The synovium provides nutrients to cartilage and produces lubricants for the joint.
The intimal lining of the synovium includes macrophage-like and fibroblast-like synoviocytes.
The sublining in normal synovium contains scattered immune cells, fibroblasts, blood vessels, and fat cells.
Fibroblast-like synoviocytes in the intimal lining produce specialized enzymes that synthesize lubricants, such as hyaluronic acid.
The synovium is a membranous structure that extends from the margins of articular cartilage and lines the capsule of diarthrodial joints, including the temporomandibular joint and the facet joints of vertebral bodies ( Fig. 2.1 ). The healthy synovium covers intra-articular tendons and ligaments, as well as fat pads, but not articular cartilage or meniscal tissue. Synovium also ensheaths tendons where they pass beneath ligamentous bands and bursae that cover areas of stress such as the patella and the olecranon. The synovial membrane is divided into two general regions: the intima, or synovial lining, and the subintima, otherwise referred to as the sublining. The intima represents the interface between the cavity containing synovial fluid and the subintimal layer. No well-formed basement membrane separates the intima from the subintima. In contrast to the pleura or pericardium, it is not a true lining because it generally lacks tight junctions, epithelial cells, and a well-formed basement membrane. 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 are arrayed on the luminal aspect of the joint cavity. SLCs, termed synoviocytes, are one to three cells deep, depending on the anatomic location, and extend 20 to 40 μm beneath the lining layer surface. The major and minor axes of SLCs measure 8 to 12 μm and 6 to 8 μm, respectively. The SLCs are not homogeneous and are conventionally divided into two major populations, namely, type A (macrophage-like) synoviocytes and type B (fibroblast-like) synoviocytes.
Ultrastructure of Synovial Lining Cells
Transmission electron microscopic analysis shows that the intimal cells form a discontinuous layer, and thus the subintimal matrix can directly contact the synovial fluid ( Fig. 2.2 ). The existence of two distinct cell types—type A and type B SLCs—was originally described by Barland and associates, and several lines of evidence, including animal models, detailed ultrastructural studies, and immunohistochemical analyses, indicate that these cells represent macrophages (type A SLCs) and fibroblasts (type B SLCs). Studies of SLC populations in a variety of species, including humans, have found that macrophages make up anywhere from 20% and fibroblast-like cells approximately 80% of the lining cell. The existence of the two cell types is substantiated by similar findings in a wide variety of species, including hamsters, cats, dogs, guinea pigs, rabbits, mice, rats, and horses.
Distinguishing different cell populations that form the synovial lining requires immunohistochemistry or transmission light microscopy. At an ultrastructural level, type A cells are characterized by a conspicuous Golgi apparatus, large vacuoles, and small vesicles, and they contain little rough endoplasmic reticulum, giving them a macrophage-like phenotype ( Fig. 2.3A and B ). The plasma membrane of type A cells possesses numerous fine extensions, termed filopodia, that are characteristic of macrophages. Type A cells occasionally cluster at the tips of the synovial villi; this uneven distribution explains, at least in part, early reports that suggested that type A cells were the predominant intimal cell type. However, the distribution is highly variable and can differ depending on the joint evaluated or even within an individual joint.
Type B SLCs have prominent cytoplasmic extensions that extend onto the surface of the synovial lining ( Fig. 2.3C and D ). 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 contain longitudinal bundles of different-sized filaments, which supports their classification as fibroblasts. Desmosomes and gap-like junctions have been described in rat, mouse, and rabbit synovium, but the existence of these structures in human SLCs has never been documented. Although occasional reports describe an intermediate synoviocyte phenotype, it is likely that these cells are functionally conventional type A or B cells.
Immunohistochemical Profile of Synovial Cells
Synovial macrophages and fibroblasts express lineage-specific molecules that can be detected by immunohistochemistry. Synovial macrophages express common hematopoietic antigen CD45 ( Fig. 2.4A ); monocyte/macrophage receptors CD163 and CD97; and lysosomal enzymes CD68 ( Fig. 2.4B ), neuron-specific esterase, and cathepsins B, L, and D. Cells expressing CD14, a molecule that acts as a co-receptor for the detection of bacterial lipopolysaccharide and is 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.
The Fcγ receptor, FcγRIII (CD16), which is expressed by Kupffer cells of the liver and type II alveolar macrophages of the lung, is expressed on a subpopulation of synovial macrophages. The synovial macrophage population also expresses the class II major histocompatibility complex (MHC) 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 Z39Ig, a complement-related protein that is a cell surface receptor and immunoglobulin superfamily member involved in the induction of human leukocyte antigen, DR subregion (HLA-DR), and implicated in phagocytosis and antigen-mediated immune responses.
Expression of the β2 integrin chains CD18, CD11a, CD11b, and CD11c varies; CD11a and CD11c may be absent or weakly expressed on a few lining cells. Osteoclasts, which are tartrate resistant, acid phosphatase positive, and express the αVβ3 vitronectin and calcitonin receptors, do not appear in the normal synovium.
Synovial Intimal Fibroblasts
Synovial intimal and subintimal fibroblasts are indistinguishable by light microscopy. They generally are considered to be closely related in terms 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. Intimal fibroblasts express uridine diphosphoglucose dehydrogenase (UDPGD), an enzyme involved in HA synthesis that is a relatively specific marker for this cell type. UDPGD converts UDP-glucose to UDP-glucuronate, one of the two substrates required by HA synthase for assembly of the HA polymer. CD44, the nonintegrin receptor for HA, is expressed by all SLCs. Recent studies in fibroblast-like synoviocytes from patients with rheumatoid arthritis (RA) have identified DNA methylation and transcriptome signatures that are joint-specific and may reflect distinct pathogenic processes. Furthermore, epigenetic alterations discovered in the fibroblast-like synoviocytes may explain some of the nongenetic risk associated with RA.
Synovial fibroblasts also synthesize normal matrix components, including fibronectin, laminin, collagens, proteoglycans, lubricin, and other identified and unidentified proteins. They have the capacity to produce large quantities 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. 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. Expression of metalloproteinases, cytokines, adhesion molecules, and other cell surface molecules is strikingly increased in inflammatory states. In a study comparing normal synovial tissue with that from subjects with seropositive arthralgia, osteoarthritis, early and established RA, the transcriptomic analysis revealed that expression of the immune checkpoint molecule, programmed death-1 (PD-1), was increased in early and established disease. The ligands for PD-1, PD-L1, and PD-L2 are increased in synovial tissue on transcriptomic analysis; however, protein expression for the ligands is minimal even before the disease becomes clinically manifest, suggesting a homeostasis between PD-1 and its ligands in normal synovium that is lost in inflammation ( Fig. 2.5 ). These data may explain why some patients receiving immune checkpoint inhibitors for treatment of cancer (e.g., nivolumab and pembrolizumab) may develop autoimmune inflammatory arthritis.
Specialized intimal fibroblasts express many other molecules that also might be expressed by the intimal macrophage population or by most subintimal fibroblasts, including decay-accelerating factor (CD55), vascular cell adhesion molecule–1, , and cadherin-11. PGP.95, a neuronal marker, might be specific for type B synoviocytes in some species. Decay-accelerating factor, which is also expressed on many other cells (most notably erythrocytes), as well as bone marrow cells, interacts with CD97, a glycoprotein that is present on the surface of activated leukocytes, including intimal macrophages, and is thought to be involved in signaling processes early after leukocyte activation. In contrast, FcγRIII is expressed by macrophages only when they are in close contact with decay-accelerating factor–positive fibroblasts or decay-accelerating factor–coated fibrillin-1 microfibrils in the extra-cellular matrix.
Toll-like receptors (TLRs) are also expressed on intimal fibroblasts, including TLR2, which is activated by serum amyloid A (among other ligands), leading to angiogenesis and cell invasion that is mediated, at least in part, via the Tie2 signaling pathway. Cadherins are a class of tissue-restricted transmembrane proteins that play important roles in homophilic intercellular adhesion and are involved in maintaining the integrity of tissue architecture. Cadherin-11, which was cloned from RA synovial tissue, is expressed in normal synovial intimal fibroblasts but not in intimal macrophages. Fibroblasts transfected with cadherin-11 form a lining-like structure in vitro, which implicates this molecule in the architectural organization of the synovial lining. This suggestion is supported by the observation that cadherin-deficient mice have a hypoplastic synovial intimal lining and are resistant to inflammatory arthritis. When fibroblasts expressing cadherin-11 are embedded in laminin microparticles, they migrate to the surface and form an intimal lining-like structure. If macrophage lineage cells are included in the culture, they can co-localize with fibroblasts on the surface. Therefore, the organization of the synovial lining, including the distribution of type A and B cells, is orchestrated by fibroblast-like synoviocytes.
β1 and β3 integrins are present on all SLCs, forming receptors for laminin (CD49f and CD49b), types I and IV collagen (CD49b), vitronectin (CD51), CD54 (a member of the immunoglobulin superfamily), and fibronectin (CD49d and CD49e). CD31 (platelet–endothelial cell adhesion molecule), a member of the immunoglobulin superfamily expressed on endothelial cells, platelets, and monocytes, is weakly expressed on SLCs.
Turnover of Synovial Lining Cells
Proliferation of SLCs in humans is low; normal human synovial explants have a labeling index of approximately 0.05% to 0.3% when exposed to 3H thymidine.
This labeling index bears a striking contrast to labeling indices of approximately 50% for bowel crypt epithelium. Similar evidence of low proliferation is found in the synovium of rats and rabbits. The proportion of SLCs expressing the proliferation marker Ki67 is between 1 in 2800 and 1 in 30,000, confirming the relatively slow rate of in situ proliferation. Proliferating cells are generally synovial fibroblasts, a finding consistent with the concept that type A synovial cells are terminally differentiated macrophages. Mitotic activity of SLCs is low in inflammatory conditions, such as RA—a condition associated with SLC hyperplasia. Some investigators have reported only rare mitotic figures in RA synovium samples.
Apart from the knowledge that synovial fibroblasts proliferate slowly, little is known about their natural life span, recruitment, or mode of death. Apoptosis is likely involved with maintaining synovial homeostasis, but cultured fibroblast-like synoviocytes tend to be resistant to apoptosis, and very few intimal lining cells display evidence of completed apoptosis by ultrastructural analysis or by labeling for fragmented DNA. The paucity of normal synovium samples for evaluation and the rapid clearance of apoptotic cells could confound the analysis.
Origin of Synovial Lining Cells
There is little doubt that the type A SLC population is bone marrow–derived and represents cells of the mononuclear phagocyte system. Studies in the Beige (bg) mouse, which harbors a homozygous mutation that confers the presence of giant lysosomes in macrophages, have confirmed the bone marrow origin of these cells. Normal mice with bone marrow depleted through irradiation were rescued with bone marrow cells obtained from the bg mouse. Electron microscopic analysis of the synovium from 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 provide powerful evidence that (1) type A SLCs represent macrophages, (2) they are recruited from the bone marrow, and (3) they are a distinct lineage from type B SLCs.
In addition to immunohistochemistry, several lines of evidence support the concept that type A SLCs are recruited from the bone marrow:
The osteopetrotic (op/op) mouse, a spontaneously occurring mutant that fails to produce macrophage colony-stimulating factor because of a missense mutation in the CSF1 gene, has low numbers of circulating and resident macrophage colony-stimulating factor–dependent macrophages, including those in the synovium.
Type A cells in rat synovium do not populate the joint until after the development of synovial blood vessels.
Type A SLCs are conspicuous around vessels in the synovium in neonatal mice.
When synovial explants are placed in culture, the reduction in type A SLCs is explained, in part, by their migration into the culture medium—an observation that reflects the process of migration of macrophages into the synovial fluid in vivo.
Macrophages constitute up to 80% of the cells found around venules in inflammatory conditions such as RA and are cleared rapidly (<48 hours) after successful treatment but will reaccumulate from the circulation if relapse occurs.
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 about how their recruitment is regulated. The existence of mesenchymal stem cells in the synovium suggests that these cells might differentiate into the synovial lining fibroblast. To date, a specific transcription factor directing mesenchymal stem cell differentiation into the synovial fibroblast, similar to factors required for commitment by this multipotential population into bone (CBFA-1), cartilage (SOX-9), and fat (peroxisome proliferator-activated receptor γ [PPARγ]), has not been identified.
Several important signaling pathways are activated in the inflamed synovium, including nuclear factor-κB (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), Notch, and hypoxia-inducible factor 1, α subunit (HIF-1α). NF-κB is a key transcriptional regulator in the inflamed synovium. NF-κB signaling is complex and may be activated by cytokines, cell surface adhesion molecules, and hypoxia. NF-κB activation could facilitate synovial hyperplasia by promoting proliferation and inhibiting apoptosis of RA fibroblast-like synoviocytes. One of the key roles of NF-κB is to protect RA fibroblast-like synoviocytes against apoptosis, possibly by countering the cytotoxicity of TNF and Fas ligand.
JAK/STAT, Notch, and HIF-1α signaling pathways are also evident in inflamed synovium. STAT3 expression in the synovium correlates with synovitis and is activated by IL-6 but also indirectly by TNF. Notch signaling pathway components are predominantly localized to perivascular/vascular regions and are regulated by vascular endothelial growth factor (VEGF) and ang2, which is consistent with the role of mediation of angiogenesis by Notch in inflammation and cancer. Interestingly, hypoxia induces activation of phospho (p)-STAT3/p-STAT1, NF-κB, and Notch in synovial cells. Furthermore, Notch/HIF-1α interactions in RA synoviocytes are in part mediated through STAT3 activation, possibly through competition of STAT3 with von Hippel–Lindau tumor suppressor for binding to HIF-1α. Although no direct link between NF-κB and HIF-1α is demonstrated in the inflamed joint, preferential activation of the canonic NF-κB pathway occurs in RA synovial tissue obtained from patients with more hypoxic joints.
SLCs are not separated from the underlying subintima by a well-formed basement membrane composed of the typical trilaminar structure seen beneath epithelial mucosa. Nevertheless, most components of basement membrane are present in the extra-cellular matrix surrounding SLCs. These components include tenascin X, perlecan (a heparan sulfate proteoglycan), type IV collagen laminin, and fibrillin-1. Of note is the absence of laminin-5 and integrin α3β3γ2, which are components of epithelial hemidesmosomes.
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 and scattered mast cells. Human synovial tissue 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 self-renew and differentiate into bone, cartilage, and fat in vitro—a phenomenon that reflects the ability of the cell to regenerate in vivo.
Three categories of subintima are well defined: areolar, fibrous, and fatty/adipose types. Under the light microscope, areolar-type subintima, the most commonly studied, generally is found in larger joints in which there is free movement. 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 it has an attenuated layer of SLCs. The adipose type, which contains abundant mature fat cells and has a single layer of SLCs, is seen more commonly with aging and in intra-articular fat pads.
The subintima contains types I, III, V, and VI collagen, glycosaminoglycans, proteoglycans, and extra-cellular matrices, including tenascin and laminins. Integrin receptors for collagens, laminin, and vitronectin are absent or at best weakly expressed by subintimal cells. In contrast, receptors for fibronectin (CD49d and CD49e) are detected, and CD44, the HA receptor, is strongly expressed in most subintimal cells. β2 integrins are largely limited to perivascular areas, particularly in the subintimal zone, as is CD54.
The vascular supply to the synovium is provided by many small vessels and is shared in part by the joint capsule, epiphyseal bone, and other perisynovial structures. Arteriovenous anastomoses communicate freely with the vascular supply to the periosteum and to periarticular bone. As large synovial arteries enter the deep layers of the synovium near the capsule, they branch 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 trans-synovial exchange of molecules. The intimal lining, however, is devoid of blood vessels. Although few in number, vessels in the normal synovium have an intact pericyte layer, suggesting vessel stability, in contrast to the inflamed joint, where a mix of mature and immature vessels were observed. Neural cell adhesion molecule (NCAM) deficiency and oxidative DNA damage suggest that vessels may remain in a plastic state even after pericyte recruitment. After TNF blockade, synovial blood vessels become more stable and resemble normal synovium.
Numerous physical factors influence synovial blood flow. Heat promotes blood flow through synovial capillaries. Exercise enhances synovial blood flow to normal joints but may reduce the clearance rate of small molecules from the joint space. Immobilization reduces synovial blood flow, and pressure on the synovial membrane can act to tamponade the synovial blood supply.
Vascular endothelial lining cells express CD34 and CD31 ( Fig. 2.6A ). 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 β3 integrin subunit). Endothelial cells express CD44, the HA receptor, and CD62P (P-selectin), which acts as a receptor that supports binding of leukocytes to activated platelets and endothelium. They are only weakly positive in uninflamed synovium, however, for expression of CD54 (intercellular adhesion molecule-1), a receptor for β2 integrins expressed by many leukocytes. The endothelial cells of capillaries in the superficial zone of the subintima are strongly positive for HLA-DR expression by immunohistochemistry, whereas cells in the larger vessels in the deep aspect of the membrane are negative.
Hypoxia is a key driver of endothelial cell activation and blood vessel formation in the inflamed joint. This theory was originally proposed in 1970, when a synovial fluid electrode was used to demonstrate that a partial pressure of O 2 in a knee joint affected by RA was 26.5 mm Hg, which was significantly lower than that in joints affected by osteoarthritis (42.9 mm Hg) or traumatic effusions (63 mm Hg). This observation was supported by studies showing increased glycolytic metabolism in the joint suggestive of increased metabolic activity. Low pO 2 in the inflamed synovial membrane was confirmed with pO 2 probes, with mean levels approximately 3% compared with normal joints at 7%. The degree of hypoxia in synovium affected by RA and normal synovium was inversely related to the number of blood vessels observed and their level of maturity. In patients responding to TNF blockade, the pO 2 increased, thus improving oxygenation to a level similar to that of normal joints.
Detailed analysis of the number and distribution of lymphatic vessels is made possible by the use of the antibody to the lymphatic vessel endothelial HA receptor (LYVE-1) ( Fig. 2.6B ). 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 VIII–related antigen. Expression of LYVE-1 in lymphatic endothelial cells is used as a marker to show that lymphatic vessels are less common in the fibrous synovium compared with areolar and adipose variants of human subsynovial tissue. Detection of this molecule reveals that lymphatics are present in the superficial, intermediate, and deeper layers of synovial membrane in synovium from healthy people or patients with osteoarthritis and joints affected by RA, 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 osteoarthritis synovium, which is characterized by lack of villous hypertrophy. Lymphatic 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 S-100 protein, terminate close to blood vessels, where they regulate vascular tone ( Fig. 2.6C through E ). Sensory nerves respond to proprioception and pain via large myelinated nerve fibers and via small (<5 μm) unmyelinated or myelinated fibers with unmyelinated free nerve ends (nociceptors). The latter are immunoreactive in the synovium for neuropeptides, including substance P, calcitonin gene–related peptide, and vasoactive intestinal peptides.
Synthetic and protective functions of individual synovial cell populations are multiple and complex. The composite synovial structure, which includes cell populations and their products, vasculature, nerves, and the intercellular matrix, possesses several specialized functions that are essential for normal joint movement, synovial fluid formation, chondrocyte nutrition, and cartilage protection at multiple anatomic locations. These functions must be preserved over a lifetime to maintain maximal mobility and independence. Absence of essential constituents of synovial fluid or inadequate cartilage protection results in early articular malfunction, which may progress to local or generalized joint failure.
Four characteristics of the synovium are essential for joint movement: deformability, porosity, nonadherence, and lubrication. In a healthy person, the synovium is a highly deformable structure that facilitates movement between other adjacent, nondeformable structures within the joint. This unique facility of the synovium, to enable movement between tissues rather than within tissues, is emphasized and can be attributed to the presence of a free surface that allows synovial tissue to remain separated from adjacent tissues. The ensuing space is maintained by the presence of synovial fluid.
The deformability of normal synovium is considerable because it must accommodate the extreme positional range available to the joint and its adjacent tendons, ligaments, and capsule. When a finger is flexed, the palmar synovium of each interphalangeal joint contracts while the dorsal synovium expands; when the finger extends, the reverse mechanism occurs. This normal contraction and expansion of synovium seems to involve a folding and unfolding component and an elastic stretching and relaxation of the tissue. During repeated rapid movement, the synovial lining cannot be pinched between cartilage surfaces for it to successfully retain its integrity and the integrity of synovial blood vessels and lymphatics. Deformability also limits the extent of synovial ischemia-reperfusion injury during joint motion by maintaining a relatively low intra-articular pressure.
The synovial microvasculature and the intimal lining must be porous to permit robust diffusion of nutrients to cartilage. The structure of the intimal lining is ideal for this requirement because of the relatively disorganized basement membrane and lack of tight junctions, although recent data suggest that macrophages in the lining form tight junctions that could be lost during inflammation. Plasma components freely diffuse into the intra-articular space, and most plasma components, including proteins, are present in synovial fluid at about one-third to one-half the plasma concentration.
The third important characteristic of the synovium that facilitates joint movement is its nonadherence to opposing surfaces. Intimal cells on the synovial surface adhere to underlying cells and matrix but do not adhere to opposing synovial and cartilage surfaces. The mechanism that preserves this phenomenon of nonadherence is unknown and might involve the arrangement of cell surface and tissue matrix molecules, such as collagen, fibronectin, and HA. Alternatively, nonadherence may result, in part, from regular movement of the normal synovial lining.
The fourth characteristic of synovium that is essential for joint motion is an efficient lubrication mechanism to facilitate movement of cartilage 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 self-repair. For a joint to maintain its function throughout a lifetime of use, protective biologic mechanisms, such as lubrication, help minimize wear and damage that result from normal daily activities. Synovial membrane may also contribute to concentration of lubricants in synovial fluid because it is a semi-permeable membrane. These functions have recently been replicated by a polytetrafluoroethylene membrane that can be used in a bioreactor system to modulate lubricant retention in bioengineered synovial fluid. Synoviocytes adherent to such membranes may serve as a source of lubricant and a barrier for lubricant transport. Furthermore, cytokines can stimulate normal lubricant production 40-fold to 80-fold in such bioreactor systems ( Fig. 2.7 ).