Irreversible Cartilage Damage Research Articles

Cartilage degradation is fully reversible in the presence of aggrecanase but not matrix metalloproteinase activity

IntroductionPhysiological and pathophysiological cartilage turnover may coexist in articular cartilage. The distinct enzymatic processes leading to irreversible cartilage damage, compared with those needed for continuous self-repair and regeneration, remain to be identified. We investigated the capacity of repair of chondrocytes by analyzing their ability to initiate an anabolic response subsequent to three different levels of catabolic stimulation.MethodsCartilage degradation was induced by oncostatin M and tumour necrosis factor in articular cartilage explants for 7, 11, or 17 days. The catabolic period was followed by 2 weeks of anabolic stimulation (insulin growth factor-I). Cartilage formation was assessed by collagen type II formation (PIINP). Cartilage degradation was measured by matrix metalloproteinase (MMP) mediated type II collagen degradation (CTX-II), and MMP and aggrecanase mediated aggrecan degradation by detecting the 342FFGVG and 374ARGSV neoepitopes. Proteoglycan turnover, content, and localization were assessed by Alcian blue.ResultsCatabolic stimulation resulted in increased levels of cartilage degradation, with maximal levels of 374ARGSV (20-fold induction), CTX-II (150-fold induction), and 342FFGVG (30-fold induction) (P < 0.01). Highly distinct protease activities were found with aggrecanase-mediated aggrecan degradation at early stages, whereas MMP-mediated aggrecan and collagen degradation occurred during later stages. Anabolic treatment increased proteoglycan content at all time points (maximally, 250%; P < 0.001). By histology, we found a complete replenishment of glycosaminoglycan at early time points and pericellular localization at an intermediate time point. In contrast, only significantly increased collagen type II formation (200%; P < 0.01) was observed at early time points.ConclusionCartilage degradation was completely reversible in the presence of high levels of aggrecanase-mediated aggrecan degradation. After induction of MMP-mediated aggrecan and collagen type II degradation, the chondrocytes had impaired repair capacity.

LIGHT is involved in the pathogenesis of rheumatoid arthritis by inducing the expression of pro‐inflammatory cytokines and MMP‐9 in macrophages

Macrophages play a crucial role in the perpetuation of inflammation and irreversible cartilage damage during the development of rheumatoid arthritis (RA). LIGHT (TNFSF14) and its receptor TR2 (TNFRSF14) are known to have pro-inflammatory activities in foam cells of atherosclerotic plaques. We tested a hypothesis that LIGHT and TR2 are involved in activation of monocyte/macrophages in RA synovium. Immunohistochemical analysis of RA synovial tissue samples revealed that both LIGHT and TR2 are expressed in CD68 positive macrophages. In contrast, synovial tissue samples from osteoarthritis (OA) patients failed to reveal the expression of LIGHT. Expression of TR2 in RA synovial macrophages was also detected using flow cytometry analysis. To identify the role of LIGHT in the functioning of macrophages in RA, we isolated macrophage enriched cells from RA synovial fluid and stimulated them with LIGHT. LIGHT induced expression of matrix metalloproteinase-9 and pro-inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8. These data indicate that LIGHT and TR2 expressed in macrophages are involved in the pathogenesis of RA by inducing the expression pro-inflammatory cytokines and matrix degrading enzymes.

Incongruity versus instability in the etiology of posttraumatic arthritis.

The etiology of posttraumatic arthritis is understood poorly but it clearly has a pathomechanical component. Posttraumatic arthritis likely results from irreversible cartilage damage sustained at the time of injury and chronic cartilage overloading resulting from articular incongruity and instability. However, the relative importance of instability and incongruity is unknown. Clinical studies show that the hip, knee, and ankle tolerate incongruity differently. However, all three joints poorly tolerate instability. Basic mechanical studies have shown that static loading of articular surface incongruities have caused relatively modest increases in contact pressure. However, static testing poorly replicates normal viscoelastic properties of cartilage, which may mask important transient stress elevations that occur during motion. Static tests also ignore potential abnormal loads that may accumulate throughout a motion cycle. We review the clinical and basic scientific evidence linking incongruity and instability to posttraumatic arthritis. Preliminary data from a newly developed dynamic ankle testing device are presented. Dynamic testing allows measurement of transient contact loads and loading rates that occur through the entire motion cycle and it opens the door to measure mechanical abnormalities associated with instability.

Deficiency of NADPH Oxidase Components p47phox and gp91phox Caused Granulomatous Synovitis and Increased Connective Tissue Destruction in Experimental Arthritis Models

Recent studies indicated that the nicotinamide dinucleotide phosphate oxidase (NADPH) oxidase-derived oxygen radicals plays a deleterious role in arthritis. To study this in more detail, gonarthritis was induced in NADPH oxidase-deficient mice. Mice received an intraarticular injection of either zymosan, to elicit an irritant-induced inflammation, or poly-L-lysine coupled lysozyme, to evoke an immune-complex mediated inflammation in passively immunized mice. In contrast to wild-type mice, arthritis elicited in both p47phox(-/-) and gp91(-/-) mice showed more severe joint inflammation, which developed into a granulomatous synovitis. Treatment with either Zileuton or cobra venom factor showed that the chemokines LTB4 and complement C3 were not the driving force behind the aggravated inflammation in these mice. Arthritic NADPH oxidase-deficient mice showed irreversible cartilage damage as judged by the enhanced aggrecan VDIPEN expression, and chondrocyte death. Furthermore, only in the absence of NADPH oxidase-derived oxygen radicals, the arthritic joints showed osteoclast-like cells, tartrate-resistant acid phosphatase (TRAP)-positive/multinucleated cells, extensive bone erosion, and osteolysis. The enhanced synovial gene expression of tumor necrosis factor-alpha, interleukin-1alpha, matrix metalloproteinase (MMP)-3, MMP-9 and receptor activator of NF-kappaB ligand (RANKL) might contribute to the aggravated arthritis in the NADPH oxidase-deficient mice. This showed that the involvement of NADPH oxidase in arthritis is probably far more complex and that oxygen radicals might also be important in controlling disease severity, and reducing joint inflammation and connective tissue damage.

Ciprofloxacin for the treatment of uncomplicated gonorrhea infection in adolescents: does the benefit outweigh the risk?

The highest rates of reported gonorrhea infections occur among adolescent females aged 15-19 years. Among the Centers for Disease Control and Prevention (CDC)-recommended single-dose gonorrhea treatment regimens, ciprofloxacin, a fluoroquinolone antibiotic, is approximately half the cost of other CDC-recommended oral treatment regimens. Fluoroquinolone use in patients aged <18 years has been limited because of irreversible articular cartilage damage demonstrated in large, weight-bearing joints of young animals. We reviewed the medical literature to assess whether the risks of a single 500-mg dose of ciprofloxacin to treat uncomplicated gonorrhea infection in adolescents appears to outweigh the benefits. We found no reports of irreversible cartilage toxicity or age-associated adverse events in 5236 human children and adolescents (aged 5 days-24 years) treated with a total of 5486 courses of fluoroquinolones.

Denaturation of type II collagen in articular cartilage in experimental murine arthritis. Evidence for collagen degradation in both reversible and irreversible cartilage damage.

Degradation of type II collagen is thought to be a key step in the destruction of articular cartilage in patients with rheumatoid arthritis or osteoarthritis. The aim of this study was to investigate whether type II collagen degradation is associated with cartilage destruction. Type II collagen degradation was studied in two murine arthritis models, zymosan-induced arthritis (ZIA), which develops reversible articular cartilage damage based on proteoglycan analysis, and antigen-induced arthritis (AIA), in which there is irreversible damage to the cartilage. Type II collagen degradation was assayed immunohistochemically using the COL2-3/4m antibody which recognizes denatured type II collagen, such as is produced by collagenase cleavage. In both models, degradation of type II collagen was observed in the non-calcified articular cartilage of arthritic but not of control knees. In the patella-femoral compartment, collagen denaturation started to increase on day 3 (ZIA) and day 7 (AIA) and remained high on day 14. In contrast, in the tibia-femoral compartment, type II collagen breakdown was not increased before 14 days in either model. By 28 days, collagen denaturation was strongly reduced in the patella-femoral compartment in the ZIA model, but persisted in the tibia-femoral compartment in both models. In conclusion, increased type II collagen degradation was found in articular cartilage of both ZIA and AIA animals. Since ZIA does not develop irreversible cartilage destruction, this indicates that cartilage may have the ability to withstand a limited degree of type II collagen degradation without developing irreversible damage.

Kinetics of aggrecanase- and metalloproteinase-induced neoepitopes in various stages of cartilage destruction in murine arthritis.

Two major cleavage sites, one mediated by metalloproteinases (MMPs) and the other by an as-yet unidentified enzyme termed aggrecanase, have been observed in aggrecan. To learn more about the relative contribution of these enzymes during cartilage degradation, this study assessed the occurrence of both specific neoepitopes in cartilage during murine arthritis and examined the correlation between neoepitope formation and different aspects of cartilage damage. Reversible cartilage damage was induced in mice in the zymosan-induced arthritis (ZIA) model, partly irreversible cartilage damage in the antigen-induced arthritis (AIA) model, and irreversible, destructive cartilage damage in the collagen-induced arthritis (CIA) model. Immunolocalization techniques were used to detect the specific C-terminal neoepitopes VDIPEN (MMPS) and NITEGE (aggrecanase). In normal cartilage from young adult mice, no VDIPEN epitopes were detected, but a limited amount of NITEGE epitopes were already present. During the early phase of proteoglycan (PG) depletion, NITEGE expression was raised substantially in all arthritis models. VDIPEN epitopes were not detected in this early phase of cartilage destruction. When PG depletion progressed toward advanced cartilage damage, VDIPEN epitopes were induced. During ZIA, minimal induction of VDIPEN was observed, whereas in AIA, strong, but partly reversible, VDIPEN staining was evident, and in CIA, an extensive presence and persistence of the MMP-induced neoepitope was seen. When VDIPEN epitopes were intensely present, NITEGE epitopes were greatly reduced at that site in the cartilage. Presence of VDIPEN epitopes in cartilage correlated with severe cartilage damage, but these epitopes were not detected during early PG degradation. This suggests a limited role for VDIPEN-inducing MMPs in early PG degradation during murine arthritis. In contrast, aggrecanase epitopes were induced before the appearance of VDIPEN epitopes, but they disappeared with progression of cartilage damage.

Agents that block fibronectin fragment-mediated cartilage damage also promote repair.

The objective was to determine if agents that suppress catabolism might also enhance repair of irreversibly damaged cartilage. Articular cartilage from bovine metacarpophalangeal joints was studied in explant culture. Fibronectin fragments or IL-1 alpha, which potently cause proteoglycan (PG) loss from cartilage, were added to cultures also containing the catabolism-blocking agents: insulin-like growth factor-1, or N-acetylcysteine, or Arg-Gly-Asp-Ser peptide, and the effects of these agents on blocking PG loss determined. To test for repair or restoration of PG, cartilage was first damaged, damage agents removed and inhibitory agents added. Each mean and SD value for cartilage PG content was determined by assays of papain digests of cartilage from three similar cultures. The agents either partially or fully blocked PG loss and promoted repair. Normally irreversible cartilage damage was reversed by slowing ongoing catabolic processes during attempted repair. Thus, catabolic inhibitors have reparative potential.

Effect of impact load on articular cartilage: development of an intra-articular fracture model.

To investigate the biological and mechanical effects of a single-impact load on articular cartilage. An in vitro laboratory study was performed using mature bovine cartilage and bone, and isolated cartilage explants. Each specimen was impacted with a single load applied with a specially designed impactor and materials test machine. Chondrocyte metabolic activity and cartilage structural integrity was investigated using force displacement curves, radionuclide labeling, histology, and changes in water content. Laboratory for Soft Tissue Research, New York, New York, U.S.A. Viable mature bovine cartilage and cartilage and bone explants. Mechanical failure, proteoglycan synthesis, water content, histology, radiography, and scanning electron microscopy changes occurring during the twenty-four-hour period immediately following impact. Force/displacement curves for the cartilage and bone explants demonstrated two failure-stress peaks, the first at fifty megapascals, representing cartilage failure, and a second peak at seventy-five megapascals, representing bone failure. Fine grain radiographs, histology, and scanning electron microscopy all confirmed the destruction of the cartilage in the area of direct impact (zone I) and subchondral bone failure and the detachment of the cartilage within the lesser impacted area (zone II). Proteoglycan synthesis was reduced significantly (p < 0.05) in the areas of direct impact (zone I) compared with areas with less or no impact (zones II and III, respectively). Significantly greater water content (p < 0.05) was found within the cartilage of zone I compared with zones II and III. Significant and possibly irreversible articular cartilage damage occurs after a single high-energy impact load.

Distal Radioulnar Joint Injuries Associated With Fractures of the Distal Radius

The most common cause of residual wrist disability after fractures of the distal radius is the distal radioulnar joint. The 3 basic conditions that produce radioulnar pain and limitation of forearm rotation are instability, joint incongruency, and ulnocarpal abutment. The last 2 entities initiate irreversible cartilage damage that eventually leads to degenerative joint disease. Early recognition and management in the acute stage aim at the anatomic reconstruction of the distal radioulnar joint including bone, joint surfaces, and ligaments in an effort to reduce the incidence of painful sequelae and functional deficit. This article provides a description and the treatment options of the distal radioulnar joint lesions that occur in association with fractures of the distal radius, and the results obtained with open and arthroscopic techniques. Both acute and chronic disorders are analyzed, and a prognostic and treatment oriented classification is presented Furthermore, the pathoanatomy and management of chronic distal radioulnar joint derangement after fracture of the distal radius are reviewed briefly.

Interactions of synovial fluid immunoglobulins with chondrocytes.

To study the interaction of synovial fluid (SF) immunoglobulins with living chondrocytes, and to evaluate the relative contribution of type II collagen (CII) antibodies. SF of patients with rheumatoid arthritis (RA), osteoarthritis (OA), and gout were incubated with isolated bovine articular chondrocytes. Ig binding was measured by flow cytometry and by quantitation with 125I-labeled anti-IgG and anti-IgM. Complement-dependent cytotoxicity was determined by 51Cr release. Immunoglobulin binding and cytotoxicity were compared between chondrocytes obtained from the superficial and from the deep cartilage zones. Significantly greater IgG and IgM binding was found with RA SF compared with OA or gout SF. Chondrocytes bound more Ig than did fibroblasts. The relative contribution of anti-CII antibodies to Ig binding was studied following absorption of the SF with bovine CII, and by incubation with bacterial collagenase-treated chondrocytes. There was a small but significant reduction in IgG and IgM binding with SF samples that were positive for anti-CII. RA SF exhibited modest, but significantly greater complement-dependent cytotoxicity than OA SF: Gel chromatography fractionation indicated that IgM antibodies were responsible for the cytotoxic activity. Additional studies showed that SF IgM antibodies bound preferentially to, and killed chondrocytes obtained from, the superficial layers of cartilage. Anti-CII antibodies contained in RA SF represent one of many antibody specificities reacting with chondrocyte membrane antigens. Chondrocyte-reactive SF antibodies may play an important pathogenic role in the processes leading to irreversible cartilage damage in RA. These deleterious effects appear to be exerted particularly on chondrocytes located near the articular surface of cartilage.

Immune mediated cartilage destruction.

We review the pathogenic role of immune complexes attached to articular cartilage in rheumatoid arthritis. The available evidence suggests that these immune complexes may contribute to irreversible cartilage damage and loss of joint function. In addition, tenacious binding of these complexes to collagenous tissues, possibly by the establishment of covalent bonds, may constitute an important chronicity factor in this disease. The biochemical mechanisms that may be responsible for covalent cross-linking of macromolecules in inflammatory foci are discussed.

Central fractures of the acetabulum

A series of 26 patients with central fractures of the acetabulum is presented with a follow-up of 3–13 years. Three patients had undisplaced fractures. In the remaining 23, long-term results of treatment by traction in 15 and by primary open reduction in 8 have been compared. A numerical grading system has been used for assessment. Results in the non-operative group were generally poor, only 2 being satisfactory. Some of the poorest scores in this group were associated with initial roof damage. Three patients required secondary salvage procedures because of severe pain and disability approximately 2 years after injury. Of the open reduction patients, all with roof damage, 4 had satisfactory results. Reasons for failure in the remaining 4 patients are discussed. ‘Galloping’ degeneration, due presumably to irreversible intra-articular cartilage damage at the initial injury, developed in 2 patients in the non-operative group and in one in the operative group.