumandinterstitium,limitedmainlybytheintercellularspacebetween
the synovial liningcells. Fat-solublemolecules candif-fuse through,
andbetween, cellmembranes, and
theirpassageacrossthesynovialsurfaceislessrestricted.additionalcomponents,includinghyaluranonandlubricin,areproducedbythesynovialliningcells.decreased
pH, and increased lactate production. The resultant matrix
remodeling.
-
33ParT1 |
sTruCTureanDFunCTionoFbone,JoinTs,anDConneCTiveTissueSUMMARY
The normal human synovial membrane is a highly specialized,
multifunctional organ that is vital for mobility, independence, and
survival. The intimal layer is composed of two distinct cell
phenotypes with characteristics of macrophage and fibroblast
lineages. Synovial macrophages express CD45, CD163 and CD97, CD68,
neuronspecific esterase, and cathepsins B, L, and D. Cells
expressing CD14 are rarely seen in the healthy intimal layer.
FcRIII (CD16), expressed by Kupffer cells of the liver and type II
alveolar macrophages of the lung, is expressed on a subpopulation
of synovial macrophages. Synovial macrophages also express the MHC
class II molecule, and play a central role in phagocytosis and in
antigenmediated immune responses.
Synovial intimal fibroblasts possess prominent synthetic
capacity and produce the essential joint lubricants HA and
lubricin. They also synthesize normal matrix components, including
fibronectin, laminin, collagens, proteoglycans, lubricin, and other
identified and unidentified proteins. They have the capacity to
produce large amounts of metalloproteinases, metalloproteinase
inhibitors, prostaglandins, and cytokines. The expression of
selected adhesion molecules on synovial fibroblasts probably
facilitates the trafficking of some cell populations, such as
polymorphs, into the synovial fluid, and the retention of others,
such as mononuclear leukocytes, in the synovial tissue.
The subintimal layer is composed of a loose connective tissue
matrix and contains branching blood and lymphatic vessels; a nerve
supply; and a variety of resident cell populations, including
infiltrating macrophages and fibroblasts. The nerve supply is
important in regulating synovial blood flow. The lymphatic vessels
allow egress of metabolic breakdown products from the synovium and
synovial fluid. The morphology of the subintimal layer varies
according to the anatomic location and local functional
requirements.
The coordinated functions of the composite synovial membrane are
essential for normal joint movement, formation of synovial fluid,
nutrition of chondrocytes, and protection of cartilage. These
functions must be preserved over a lifetime at multiple anatomic
locations. The absence of essential constituents of synovial fluid,
such as lubricin, or inadequate cartilage protection results in
early articular malfunction, which may progress to variable degrees
of joint failure. The characteristics of lubricin deficiency have
been elegantly described in animal models and in humans. Further
studies may define novel clinical categories of degenerative
polyarthritis that are associated with other specific disorders of
synovial membrane function.
AcknowledgmentsThe authors thank Suhel Miah, Institute of
Orthopaedics and Musculoskeletal Science, and Bethany Crane and
Steve Crane, Royal National Orthopaedic Hospital, for preparing
many of the images included in this chapter.
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Arthroplasty 18:499505, 2003.
SynoviumSTRUCTURESYNOVIAL LINING CELLSUltrastructure of Synovial
Lining CellsImmunohistochemical Profile of Synovial Intimal
CellsTurnover of Synovial Lining CellsOrigin of Synovial Lining
Cells
SUBINTIMAL LAYERSubintimal VasculatureSubintimal
LymphaticsSubintimal Nerve Supply
FUNCTIONJOINT
MOVEMENTDeformabilityNonadherenceLubricationHyaluronic Acid
FORMATION OF SYNOVIAL FLUIDNUTRITION OF CHONDROCYTES
SUMMARYAcknowledgments
REFERENCES