The role of inflammation in the initiation of osteoarthritis after meniscal damage.

Meniscal damage and meniscectomy lead to subsequent osteoarthritis (OA) of the knee joint through multiple and diverse mechanisms, yet the interaction of these mechanisms remains unknown. Therefore, the aim of this review is to suggest the multi-scale, multi-faceted components involved between meniscal injury or meniscectomy and the initiation of OA. There is evidence of structural, mechanical, and biological changes after meniscal damage, all of which can be greatly affected by the presence of local or systemic inflammation. Meniscal damage or resection causes changes in knee mechanics during walking, resulting in altered cartilage loading. Because cartilage is mechanically sensitive, these loading changes can initiate a catabolic effect, culminating in tissue degeneration. The evidence suggests that the addition of elevated inflammation at the time of meniscal damage or meniscectomy results in an accelerated progression toward cartilage degradation. Initial cartilage degradation produces inflammation and pain in conjunction with structural changes to the joint, thus perpetuating the cycle of altered cartilage loading and subsequent degradation. Furthermore, the inflammation secondary to obesity and aging introduces an increased risk of developing OA following meniscal injury. Therefore, an overall route between meniscal damage or resection and OA is presented here in a manner that considers two distinct pathways; these pathways reflect the absence or presence of conditions that cause elevated inflammation.

Mesenchymal stem cells in synovial fluid increase after meniscus injury.

BACKGROUND: Although relatively uncommon, spontaneous healing from a meniscus injury has been observed even within the avascular area. This may be the result of the existence of mesenchymal stem cells in synovial fluid. QUESTIONS/PURPOSES: The purpose of this study was to investigate whether mesenchymal stem cells existed in the synovial fluid of the knee after meniscus injury. METHODS: Synovial fluid was obtained from the knees of 22 patients with meniscus injury just before meniscus surgery and from 8 volunteers who had no history of knee injury. The cellular fraction of the synovial fluid was cultured for 14 days followed by analysis for multilineage potential and presentation of surface antigens characteristic of mesenchymal stem cells. Colony-forming efficiency and proliferation potential were also compared between the two groups. RESULTS: Cells with characteristics of mesenchymal stem cells were observed in the synovial fluid of injured knees to a much greater degree than in uninjured knees. The colony-forming cells derived from the synovial fluid of the knee with meniscus injury had multipotentiality and surface epitopes identical to mesenchymal stem cells. The average number of colony formation, obtained from 1 mL of synovial fluid, in meniscus-injured knees was 250, higher than that from healthy volunteers, which was 0.5 (p < 0.001). Total colony number per synovial fluid volume was positively correlated with the postinjury period (r = 0.77, p < 0.001). CONCLUSIONS: Mesenchymal stem cells were found to exist in synovial fluid from knees after meniscus injury. Mesenchymal stem cells were present in higher numbers in synovial fluid with meniscus injury than in normal knees. Total colony number per synovial fluid volume was positively correlated with the postinjury period. CLINICAL RELEVANCE: Our current human study and previous animal studies suggest the possibility that mesenchymal stem cells in synovial fluid increase after meniscus injury contributing to spontaneous meniscus healing.

Polyethylene wear particles play a role in development of osteoarthritis via detrimental effects on cartilage, meniscus, and synovium.

OBJECTIVE: While ultra-high molecular weight polyethylene (UHMWPE) wear particles are known to cause periprosthetic osteolysis, its interaction with other intra-articular tissues in the case of partial joint arthroplasties is not well understood. We hypothesized that UHMWPE particles per se would interact with intra-articular tissue, which by acting as inflammatory reservoirs, would subsequently induce osteoarthritic (OA) changes. Our goal was to assess the inflammatory response, phagocytic activity, as well as apoptosis of intra-articular cells in the presence of UHMWPE particles in vitro, and the in vivo response of those tissues after intra-articular injection of particles in a murine model. DESIGN: Three cell types were used for the in vitro study; chondrocytes, meniscal fibrochondrocytes, and synoviocytes. Each cell type was cultured with two different concentrations of UHMWPE particles. Pro-inflammatory cytokine production, phagocytosis, and apoptosis were analyzed. In vivo experiments were done by injecting two concentrations of UHMWPE particles into normal and murine OA model knee joints. RESULTS: In vitro experiments showed that UHMWPE particles increase pro-inflammatory cytokine and mediator (IL-1ß, IL-6, TNF-α, Nitric Oxide, and Prostaglandin E2) production, phagocytosis of particles, and apoptosis in all cell types. In vivo experiment showed degeneration of cartilage and meniscus, as well as synovitis after particle injection. CONCLUSIONS: UHMWPE wear particles per se exert detrimental effects in cartilage, synovium, and meniscus of the knee joint resulting in pro-inflammatory cytokine release, phagocytosis of particles and apoptosis. Particles induced and exacerbated OA changes in a murine model.

Muscle morphometric effect of anterior cruciate ligament injury measured by computed tomography: aspects on using non-injured leg as control.

BACKGROUND: Anterior cruciate ligament (ACL) tears are common, functionally disabling, and predispose to subsequent injuries and early onset of osteoarthritis in the knee. Injuries result in muscular atrophy and impaired muscular activation. To optimize surgical methods and rehabilitation strategies, knowledge of the effects of ACL injuries on muscles size and function is needed. Asymmetry due to limb dominance implies that the effect of ACL-injury might be different in right-sided and left-sided injuries which, should be taken in account when evaluating the effect of an injury. Evaluation of the effects of injuries is usually made with the contralateral leg as control. The aim of this study is to describe the effect of ACL-injuries on thigh muscle size and also to analyze feasibility of using contralateral limb as control. METHODS: Sixty-two patients scheduled to undergo ACL reconstruction were examined with computed tomography (CT). Muscle cross sectional area (CSA) was recorded for quadriceps, hamstrings, gracilis and sartorius 15 cm above the knee joint. Comparisons were made between the injured and non-injured side and between individuals separated by gender and side of injury. Comparisons were also made for patients with or without concomitant meniscal tear, for patients differing in time between injury and examinations and for patients with different level of physical activity after the injury. RESULTS: Quadriceps CSA was 5% smaller on the injured side. There was an indication that the muscles of the right thigh were generally bigger than those of the left thigh. The difference between the injured and the non-injured side was larger for right-sided injuries than for left-sided. There was also a greater difference in semimembranosus for women than for men. There were no differences related to meniscal injury, time since injury or physical activity. CONCLUSION: The use of contralateral leg for evaluating the effect of ACL-injury is often the only available alternative but our study indicates that the difference in CSA between injured and non-injured side does not necessarily reflect the true degree of atrophy, as there are side differences both in muscle size in general and in the effect of an ACL-injury on muscle size.

Cartilage as a target of autoimmunity: a thin layer.

The articular cartilage is an important component of human organism that has elasticity, low-friction surface, and ability to withstand great physical forces. The structure consists of collagens and proteoglycans, whereas non-collagenous proteins are needed for the organization and modulation of the molecular networks. The structural elements of the cartilage are typical to that tissue and could, in part, account for the localization of the inflammatory response to the joint. For this reason cartilage is of particular interest in autoimmunity as it may represent a source of antigens. It is well known that sensitization with collagens can produce autoimmune rheumatic diseases in experimental models. So far, the cartilage proteins that have been clearly characterized to be arthritogenic in experimental models involve types II and XI collagen, cartilage oligomeric matrix protein, and aggrecan. It is likely that these proteins are also recognized at different stages in the development of rheumatoid arthritis and in other autoimmune diseases. The mechanisms determining the trigger of a cartilage-specific immune response, its development and outcome are poorly understood. Most likely, the distribution and concentration of a specific cartilage protein may play a role by eliciting an autoimmune response. Indeed, the inflammatory processes lead to tissue damage mediated by the intervention of several factors such as autoantibodies, cytokines as well as cells of the innate an adaptive immunity. For this reason, even previously-considered degenerative diseases, such as osteoarthritis, should now be re-evaluated as at least partly inflammatory-driven. Thus, the objective of this review is to describe the clinical conditions sustained by the immune-mediated reactions to cartilage, which represents the target organ in a number of autoimmune diseases.

Immunogenicity of bovine and leporine articular chondrocytes and meniscus cells.

Immune rejection is a major concern for any allogeneic or xenogeneic graft. For in vivo investigations of cartilage tissue engineering strategies, small animal models such as the leporine model are commonly employed. Many studies report little to no immune rejection upon allogeneic or xenogeneic implantation of native articular and meniscal cartilages. This study investigated whether bovine and leporine articular chondrocytes (ACs) and meniscus cells (MCs) have immunoprivileged characteristics because of their ability to stimulate proliferation of leporine peripheral blood mononuclear cells (PBMCs) in vitro. After 6 days of co-culture, none of the cell types caused a proliferative response in the leporine PBMCs, indicating that these cells may not elicit immune rejection in vivo. Reverse transcriptase polymerase chain reaction analysis for major histocompatibility complex class (MHC) I and II and costimulation factors CD80 and CD86 revealed that all cell types produced messenger RNA for MHC I and II, but only some were CD80 or CD86 positive, and none were positive for both costimulation factors. Flow cytometry found that bovine MCs and ACs displayed MHC II (MCs: 32.5%, ACs: 14.4%), whereas only leporine ACs were MHC II positive (7.5%). Although present in isolated cells, MHC I and II were not observed in intact bovine or leporine hyaline cartilage or meniscus tissues. Despite some presence of MHC II and costimulation factors, none of the cell types studied were able to cause PBMC proliferation. These findings indicate that bovine and leporine MCs and ACs share a similar immunoprivileged profile, bolstering their use as allogeneic and xenogeneic cell sources for engineered cartilage.

Interleukin-1alpha treatment of meniscal explants stimulates the production and release of aggrecanase-generated, GAG-substituted aggrecan products and also the release of pre-formed, aggrecanase-generated G1 and m-calpain-generated G1-G2.

Pro-inflammatory cytokines induce meniscal matrix degradation and inhibition of endogenous repair mechanisms, but the pathogenic mechanisms behind this are mostly unknown. Therefore, we investigated details of interleukin-1 (IL-1alpha)-induced aggrecan turnover in mature meniscal tissue explants. Fibro-cartilagenous disks (3 mm diameter x 1 mm thickness) were isolated from the central, weight-bearing region of menisci from 2-year-old cattle. After 3 or 6 days of IL-1alpha-treatment, GAG loss (DMMB assay), biosynthetic activity ([(35)SO(4)]-sulfate and [(3)H]-proline incorporation), gene expression (quantitative RT-PCR) and the abundance (zymography, Western blot) of matrix-degrading enzymes and specific aggrecan products were determined. Meniscal fibrocartilage had a 4-fold lower GAG content (per wet weight) than adjacent articular cartilage, and expressed MMPs-1, -2, -3 and ADAMTS4 constitutively, whereas ADAMTS5 m-RNA was essentially undetectable. Significant IL-1 effects were a decrease in biosynthetic activity, an increase in GAG release and in the expression/abundance of MMP-2, MMP-3 and ADAMTS4. Fresh tissue contained aggrecan core protein products similar to those previously described for bovine articular cartilage of this age. IL-1 induced the release of aggrecanase-generated CS-substituted products including both high (>250 kDa) and low molecular weight (about 75 kDa) species. TIMP-3 (but not TIMP-1 and -2 or a broad spectrum MMP inhibitor) inhibited IL-1-dependent GAG loss. In addition, IL-1 induced the release of preformed pools of three known G1-bearing products. We conclude that aggrecanases are responsible for IL-1-stimulated GAG release from meniscal explants, and that IL-1 also stimulates release of G1-bearing products, by a process possibly involving hyaluronan fragmentation.

Surgical stress-induced immune cell redistribution profiles predict short-term and long-term postsurgical recovery. A prospective study.

BACKGROUND: The experience of undergoing surgery is known to induce a short-term, fight-or-flight physiological stress response. As an optimum immune response at the site of surgery would enhance tissue repair, we examined surgical stress-induced immune cell redistribution profiles as predictors, and potential mediators, of short and long-term postoperative recovery. We tested the a priori hypothesis that predefined adaptive immune cell redistribution profiles observed during surgery will predict enhanced postoperative recovery. METHODS: This prospective longitudinal study involved fifty-seven patients undergoing meniscectomy. Knee function was assessed preoperatively and at one, three, eight, sixteen, twenty-four, and forty-eight weeks postoperatively with use of the clinically validated Lysholm scale, which assesses mechanical function, pain, mobility, and the ability to perform daily activities. Surgery-induced immune cell redistribution was measured in the blood at baseline, before surgery, and after surgery. RESULTS: Mixed-model repeated-measures analyses revealed a main effect of immune cell redistribution: patients who showed the predefined "adaptive" lymphocyte and monocyte redistribution profiles during surgery showed enhanced recovery. Interesting differences were also observed between the sexes: women as a group showed less adaptive redistribution and correspondingly showed significantly delayed maximum recovery, requiring forty-eight weeks, compared with men, who required only sixteen weeks. Inter-individual differences in leukocyte redistribution predicted the rate of recovery across both sexes. CONCLUSIONS: Immune cell redistribution that is induced by the stress of undergoing surgery can predict (and may partially mediate) postoperative healing and recovery. These findings may provide the basis for identifying patients (either prospectively or during surgery) who are likely to show good as opposed to poor recovery following surgery and for designing interventions that would maximize protective immune responses and enhance the rate and extent of recovery.

Contributions of different intraarticular tissues to the acute phase elevation of synovial fluid MMP-2 following rat ACL rupture.

Inflammation and accumulation of matrix metalloproteinases (MMPs) in synovial fluids may be involved in the poor healing ability of the anterior cruciate ligament (ACL) after injury. With a rat ACL rotating injury model, we found that levels of IL-1beta, IL-6, and TNF-alpha were significantly higher in synovial fluids after ACL injury. MMP-2 activity and global MMP activity in synovial fluids also increased significantly in a time-dependent manner. Ex vivo studies showed that all tissues contributed to the elevation of MMP-2 in synovial fluids, especially synovium and the injured ACL. We concluded that although the regular wound-healing mechanism also occurs after ACL injury, accumulation of MMP activity in the synovial fluids, due to all of the intraarticular tissues, may be at least one of the important reasons why an injured ACL cannot be repaired.

[Degradation of antigen-extracted meniscus in vitro].

OBJECTIVE: To study degradation of the antigen-extracted meniscus in PBS solution with no enzyme or with different enzymes. METHODS: Four types of enzymes (collagenase, hyaluronidase, trypsin, papain) were used to enzymolyze the antigen-extracted meniscus and the fresh meniscus for 3, 7, 15 and 30 days (37 degrees C). The antigen-extracted meniscus and the fresh meniscus were immersed in PBS solution (37 degrees C) for 30 days. Weight loss measurement, UV spectrophotometry, and scanning electron microscopy (SEM) were used to characterize the degraded materials. RESULTS: The two types of the materials were remarkably digested under the enzymes, especially under trypsin. The degradation curves showed that the antigen-extracted meniscus was enzymolyzed less than the fresh meniscus. The degradation products were grouped as amino, peptide, and polycose by the analysis. Both of the materials could hardly be hydrolyzed in PBS solution without the enzymes. The four different enzymes had different surface morphologies under the examination of SEM. CONCLUSION: The antigen-extracted meniscus is enzymolyzed more slowly than the fresh meniscus in vitro, and the result can be used as a guideline to the further research.

Meniscal allograft transplantation--part I: background, results, graft selection and preservation, and surgical considerations.

Removal of the meniscus leads to progressive degenerative arthritis of the knee on a long-term basis. Therefore, meniscal allograft transplantation has been proposed as an alternative to meniscectomy. Although several experimental and clinical studies have documented that meniscal allografts show capsular ingrowth in meniscectomized knees, it remains to be established whether meniscal allograft transplantation can prevent degenerative changes after meniscectomy. Part 1 of this Current Concepts review will discuss the function, anatomy, and composition of the meniscus, followed by the history of surgery of meniscal tears and the healing of meniscal allografts in experimental and clinical studies. In addition, issues concerning preservation techniques, immunological reactions, sizing, disease transmission, indications, surgical technique, graft fixation, rehabilitation, and complications, will be taken into consideration. It can be concluded that the use of meniscal allografts in clinical practice has progressed to a point where relief of pain may be expected for the short-term.

Interleukin-1, tumor necrosis factor alpha, and interleukin-17 synergistically up-regulate nitric oxide and prostaglandin E2 production in explants of human osteoarthritic knee menisci.

OBJECTIVE: In osteoarthritis (OA), a combination of biochemical and biomechanical factors may damage both menisci and articular cartilage. Nitric oxide (NO) and prostaglandin E2 (PGE2) have been implicated as mediators of inflammation in OA. The goals of this study were to determine if menisci from patients with OA produce NO and PGE2, and if the proinflammatory cytokines interleukin-1beta (IL-1beta), tumor necrosis factor a (TNFalpha), and IL-17 augment NO and PGE2 production by these tissues. METHODS: Menisci were obtained from 17 patients (age 47-75 years) undergoing total knee replacement for OA. Tissue explants were cultured alone or with IL-1beta, IL-17, or TNFalpha, and the release of NO and PGE2 from the tissue as well as the presence of type 2 nitric oxide synthase (NOS2) and cyclooxygenase 2 (COX-2) antigens were measured. RESULTS: All menisci constitutively produced NO, and significant increases in NO production were observed in the presence of IL-1beta, TNFalpha, or IL-17 (P < 0.05). The combination of IL-17 and TNFalpha significantly increased NO production compared with either cytokine alone. Basal and cytokine-stimulated NO synthesis was inhibited by the NOS inhibitors NG-monomethyl-L-arginine or N-3-aminoethylbenzylacetamidine (1400W). IL-1beta significantly increased PGE2 production. The combination of IL-1beta and TNFalpha had an additive effect on PGE2 production, while addition of IL-17 to TNFalpha or IL-1beta synergistically enhanced PGE2 production. Inhibition of NO production by 1400W significantly increased IL-1beta-stimulated PGE2 production, and inhibition of PGE2 production by the COX-2 inhibitor N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide significantly increased IL-17-stimulated NO production. CONCLUSION: Menisci from humans with OA spontaneously produced NO and PGE2 in a manner that was synergistically or additively augmented by cytokines. NO and PGE2 exhibited reciprocal regulatory effects on one another, suggesting that pharmaceutical agents designed to inhibit NOS2 or COX-2 production may in fact be influencing both pathways.

Histological analysis of human meniscal allografts. A preliminary report.

BACKGROUND: Little is known about the biology of meniscal allograft transplantation in humans. In particular, little information is available about the phenotype of the cells that repopulate the allograft, whether an immune response is elicited against the graft, and whether the repopulating cells synthesize normal extracellular matrix components. METHODS: A small biopsy specimen of the meniscal allograft (twenty-eight menisci in twenty-five patients) and the adjacent synovial membrane (sixteen patients) was harvested during follow-up arthroscopy in patients who had undergone meniscal allograft transplantation at a mean of sixteen months earlier. Seventeen patients had undergone concomitant reconstruction of the anterior cruciate ligament with an allograft. Normal menisci (unimplanted allografts) and synovial specimens from age-matched controls were examined as well. All twenty-eight meniscal allografts were examined histologically. Immunohistochemical analysis was carried out on ten menisci and nine synovial specimens with use of monoclonal antibodies to class-I and class-II major histocompatibility complex antigens, CD-8, CD-11b, and CD-19 epitopes, as well as other epitopes, to demonstrate immunogenic macromolecules, cytotoxic T-lymphocytes, activated macrophages, and B-lymphocytes. RESULTS: Most of the specimens demonstrated incomplete repopulation with viable cells. The repopulating cells stained positively with phenotype markers for both synovial cells and fibroblasts. Polarized light microscopy demonstrated evidence of active remodeling of the matrix. The cells in frozen, unimplanted menisci stained positively for class-I and class-II human leukocyte antigens, indicating immunogenicity at the time of transplantation. Overall, nine of twelve specimens contained immunoreactive cells (B-lymphocytes or cytotoxic T-cells) in the meniscus or synovial tissue. However, only a small number of these cells was present. There was no evidence of frank immunological rejection. The clinical outcome (success or failure of the transplant) was not related to the overall histological score or to the presence of an immune response in the meniscal or synovial biopsy specimen. CONCLUSIONS: Human meniscal allograft transplants are repopulated with cells that appear to be derived from the synovial membrane; these cells appear to actively remodel the matrix. Although there is histological evidence of an immune response directed against the transplant, this response does not appear to affect the clinical outcome. The presence of histocompatibility antigens on the meniscal surface at the time of transplantation (even after freezing) indicates the potential for an immune response against the transplant. CLINICAL RELEVANCE: Despite the absence of frank immunological rejection, a subtle immune reaction may affect the healing, incorporation, and revascularization of the graft. It is possible that the structural remodeling associated with cellular repopulation may render the meniscus more susceptible to injury.

Immunolocalization of types I, II, and X collagen in the tibial insertion sites of the medial meniscus.

The medial meniscus of the rabbit knee joint attaches to the tibial plateau via anterior and posterior insertions. Intact meniscal tibial insertions are essential for meniscal function. In the present study the distributions of types I, II, and X collagen in meniscal tibial insertions were investigated by indirect immunohistochemistry in a rabbit model. Four tissue zones were histologically identified in the anterior insertion site, including the ligamentous zone, uncalcified and calcified fibrocartilaginous zones and bone; the ligamentous zone was not observed in the posterior insertion site. Labeling for type I collagen was found to be strong in the ligament tissue and bone, and weak in the fibrocartilages which were also labeled for type II collagen. Tissues positive for different types of collagen overlapped and formed an irregular interface with various angles and depths, especially at the interface between the calcified fibrocartilage and bone. Positive labeling for type X collagen was identified only in the calcified fibrocartilage zone. The coexistence of types I and II collagen in the meniscal tibial insertions may indicate that this structural unit is subjected to both compressive and tensile loads. Type X collagen may play a role in maintaining the calcifying status of this tissue zone, so that its mechanical stiffness is kept between that of uncalcified fibrocartilage and hard bone. Restoration of the insertional structure including the distinct collagen distribution should be considered for a functional meniscal substitution.

Localized amyloid in the menisci of the knee joint.

This is, to the best of our knowledge, the first report on amyloid deposits in menisci. Fragments of menisci gained by arthroscopy from 316 patients between 20 and 80 years of age were examined. Amyloid was found in 70% of the cases from male, as well as female patients. The amyloid amount found was always very small, but the deposits seemed to increase with age. Patients more than 50 years of age all had menisceal amyloid. Two types of deposits were observed: a)stroma-deposits in the deep central portions of the menisci (tiny dots of intensely stained amyloid and/or ill defined patches of low staining intensity) and b) surface associated deposits: band-like amyloid imbibition of the collagenous stroma immediately beneath the surface of the menisci but not deeper than 0.2 mm. In all cases, amyloid was resistant when pretreated by KMn04 and immunohistologically antisera against amyloid types AA, AB and AF were negative. 3/25 cases showed a reaction with an amyloid-lambda-antibody. We assume, that amyloid in menisci is a further type of localized senile amyloidosis.

Immune response to fresh meniscal allografts in mice.

To date, no study of allogeneic meniscal transplantation has investigated both the host cellular immune response and the humoral immune response. Using inbred mice, we examined cellular and humoral immunity to meniscal allografts through the mixed lymphocyte culture reaction and a complement-dependent cytotoxicity test. We also examined the histology of an allogeneic meniscus transplanted subcutaneously. The stimulation index of the mixed lymphocyte culture seen after placing fresh meniscal allografts subcutaneously was not significantly higher than when isograft controls were similarly placed. Following placement of the allografts, no specific antibodies were detected in serum throughout the 24-week period after grafting. Although viable fibrochondrocytes in the allogeneic meniscus decreased in number and lymphocyte infiltration around the allogeneic meniscus was noted at Week 2, no remarkable infiltration of lymphocytes into the meniscus was observed. These results indicate that in our experimental mouse model, a fresh meniscus apparently is not sufficiently immunogenic to induce a systemic reaction. Our results suggest that a fresh allogeneic meniscus can be transplanted without any special treatment to decrease its immunogenicity.

Demonstration of HLA and ABH antigens in fresh and frozen human menisci by immunohistochemistry.

The expression of HLA and ABH antigens in fresh, frozen, and twice-frozen normal human meniscal tissue was evaluated with use of immunohistochemistry. A generalized expression of Class-I and Class-II HLA antigens was found in the endothelial and synovial cells of all three forms of tissue. Fibrochondrocytes were Class-I positive and Class-II negative. ABH antigens were expressed by endothelial cells in relationship to the blood group of the patient. Freezing preserved most of the HLA and ABH molecular structure. Although the normal meniscus consists of a relatively few chondrocytes embedded in an extracellular matrix, it also contains Class-II and ABH-positive endothelial cells and Class-II-positive synovial cells. These antigens are present at the moment of transplantation and could evoke an immune response in the host that would modulate the results of meniscal allografting.

An analysis of the levels of complement components in the synovial fluid in rheumatic diseases.

A linear relationship between the synovial fluid to serum concentration ratios and log molecular weight was found for six plasma proteins, which are largely synthesized by the liver. Production or utilization of a given protein in the joint can, therefore, be determined by its deviation from the calculated diffusion line. Based on this diffusion model the role of the complement system was investigated in the joint effusions of 48 patients with rheumatoid arthritis (RA), 6 patients with osteoarthritis (OA) and 7 patients with meniscus lesions (ML). Among these three groups quantitative differences were found in the metabolism or utilization of several complement components, based on the fact that the ratios were lower than expected for diffusion of proteins of similar molecular weight. The ratios for the RA group were the lowest. In the three patient groups, results showed increased consumption mainly of C3 and C4 locally in the joint. The existence of a real complement activation in the joints of the three different patient groups was further proved by the elevated levels of C3 breakdown products (C3d). Overall this kind of calculation provides us with a method for studying the role of other proteins which may be important in the inflammatory process of the joint.

Interaction of polymorphonuclear leukocytes with immune complexes trapped in joint collagenous tissues.

The present experiments were designed to investigate in vitro interactions between polymorphonuclear leukocytes (PMN) and rabbit joint collagenous tissues containing trapped immune complexes. Articular cartilages and menisci from antigen-injected and control joints were incubated with normal PMN isolated from rabbit peritoneal exudates or blood. After incubation of cartilage and menisci from antigen-injected joints with PMN, large numbers of PMN became attached to the articular surface. In areas of superficial erosion, the PMN invaded the tissue several cell diameters below the articular surface. Through immunoelectron microscopy, degranulated PMN were observed in scattered areas to phagocytose amorphous material containing rabbit Ig. Following addition of PMN to control tissues, only a few PMN became attached to the articular surface. When tissues from monosodium urate-injected joints were incubated with PMN, these cells were found attached to the surface in moderate numbers, but invasion into the tissues was not seen. These studies indicate that immune complexes trapped in joint collagenous tissues may lead to enhanced release of lysosomal hydrolases.