Orthopedics

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Review Article 

Current Concepts in Synovial Tissue of the Knee Joint

Rafael Inigo Pavlovich, MD, PhD, FACS; James Lubowitz, MD

Abstract

Synovial tissue, an important component of the knee joint, is seldom noted in the orthopedic literature other than as related to rheumatoid arthritis. However, synovium is a key component in cartilage degradation, overuse syndromes, and impingement syndrome where synovial impingement may mimic a torn meniscus. Synovium may be responsible for nontraumatic knee pain and is sometimes referred to as the “forgotten tissue.”1

Synovial cells come from the mesenchymal layer between the fourth and sixth months of embryonic development. Anatomically these can be divided in 3 layers: the intimal layer varying from 20 to 40 microns with highly oxidative cells rich in hyaluronic acid; the subintimal layer rich in vascularity as well as mucopolysaccharides; the subsynovial layer that contains an infiltrate of adipose cells embedded in conjunctive tissue.2 In general, 2 types of cells are found: synoviocytes Type A and Type B.

Type A cells are greater in number and contain vacuoles related to phagocytic function. Type B cells have a developed ergastoplasm and are capable of transforming into fibrocytes depending on the inflammatory response to coexistent cytokines. A wide array of cytokines are produced by synovial stimulation including tumor necrosis factor, interleukin (IL)-1, IL-6, and IL-8; all play a role in the inflammatory process and tissue necrosis.2

Interleukin-1 receptor antagonist is frequently detected in the synovial membrane of normal patients, but both tumor necrosis factor alpha and IL-1b are rarely detected.3 In addition, cell adhesion molecules are rarely detected in the normal synovial membrane, with the exception of intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1. Osteoprotegerin expression is abundant in parasynovial macrophages as well as endothelial cells, but receptor activator of nuclear factor kappa ligand expression is rarely seen. The normal synovial membrane has a variable architecture, including thickness of the lining and the subintimal cell infiltrate, with little inflammatory cytokine production or expression of cell adhesion molecules. The excess of osteoprotegerin expression over receptor activator of nuclear factor kappa ligand and IL-1 receptor agonist over IL-1 may be important for protection against joint damage.3

Freeman and Wyke4 classified encapsulated nerve endings in the synovium: Ruffini endings are low threshold, slow adapting mechanoreceptors (Type 1); Pacinian corpuscles are low threshold, rapidly adapting mechanoreceptors (Type 2); Google organs, characterized by their poor association with to blood vessels, are high threshold, slowly adapting mechanoreceptors (Type 3); and free nerve endings are pain receptors (Type 4). In addition, Grönblad et al5 reported substance P-immunofluorescent nerves that are closely associated with pain transmission and are found in human knee synovial membrane and menisci. Both tissues also contain enkephalin-immunofluorescent nerves, which may be involved in the modulation of pain transmission. Previous suggestions of the presence of nociceptive receptors in these noncartilaginous joint structures, made on a histological basis, are thus confirmed by immunohistochemical methods.

With regard to function, synovium has various purposes including an immune function, phagocytosis, lubrication, and cartilage nutrition. With regard to phagocytosis, synovium can not only remove bacteria but can also envelop small cartilage fragments that may result from joint overload, arthritis or direct trauma. Elimination of intraarticular debris reduces the deleterious effect of inflammation over time.2 Synovial lubrication is extremely important to the healthy joint; synovial fluid diminishes the joint frictional coefficient reducing heat and wear.3,6 Hyaluronic acid, a deformable gel that with increased elasticity as force is applied is synthesized by Type A synoviocytes, and joint forces promote the secretion of hyaluronic acid, in part through stimulation of a Ca(21) influx-dependent activation of the PKCalpha-MEK-ERK1/2 cascade, which are extracellular signal-regulated kinases. This is functionally important because this links joint lubrication to joint use.7 In addition, chondroprotection of articulating…

Synovial tissue, an important component of the knee joint, is seldom noted in the orthopedic literature other than as related to rheumatoid arthritis. However, synovium is a key component in cartilage degradation, overuse syndromes, and impingement syndrome where synovial impingement may mimic a torn meniscus. Synovium may be responsible for nontraumatic knee pain and is sometimes referred to as the “forgotten tissue.”1

Normal Histology, Function, and Physiology

Synovial cells come from the mesenchymal layer between the fourth and sixth months of embryonic development. Anatomically these can be divided in 3 layers: the intimal layer varying from 20 to 40 microns with highly oxidative cells rich in hyaluronic acid; the subintimal layer rich in vascularity as well as mucopolysaccharides; the subsynovial layer that contains an infiltrate of adipose cells embedded in conjunctive tissue.2 In general, 2 types of cells are found: synoviocytes Type A and Type B.

Type A cells are greater in number and contain vacuoles related to phagocytic function. Type B cells have a developed ergastoplasm and are capable of transforming into fibrocytes depending on the inflammatory response to coexistent cytokines. A wide array of cytokines are produced by synovial stimulation including tumor necrosis factor, interleukin (IL)-1, IL-6, and IL-8; all play a role in the inflammatory process and tissue necrosis.2

Interleukin-1 receptor antagonist is frequently detected in the synovial membrane of normal patients, but both tumor necrosis factor alpha and IL-1b are rarely detected.3 In addition, cell adhesion molecules are rarely detected in the normal synovial membrane, with the exception of intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1. Osteoprotegerin expression is abundant in parasynovial macrophages as well as endothelial cells, but receptor activator of nuclear factor kappa ligand expression is rarely seen. The normal synovial membrane has a variable architecture, including thickness of the lining and the subintimal cell infiltrate, with little inflammatory cytokine production or expression of cell adhesion molecules. The excess of osteoprotegerin expression over receptor activator of nuclear factor kappa ligand and IL-1 receptor agonist over IL-1 may be important for protection against joint damage.3

Freeman and Wyke4 classified encapsulated nerve endings in the synovium: Ruffini endings are low threshold, slow adapting mechanoreceptors (Type 1); Pacinian corpuscles are low threshold, rapidly adapting mechanoreceptors (Type 2); Google organs, characterized by their poor association with to blood vessels, are high threshold, slowly adapting mechanoreceptors (Type 3); and free nerve endings are pain receptors (Type 4). In addition, Grönblad et al5 reported substance P-immunofluorescent nerves that are closely associated with pain transmission and are found in human knee synovial membrane and menisci. Both tissues also contain enkephalin-immunofluorescent nerves, which may be involved in the modulation of pain transmission. Previous suggestions of the presence of nociceptive receptors in these noncartilaginous joint structures, made on a histological basis, are thus confirmed by immunohistochemical methods.

With regard to function, synovium has various purposes including an immune function, phagocytosis, lubrication, and cartilage nutrition. With regard to phagocytosis, synovium can not only remove bacteria but can also envelop small cartilage fragments that may result from joint overload, arthritis or direct trauma. Elimination of intraarticular debris reduces the deleterious effect of inflammation over time.2 Synovial lubrication is extremely important to the healthy joint; synovial fluid diminishes the joint frictional coefficient reducing heat and wear.3,6 Hyaluronic acid, a deformable gel that with increased elasticity as force is applied is synthesized by Type A synoviocytes, and joint forces promote the secretion of hyaluronic acid, in part through stimulation of a Ca(21) influx-dependent activation of the PKCalpha-MEK-ERK1/2 cascade, which are extracellular signal-regulated kinases. This is functionally important because this links joint lubrication to joint use.7 In addition, chondroprotection of articulating joint surfaces is provided by lubricin, a mucinous glycoprotein that is a product of megakaryocyte-stimulating factor gene (GenBank U70136) expression; loss of synovial lubricating ability has been implicated in the pathogenesis of degenerative joint disease.8

In cases of arthrosis, hyaluronic acid concentration in the synovial fluid is diminished, and hyaluronic acid molecular weight is reduced resulting in a lower viscosity fluid. This may be caused by the depolymerization of long chain of polysaccharides by free radicals produced by leukocytes and to components of joint effusion that diminish the hyaluronic acid concentration.9 Hyaluronic acid has analgesic and anti-inflammatory effects on a joint: hyaluronic acid inhibits prostaglandin E2 in synovial fluid; regulates cellular activities; inhibits migration of neutrophils; phagocytosis by macrophages; and hyaluronic acid modifies the metabolic activity of chondrocytes and synovial fibroblasts. Chondrocytes cultured with high molecular weight hyaluronic acid synthesize more hystic inhibitor of the metalloproteinase, thus promoting chondroprotection.9,10 Although rheumatoid arthritis and related autoimmune disorders of joints are beyond of the scope of this article, it is important to mention that synovial tissue plays a key role in the immune function of the joints. Type A synoviocytes have macrophage-like properties and carry surface antigens that are relevant to such disorders.9,10

The Role of Synovium in the Repair Process

Synovium is an extremely reactive tissue which plays a key roll in the repair process within the knee joint. Proinflammatory cytokines are released in response to intraarticular damage initiating a repair process.2,3 In a similar fashion, synovial cell response plays a critical role in the healing of meniscal tears. Regardless of whether the tear is in the vascular zone, invasion of Type B synovial cells results in a fibroblast-like response enhancing healing.11

In a study by Okuda et al,12 rasping of parameniscal-tear synovium was compared to contralateral control without rasping in an animal model. Two to 4 weeks after surgery, hypertrophic synovium was observed to migrate from the parameniscal region to the tear in the rasping group. Eight to 16 weeks after surgery, the tear was almost completely healed as compared to the controls.12 Kobuna et al13 reported a study in dogs related to the use of a synovial flap to promote healing of meniscal tears in the avascular zone. In contrast to control meniscal tears without the flap, longitudinal tears were repaired with fibrovascular tissue at 6 weeks, and the vessels extended to the white-white zone over the femoral surface of the meniscus. Healing of the meniscal lesion is thought to occur due to the vascularized synovial pedicle flap promoting neovascularization from the parameniscal area.

Synovium can also be stimulated to enhance meniscal repair with the application of radiofrequency pulses. Pavlovich14 presented 4 cases of meniscal tears in humans in the vascular and avascular zones treated with monopolar radiofrequency pulses. Second look arthroscopy demonstrated synovial tissue migration to the avascular zone, and healing of the now “red” meniscus tear at 6 weeks. This may be considered a “tidal wave effect” as the synovium washes ashore to the torn section of the meniscus.15 In addition, the synovial tissue fills thin gaps of necrotic tissue that occur after limited exposure to radiofrequency while invading the meniscus from the periphery; similar cases have subsequently been reported.16-18

Meniscal allograft healing is also dependant on synovial cell recruitment. Following meniscal allograft transplantation in a knee joint, menisci are repopulated with cells that originate from adjacent synovium. These cells migrate along the surface of the meniscus and additionally penetrate the deeper layers of the tissue. However, at 6 months, the central core of the meniscus remains acellular. The migrating cells appear to undergo metaplasia and are similar to meniscal fibrochondrocytes, and the exact phenotypic expression of these newly differentiated cells has yet to be determined.19,20

Anterior cruciate ligament (ACL) allograft, and ACL autografts once harvested and deprived of their original blood supply, serve as scaffolds that undergo cellular repopulate, reorganization, and collagen maturation. Both synovial cells and fibroblast migration result in vascularization of the graft from both the femoral and tibial bone tunnels and from the synovial joint lining.21

The Role of the Synovial Tissue in Nonrheumatic Pathological Conditions

Synovial irritation may result from mechanical injury, either traumatic or as a result of repetitive microtrauma, or as a result of altered metabolism, the latter is usually associated with chondral pathology.22

A vicious cycle may begin with an injury of the cartilage by overload or repetitive microtrauma. When chondral fragments are sensed by the synovium, synovial cells may respond by release of cytokines creating inflammation. If this persists, synovial fluid will no longer properly nourish health cartilage leading continued degeneration and accelerated cytokine release.23,24

As above, nonmechanical synovial inflammation may also result as a reaction to small particles of collagen type II and other cartilage derived macromolecules. This results in a vicious cycle where additional cartilage deterioration occurs due to the inflammatory mediators. In a study performed by Saxne et al,22 two groups of proteoglycan epitopes, a glycosaminoglycan-rich region of aggrecan (referred to as proteoglycan) and a hyaluronan-binding region, as well as one matrix protein, cartilage oligomeric matrix protein, were quantified by immunoassay. Synovial fluid proteoglycan concentrations were initially elevated but decreased significantly with prolonged arthritis, whereas cartilage oligomeric matrix protein levels changed less markedly and levels of hyaluronan-binding region remained stable. There was a positive correlation between synovial fluid and serum concentrations of cartilage oligomeric matrix protein in samples obtained during the early phase of the disease. This demonstrates that injury as a result of reactive, inflammatory arthritis may be temporary, as compared to rheumatoid arthritis is permanent and progressive. In addition, mononuclear cell infiltration and excessive expression of inflammatory mediators are noted in early osteoarthritis as compared to late osteoarthritis. Isolated fibroblast-like-synoviocytes are noted in different phases of osteoarthritis. In the future these observations may have therapeutic implications for patients during the early stages of arthritis.25

Knee synovial tissue may hypertrophy or fibrose and result in mechanical symptoms that may be mistaken for a meniscal tear or loose body. In particular, synovial vestigial remnants may cause pain or mechanical knee symptoms. The suprapatellar plica is a septum, sometimes fenestrated, may divide the suprapatellar pouch.26-28 The medial plical band is noted in approximately 50% of adult cadavers26,28; while usually asymptomatic, the plica may become taut, hypertrophic, or fibrous and again produce pain, crepitus, or even pseudoblocking.29-31 This medial synovial shelf may then erode the cartilage and cause impingement or medial condyle chondrosis.32 Finally, a careful history and examination can distinguish symptomatic hypertrophy and impingement of Hoffa’s fat pad. Synovial impingement is often associated with overload or overtraining.24,25,33 Dysphoria occurs during joint line compression where the patient can not explain the exact nature of the sensation and may deny pain but resists palpation and perceive a feeling of running on the knee.24

Conservative Treatment of the Synovial Disorders of the Knee

The treatment of synovial tissue in nonrheumatic disorders is based on an understanding of the inciting cause. Transient synovial irritation due to microtrauma and chondral macromolecule release will resolve with relative rest.22 Early inflammation due to cytokine release may respond to nonsteroidal anti-inflammatory drugs (NSAIDs) that block prostaglandins achieving relief of both symptoms and prevention of the vicious circle. It is controversial whether acetaminophen, which is not a NSAID, may have a similar mechanism in conditions of painful synovitis.34-36 In a murine model, the citrus bioflavonoid, Hesperidine, diminished reactive inflammatory arthritis; in the future, this must be investigated for potential human application.

Surgical Treatment of Synovial Disorders

When synovial inflammation or impingement does not respond to conservative treatment arthroscopic partial or subtotal synovectomy must be thoughtfully considered.37 Open surgical synovectomy is time honored procedure, and arthroscopic synovectomy has been performed since the 1970s.34 Arthroscopic debridement and removal of a symptomatic medial plica may resolve pain and pseudoblocking of the knee joint, but only for appropriate indications and symptoms.38 In a study of synovial impingement syndrome mimicking a torn meniscus, similar focal synovectomy with excision of hemorrhagic, hypertrophic, fibrotic and impinging synovial tissue demonstrated good clinical outcomes.24

Focal synovectomy for nonrheumatic disorders should only be considered after other causes of mechanical knee pain have been ruled-out and after failure of nonsurgical treatment. In such cases, arthroscopic partial synovectomy is of great help in eliminating or reducing symptoms.24,39-41

References

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Authors

Dr Pavlovich is from the Knee Clinic, Orthopedica Institute for Musculoskeletal Diseases, and the Biomedical Division, University of Sonora, Hermosillo, Sonora, Mexico; and Dr Lubowitz is from the Research Foundation and Fellowship Training Program, Taos Orthopaedic Institute, Taos, New Mexico.

Dr Pavlovich has disclosed no relevant financial relationships. Dr Lubowitz is a consultant and paid researcher for Arthrex and Smith & Nephew. Dr Morgan, CME Editor, has disclosed the following relevant financial relationships: Stryker, speakers bureau; Smith & Nephew, speakers bureau, research grant recipient; AO International, speakers bureau, research grant recipient; Synthes, institutional support. Dr D’Ambrosia, Editor-in-Chief, has disclosed no relevant financial relationships. The staff of Orthopedics have disclosed no relevant financial relationships.

The material presented at or in any Vindico Medical Education continuing education activity does not necessarily reflect the views and opinions of Vindico Medical Education or Orthopedics. Neither Vindico Medical Education or Orthopedics, nor the faculty endorse or recommend any techniques, commercial products, or manufacturers. The faculty/authors may discuss the use of materials and/or products that have not yet been approved by the US Food and Drug Administration. All readers and continuing education participants should verify all information before treating patients or utilizing any product.

Correspondence should be addressed to: Rafael Iñigo Pavlovich, MD, PhD, Centro Medico del Rio, Reforma 273 y Rio San Miguel, Suites 6 & 7, Proyecto Rio Sonora, Hermosillo, Sonora, Mexico 83280.

10.3928/01477447-20080201-24

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