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Current Concepts of the Non-rheumatic Synovial Tissues of the Knee Joint in Different Scenarios R a f a e l I ñ i g o - Pa v l o v i c h , M D, P h D, FA C S 1 a n d J o a n C M o n l l a u , M D, P h D 2 Post and Organisation
Abstract Studies on synovial tissue of the knee joint are seldom presented at orthopaedic meetings. This may be due to the lack of a commercial value of this precious tissue for the orthopaedic market other than when a non-steroidal anti-inflammatory drug (NSAID) is involved. Synovialis is a highly interactive tissue that responds to the slightest trauma onto greater problems such as infections. It also has functions related to the immune system. In secreting the hyaluronic acid (HA)-rich synovial fluid (from the Greek words syn [together] and oon [egg], meaning ‘like the white of an egg’), it lubricates, nourishes, and protects the hyaline cartilage from wear and tear. This tissue aids in pathological conditions as well as in the repair of cartilage, menisci, and ligament tissues. Synovial tissue should not be forgotten by orthopaedic surgeons.
Keywords Xxx Disclosure: The authors have no conflicts of interest to declare. Received: date Accepted: date Correspondence: Rafael Iñigo-Pavlovich, MD, PhD, FACS, 273 suites 6 and 7, Proyecto Río Sonora. Hermosillo. Sonora. México. 83280. E:
[email protected]
Ultrastructure and Physiology The synovial membrane is a vascular connective tissue lining the inner surface of the capsule but not the articular cartilage. It is derived from mesenchyme at the fourth month of embryonic life and composed of lax tissue divided into two layers. The inner surface is a thin cellular layer 40 microns thick, which produces the hyaluronic acid (HA). The outer vascular underlying layer, or subintima, where most of the microvessels are located, has some mastocytes, histiocytes, and collagen fibers. The synovial tissue mainly has two types of cell. Those called type A synoviocytes have a monocytic origin and they are macrophage-like. Qlthought they normally account for 20–20% of the tissue, this can increase to 80% in pathological situations. Type A synoviocytes can phagocyte collagen type II and are involved in reactive synovitis derived from contact with this type of collagen and also other irritant components such as agreccan and some peptides. Type B synoviocytes have dendritic-like prolongations and produce HA, an important component of synovial fluid. Chemically, the synovial fluid is a dialyzed form of blood plasma plus a large amount of HA. HA is a member of the glycosaminoglycan family, which includes chondroitin sulphate, dermatin sulphate, and heparan sulphate. Unlike other members of this family, it is not found covalently bound to proteins. HA has lubricating and buffering functions in joints. Characteristically, HA solutions are viscoelastic and pseudoplastic and these rheological properties make synovial fluid very important in the optimum performance of articular joints.
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In normal joints, the synovial fluid secretion providing low friction, low wear is in homeostasis, although its regulatory mechanisms seem to be quite complex. It has recently been demonstrated in vitro that a cyclic tensile load induces the expression and activity of hyaluronidase, the catabolic enzyme of HA, in synovial membrane cells. The results of this work suggest that an increase in hyaluronidase induced by mechanical load affects HA catabolism in synovial fluid. Therefore, HA metabolism synovial membrane cells seems to be modulated by mechanical load.1 However, HA has more than mechanical properties. Its secretion inhibits chemotaxis of the neutrophils and macrophages. HA also modifies the activity of the chondrocytes and fibrocytes over the production of metalloproteinases, a large family of proteolytic enzymes involved in the degradation of cartilage matrix components that have been implicated in osteoarthritis.2–4 This is especially important since a recent study has demonstrated that metalloproteinases play a key role in regulating the balance of structural proteins of the articular cartilage according to local mechanical loads.5 All of these mechanisms suggest the complex role the synovial tissue plays via HA to self-control joint homeostasis in response to different stimuli.
Pain There are mechanoreceptors such as Ruffini end-organs and Pacinian corpuscles (proprioceptors) in the superficial and deep layers of the
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SCurrent Concepts of the Non-rheumatic Synovial Tissues of the Knee Joint in Different Scenarios
joint capsule, as well as free-ending nerves. 6 The role of proprioceptive sensors is to provide information on actual motor performance. Innervations of the joint, with thinly myelinated and unmyelinated sensory nerve fibers, are crucial for the occurrence of joint pain. During joint inflammation, the sensory fibers show changes in the expression of receptors that are important for the activation and sensitization of the neurones and the generation of joint pain. Both neurokinin 1 receptors and bradykinin 2 receptors are upregulated in dorsal root ganglion (DRG) neurones (the cell bodies of sensory fibers) in the course of acute and chronic antigen-induced arthritis in the rat. In this study, the mechanisms of the interaction between fibroblast-like synovial cells (FLS) and sensory neurones by establishing a co-culture system of FLS cells and DRG neurones 7 is addressed. Substance P (SP), a well-known peptide participating in painful conditions, located in the synovial tissue, plays a significant role in pain of knee joint.8 The occurrence and distribution of SP nerves inside the infrapatellar fat pad suggest a nociceptive function and a neurohystological role in anterior knee pain syndrome. Data support the hypothesis that a neurogenous infection of the infrapatellar fat pad could contribute to anterior knee pain syndrome.9 It has also been hypothesized that periodic short episodes of ischemia in the lateral patellar retinaculum may be implicated in the pathogenesis of anterior knee pain by triggering neural proliferation of nociceptive axons (SP-positive nerves), mainly in a synovial perivascular location.10 The physiology of the synovial membrane has been evaluated using in vivo microdialysis. In this study, an increase in the local production of lactate and pyruvate compared with subcutaneous fat has been found. There was also consumption of glucose in the synovial membrane, which was not observed in the tissue used as a control. Therefore, it was concluded that a state of reperfusion occurs in the synovial membrane after moderate trauma such as standard arthroscopy of the knee. 11 Increased prostaglandin E2 (PGE2) release has been suggested as contributing to the enhanced nociceptor sensitivity that underlies chronic osteoarthritic pain. An interesting study conducted after arthroscopic procedures monitored metabolic and inflammatory changes with microdialysis in the knee joint synovial membrane of 14 patients in relation to pain requiring systemic opioids. It was demonstrated that in the group that needed opioids a rise in glucose and PGE2 was noticed, and that after the administration of this analgesic drug, a lowering in the PGE2 and glucose was noticed.12 Finally, a recent study has suggested a relationship between glucosamine, a common treatment for patients affected by osteoarthritis (OA), and the production of HA. When used by osteoarthritic patients, glucosamine has been demonstrated to reduce pain, but the working mechanism is still not clear as cartilage is not innervated. In the aforementioned study, an increase in the production of HA in the synovium was obtained in vitro when high concentrations of glucosamine were used. Therefore, it has been
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speculated that since glucosamine is an important building block of HA and HA is found in high amounts in articular joints, increasing HA production through the administration of this drug might be a way to explain its pain-relieving effect.13
Defense and Repair Scenario The synovial membrane is a very active tissue and a reactive barrier to antigens, microbes, and viruses. A study conducted to determine the expression of bactericide peptides by healthy and inflamed synovial membrane was carried out. Deposition of the antimicrobial peptides lysozyme, lactoferrin, secretory phospholipase A(2) (sPA[2]), matrilysin (MMP7), human neutrophil alpha-defensins 1–3 (HNP 1–3), human b-defensin 1 (HBD-1), and human b-defensin 2 (HBD-2) was determined by immunohistochemistry (IHC). Data suggest that human synovial membranes produce a broad spectrum of antimicrobial peptides not only in inflamed but also in healthy synovial membrane.14 When a tendon, auto or allograft, is placed in the knee for the reconstruction of the anterior cruciate ligament (ACL), the tendon, which originally had a different microstructure and function, slowly becomes a ligament. This process is called ‘ligamentization.’ This occurs in stages, and includes the synovialization, angioblastic, collagenization, and maturation phases. Synoviocite type B is a fibroblast-like cell and migrates to the chemical call of the repair zone. Chemotactic factors and expression of vascular growth factors succeed in transforming a tendon tissue into a ligament.15–18 The ability of meniscal tissue to heal is known to be limited. Thermal damage by applying radiofrequency (RF) to the meniscal tissue acts as a stimulant for the synovial tissue in the repair process. It has been shown in animal studies after meniscal tissue was exposed to RF due to a meniscectomy that the remaining tissue passed a curve of small necrosis; and further cell repopulations19 these results were confirmed in human meniscus after meniscectomy with RF probes.20,21 Is this correct?
The first report in human displaced injuries of the menisci was Do you mean reported in four cases with second looks after the use of RF, not as a follow-up? cutting tool, but as a stimulating procedure bound to the repair process.22 Further reports pointed to the role of RF in awakening synovial response to aid the meniscal repair process.23–25 Allograft meniscal transplants are modulated and repopulated by synovial cells.26,27 Cartilage is a tissue with a poor auto-repair response; some studies are now trying to regenerate the hyaline layer with the inclusion of synovial tissue. A recent paper relates synovial cells to cartilage repair in Sprague Dawley (SD) and green fluorescent protein (GFP) rats. The purpose of this study was to examine the role of the synovium in the transitional zone between the articular cartilage and the synovial membrane in cartilage repair and the relationship between the origin of the repaired cartilage and the grafted synovium. In study one, one group had the synovial tissue resected and a full thickness cartilage defect in the medial femur condyle (cartilage defect without synovium group) with the contralateral medial condyle full-thickness defect
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Section Heading Section Sub without resection of the synovial tissue (cartilage defect with intact synovial group). In study two, the synovium of the GFP rats was transplanted into the unilateral knee (cartilage defect with transplanted synovium group) after the creation of a full-thickness cartilage defect and resection of the synovium. Histological studies were performed at two, four, six, and eight weeks after surgery and the samples were tested immunohistochemically; the expression of agreccan and type II collagen in the repaired tissue was also investigated using reverse transcriptase-polymerase chain reaction (RT-PCR). Type II collagen was found in the cartilage defect with transplanted synovium group. It was concluded that the synovial invades the defect and that this tissue can be chondrogenic. 28 Another promising investigation confirms the ability of synovial tissue in repairing chondral defects with hyaline-like cartilage. In this study, a rabbit model comparing cartilage defects in the knee using pedunculated synovial graft and those without (incomplete sentence). Sections of the comparing groups were stained with hematoxilylin-eosin and safranin-O fast green staining, and also IHC for collagen type II. The results at 24 months showed much more type II collagen than in controls, suggesting pedunculated synovium transplantation to be a promising method for repairing hyaline cartilage defects. 29
Synovial and Non-rheumatic Osteoarthritis Osteoarthritis has been considered a degenerative disease for years. However, the pathogenesis of osteoarthritis is not yet completely understood. The synovial tissue has been identified as one of the contributing factors since the concentration and molecular size of HA usually declines in osteoarthritic joints. Smith and Ghosh were among the first to analyze the behavior of several cell lines of human synovial fibroblasts derived from synovium in an experimental study. They determined the synthesis of 3H-labeled HA in these cells, and the effects of adding HA of varying molecular sizes to the cultured cells were examined. The results obtained show that the in vitro synthesis of HA by these cells is influenced by the concentration and molecular weight of the HA in their extracellular environment. 30 As a consequence, intra-articular administration of HA, so-called viscosupplementation, has been proposed as a treatment for certain arthropathies, and clinical trials have been conducted in humans to this end in recent years. The exact mechanism of action of viscosupplementation is unclear. Although
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Kitamura R, et al., J Biomed Mater Res A, 2009; in press. Pavlovich RI, Lubowitz J, Orthopaedics, 2008;31(2):160–63, 164–5. 3. Flaisler F, Combe B, Encycl Med Chyr, 1995;6. 4. Takahashi K, et al., J Rheumatol, 2000;27(7):1713–20. 5. Montfort J, et al., Arthritis Res Ther, 2006;8:R149. 6. Freeman MAR, Wyke B, J Anat, 1967;101:505–32. 7. von Banchet GS, et al., Arthritis Res Ther, 2007;9(1):R6. 8. Bohnsack M, et al., Arch Orthop Trauma Surg, 2005;125(9): 592–7. 9. Gronblad M, et al., Acta Orthop Scand, 1985;56(6):484–6. 10. Sanchis-Alfonso V, Orthopade, 2008;37(9):835–6. 11. Felländer-Tsai L, et al., J Bone Joint Surg Br, 2002;84(8):1194–8.
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restoration of the elastoviscous properties of synovial fluid seems to be the most logical explanation, other mechanisms must exist and recent evidence supports involvement of immunological mechanisms in this pathophysiology. Synoviocytes are reactive to foreign substances or to strange materials present in the knee joint. A number of cytokines are expressed in response to aggression, among them interleukin-1 (IL-1) and tumor necrosis factor (TNF), two well-known proinflammatory cytokines, promoters of inflammation and metalloproteinase releasers. 31 Particularly in osteoarthritis, IL-1, which is produced by activated synoviocytes and mononuclear cells and has catabolic effects on chondrocytes, is one of the most involved. In that sense, various new pharmacological strategies have been developed to control this process. A metabolite of diacerhein (1,8-dihydroxy-3-carboxyanthraquinone) has shown the ability to reduce the deleterious effects of interleukin-1b on osteoarthritic cartilage through inhibition of the expression of degrading enzymes. More recently, the effects of relevant concentrations of the same drug on the cell proliferation rate of human chondrocytes and synoviocytes were analyzed. It was found to inhibit proliferation of both synoviocytes and chondrocytes, suggesting that the drug may decrease the development of the inflammatory synovial tissue that accompanies joint pathologies. Both its anticatabolic and antiproliferative effects may explain its beneficial effect in the treatment of degenerative joint diseases.32 Reactive arthritis to type II collagen is the resultant of microparticles of type II collagen detaching from the cartilage layer and being phagocyted by type A macrophage-like synoviocytes. Cartilage breaks down when overused and gets fatigued or when major trauma is applied.33,34 A mechanism for the pathophysiology of the resultant synovial hyperplasia from cartilage breakdown has been proposed. The cartilage, once broken, releases agreccans and peptide molecules into the joint. Macrophages react to type II collagen and to the peptides releasing cytokines that promote fibrocytes to migrate and produce fibrosis; meanwhile the synovial fluid gets altered in the nutritious and lubricant properties. Therefore, the cartilage becomes weak and prone to further breakage and thus perpetuates the vicious circle. 35 n
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Pavlovich RI, et al., Sports Med Arthrosc Rev, 2005;13(4). Arnoczky SP, et al., Arthroscopy, 1992;8(4):428–36. Arnockzky SP, J Knee Surg, 2006;19(3):207–14. Miyamoto A, et al., Knee Surg Sports Traumatol Arthrosc, 2007;15(9):1083–93. Tuncay IC, et al., J Invest Surg, 2005;18(3):115–22. Smith MM, Ghosh P, Rheumatol Int, 1987;7:113–22. Berumen-Nafarrate E, et al., J Knee Surg, 2002;15(1):46–8. Legendre F, et al., Scand J Rheumatol, 2009;38(2):104–11. Saxne T, et al., Arthritis Rheum, 1993;36(1):20–25. Bellucci G, Seedhom BB, Biorheology, 2002;39(1-2):193–9. Pavlovich RI, et al., J Knee Surg, 2002;15(1):49–52.
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