The objectives of this study are to review the long-term consequences of injuries to the anterior cruciate ligament and menisci, the pathogenic mechanisms, and the causes of the considerable variability in outcome. Injuries of the anterior cruciate ligament and menisci are common in both athletes and the general population. At 10 to 20 years after the diagnosis, on average, 50% of those with a diagnosed anterior cruciate ligament or meniscus tear have osteoarthritis with associated pain and functional impairment: the young patient with an old knee. These individuals make up a substantial proportion of the overall osteoarthritis population. There is a lack of evidence to support a protective role of repair or reconstructive surgery of the anterior cruciate ligament or meniscus against osteoarthritis development. A consistent finding in a review of the literature is the often poor reporting of critical study variables, precluding data pooling or a meta-analysis. Osteoarthritis development in the injured joints is caused by intra-articular pathogenic processes initiated at the time of injury, combined with long-term changes in dynamic joint loading. Variation in outcome is reinforced by additional variables associated with the individual such as age, sex, genetics, obesity, muscle strength, activity, and reinjury. A better understanding of these variables may improve future prevention and treatment strategies. In evaluating medical treatment, we now expect large randomized clinical trials complemented by postmarketing monitoring. We should strive toward a comparable level of quality of evidence in surgical treatment of knee injuries. In instances in which a randomized clinical trial is not feasible, natural history and other observational cohort studies need to be as carefully designed and reported as the classic randomized clinical trial, to yield useful information.

/pdf/the-long-term-consequence-of-anterior-cruciate-ligament-and-3mhkqdkmu4.pdf

The Long-term Consequence of Anterior Cruciate Ligament and Meniscus Injuries Osteoarthritis

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(11)60243-2.pdf

Osteoarthritis: an update with relevance for clinical practice

Oxidative stress generated by an imbalance between reactive oxygen species (ROS) and antioxidants contributes to the pathogenesis of arthritis, cancer, cardiovascular, liver and respiratory diseases. Proinflammatory cytokines and growth factors stimulate ROS production as signaling mediators. Antioxidants such as N-acetylcysteine (NAC) have been used as tools for investigating the role of ROS in numerous biological and pathological processes. NAC inhibits activation of c-Jun N-terminal kinase, p38 MAP kinase and redox-sensitive activating protein-1 and nuclear factor kappa B transcription factor activities regulating expression of numerous genes. NAC can also prevent apoptosis and promote cell survival by activating extracellular signal-regulated kinase pathway, a concept useful for treating certain degenerative diseases. NAC directly modifies the activity of several proteins by its reducing activity. Despite its nonspecificity, ability to modify DNA and multiple molecular modes of action, NAC has therapeutic value for reducing endothelial dysfunction, inflammation, fibrosis, invasion, cartilage erosion, acetaminophen detoxification and transplant prolongation.

Molecular mechanisms of N-acetylcysteine actions.

The classical view of the pathogenesis of osteoarthritis (OA) is that subchondral sclerosis is associated with, and perhaps causes, age-related joint degeneration. Recent observations have demonstrated that OA is associated with early loss of bone owing to increased bone remodelling, followed by slow turnover leading to densification of the subchondral plate and complete loss of cartilage. Subchondral densification is a late event in OA that involves only the subchondral plate and calcified cartilage; the subchondral cancellous bone beneath the subchondral plate may remain osteopenic. In experimental models, inducing subchondral sclerosis without allowing the prior stage of increased bone remodelling to occur does not lead to progressive OA. Therefore, both early-stage increased remodelling and bone loss, and the late-stage slow remodelling and subchondral densification are important components of the pathogenetic process that leads to OA. The apparent paradoxical observations that OA is associated with both increased remodelling and osteopenia, as well as decreased remodelling and sclerosis, are consistent with the spatial and temporal separation of these processes during joint degeneration. This Review provides an overview of current knowledge on OA and discusses the role of subchondral bone in the initiation and progression of OA. A hypothetical model of OA pathogenesis is proposed.

Bone remodelling in osteoarthritis.

A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study.

Haemophilic arthropathy is characterised by iron deposits in synovial tissues. We investigated the suggestion that iron plays an important role in synovial changes. We obtained synovial tissue from six patients with haemophilia during arthroplasty, finding that brown haemosideritic tissue was often adjacent to tissue with a macroscopically normal appearance in the same joint. Samples from both types of synovial tissue were analysed histologically and biochemically to determine catabolic activity. Macroscopically haemosideritic synovium showed a significantly higher inflammatory activity than that with a normal appearance. Cultures of abnormal synovial tissue gave a significantly enhanced production of IL-1, IL-6 and TNF alpha compared with cultures of synovial tissue with a normal appearance. In addition, the supernatant fluids from the cultures showed greater catabolic activity from haemosideritic tissue, as determined by the inhibition of the synthesis of articular cartilage matrix. We conclude that in patients with haemophilic arthropathy, local synovial iron deposits are associated with increased catabolic activity.

Iron deposits and catabolic properties of synovial tissue from patients with haemophilia

Objective

To investigate mechanisms underlying cartilage damage caused by brief exposure of cartilage to blood, such as that occurring during intraarticular bleeding.



Methods

Human articular cartilage was cultured for 4 days in the presence of blood (components; 7.5–50% volume/volume). The synthesis of cartilage matrix, as determined by proteoglycan synthesis (incorporation of 35SO42−), was measured directly after exposure and after a recovery period of 20 days, during which the cartilage was cultured in the absence of blood or blood components. The production of the cytokines interleukin-1 (IL-1) and tumor necrosis factor α (TNFα), which have a destructive effect on cartilage, was determined by enzyme-linked immunosorbent assay, and the viability of chondrocytes was determined by measuring lactate dehydrogenase release and with electron microscopy. The involvement of oxygen metabolites was evaluated by using N-acetylcysteine.



Results

Brief exposure to blood resulted in dose-dependent inhibition of proteoglycan synthesis. The combination of mononuclear cells and red blood cells was responsible for this effect. The effect was irreversible, independent of IL-1 and TNFα production, and was accompanied by chondrocyte death. These effects were partially prevented by N-acetylcysteine.



Conclusion

Brief exposure of cartilage to blood, as occurs after a single episode or a limited number of bleeding episodes, results in lasting cartilage damage in vitro, in which cytotoxic oxygen metabolites play a role.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/1529-0131%28199905%2942%3A5%3C1025%3A%3AAID-ANR23%3E3.0.CO%3B2-3

Blood-induced joint damage: a human in vitro study.

Objective. To investigate the direct effect of blood and blood components on human cartilage in vitro. Methods. Healthy human articular cartilage tissue was obtained post mortem and cultured according to standard procedures. The harmful effects of whole blood and various isolated blood components as well as the reversibility of these effects were assessed by means of proteoglycan synthesis and proteoglycan release. Results. Whole blood anticoagulated with heparin, coagulated blood, mononuclear cells (MNC), erythrocytes [red blood cells (RBC)] and plasma, in this order of potency, decreased proteoglycan synthesis in a dose dependent manner. The effect of the combination of MNC and RBC in concentrations equivalent to those in whole blood was significantly greater than the effect of each of these isolated components alone and did not differ from that of whole blood. Moreover, cartilage exposed for 4 days to this combination exhibited irreversible inhibition of proteoglycan synthesis. The effect was similar to that of whole blood, the opposite of that of the individual components or other combinations. Conclusion. Results suggest a direct irreversible harmful effect of whole blood on cartilage, whereby MNC and RBC together are the main factors. Taking into account that the concentration of blood during hemarthrosis approaches 100% and the natural evacuation time of blood from a joint is about 4 days, our results suggest that prompt evacuation of intraarticular blood or prevention of intraarticular bleeding might be crucial in preventing cartilage damage.

Cartilage damage as a result of hemarthrosis in a human in vitro model.

Objective

To investigate the direct and indirect (via synovial inflammation) effects of intraarticular bleeding on cartilage in vivo.



Methods

Right knees of 14 beagle dogs were injected with autologous blood on days 0 and 2. Cartilage matrix proteoglycan turnover, collagen damage, and synovial inflammation of these knees, including the cartilage-destructive properties of the synovial tissue, were determined and compared with those of the left control knees on day 4 (short-term effects; n = 7) and day 16 (long-term effects; n = 7).



Results

Injected knees had a diminished content of proteoglycans in the cartilage matrix, and release of proteoglycans was enhanced (days 4 and 16). The synthesis of proteoglycans was significantly inhibited on day 4 but was enhanced on day 16. On day 4 more collagen was denatured in the injected joint than in the control joint; this effect was no longer detectable on day 16. Synovial tissue showed signs of inflammation on day 4 and day 16 but had cartilage-destructive properties only on day 16.



Conclusion

In vivo exposure of articular cartilage to blood for a relatively short time results in lasting changes in chondrocyte activity and in cartilage matrix integrity, changes that may predict lasting joint damage over time. Interestingly, the direct effect of blood on cartilage precedes the indirect effect via synovial inflammation.

Blood-induced joint damage: a canine in vivo study.

OBJECTIVE: We previously showed that 4-day in vitro exposure of human cartilage to blood, as well as a single experimental joint bleeding in dogs, resulted in a disturbed cartilage matrix turnover lasting at least 2 weeks. We now evaluate the longterm outcome of the adverse in vitro and in vivo effects of blood on cartilage matrix turnover. METHODS: Human and canine articular cartilage tissue was cultured in the presence of homologous whole blood during 4 days. The in vitro cartilage matrix turnover was analyzed directly after blood exposure or following culture for additional periods of 2, 5, and 10 weeks in the absence of blood. The in vivo longterm effects were determined by injecting autologous blood into the right knee of 12 Beagle dogs. Six dogs were killed shortly after blood injections; the 6 remaining dogs were killed 10 weeks later. Cartilage matrix turnover and the cartilage destructive properties of the synovial tissue were analyzed. RESULTS: Short term (4 days) in vitro exposure of human or canine cartilage to whole blood inhibited proteoglycan synthesis by more than 98% (day 4), an inhibition which lasted until week 10 (70 and 75% inhibition, respectively). Also the in vivo short term exposure of cartilage to blood induced the adverse changes in cartilage proteoglycan turnover seen shortly after exposure. However, in vivo 10 weeks after the last injection, normalization of cartilage matrix turnover was observed. Synovial inflammation was absent and no destructive activity was found. CONCLUSION: These data show a discrepancy between the in vitro and in vivo longterm effects of blood on cartilage. A possible explanation for the in vivo recovery after experimental joint bleeding in dogs could be that the observed changes in cartilage only predispose to acute damage but that additional (e.g., mechanical) factors are needed to induce permanent joint damage.

https://www.jrheum.org/content/jrheum/30/2/339.full.pdf

M. E. Vianen

Papers

Iron deposits and catabolic properties of synovial tissue from patients with haemophilia

Blood-induced joint damage: a human in vitro study.

Cartilage damage as a result of hemarthrosis in a human in vitro model.

Blood-induced joint damage: a canine in vivo study.

Blood-induced joint damage: longterm effects in vitro and in vivo.