A significant decrease in the synovial tissue lubricin gene expression was associated with elevated TNF- and IL-1 concentrations in SF lavages. joints. A significant decrease in the synovial tissue lubricin gene expression was associated with elevated TNF- and IL-1 concentrations in SF lavages. Blocking of TNF- significantly increased the lubricin bound to cartilage for all etanercept treatment strategies, coupled with a significant decrease in sGAG release. However, there were variable changes in SF lubricin concentrations. Discussion and Conclusions Blocking TNF- resulted in a chondroprotective effect, exemplified by increased lubricin deposition on articular cartilage and a decrease in sGAG release from articular cartilage in a post-traumatic arthritis animal model. and respectively) at 1 week following ACLT. Lubricin immunostaining in the ACLT joint at 1 week following ACLT exhibited immunopositivity on the surface of articular cartilage, with reduced staining in the superficial zone of articular cartilage (Panel values of ACLT and CL joints of etanercept-treated and non-treated animals are depicted in Figure 4B. The lowest coefficient of friction values clustered around a combination of high lubricin cartilage staining and SF lavage lubricin concentrations. The significant negative relationship between SF lavage lubricin and SF lavage sGAG is presented in Figure 4C (p=0.0095). The relationship between lubricin surface coverage and SF lavage sGAG is presented in Figure 4D. There was evidence of different relationships between limbs (interaction p=0.044). Follow-up analyses revealed a statistically significant negative relationship between SF lavage sGAG and lubricin surface coverage in the ACLT limbs (regression line and 95% CI plotted adj. p=0.015), but not within the contralateral limbs (adj. p=0.074), which was also lower in general (p=0.0052). Discussion ACL injury is an acute traumatic injury leading to increased risk of long-term development BAY 293 of degenerative joint diseases. Following ACL injury, SF concentrations of pro-inflammatory cytokines such as IL-1, TNF-, and IL-6, have been shown to be highest within 24 hours14, and associated with an increase in SF proteoglycans15. These findings corroborated our study of SF from patients with an acute unilateral ACL injury6. In this present study, we examined the time course of the impact of an ACL injury on cartilage chondroprotective abilities. Following BAY 293 the ACL injury in the rat model, an early increase in pro-inflammatory cytokines in the SF was detected at 1 week, and was also detected at week 4 (Fig 1). The elevated levels were significantly related to the levels of decreased synovial tissue lubricin gene expression, and with lubricin deposition on the articular cartilage surface. This association is consistent with previous reports that the pro-inflammatory cytokines TNF- and IL-1 to significantly decrease lubricin gene expression in synoviocytes and superficial zone chondrocytes10,11. However, the larger quantities of lubricin detected on the cartilage surface as IL-1 and TNF- is increased (Fig 2D) suggests that lubricin already present on the surface has CACNA1G a long half-life. This has been observed in other work where cartilage surface interaction of labeled lubricin increased its half-life to 6.3 days 16. At 1 week following ACLT, SF lavage lubricin concentrations were significantly lower in the ACLT joints than in the uninjured joints (Fig 1C). BAY 293 This decrease was also paralleled with a significant decrease in lubricin deposition on weight-bearing areas of cartilage surfaces. These results, coupled with the observation that the coefficient of friction was significantly elevated in the ACLT limb relative to CL in the 4-week untreated ACLT group (worst damage), indicate compromised joint lubrication at a relatively early stage following an ACL injury. The compromised lubrication may be due to a significant reduction in lubricin gene expression leading to decreased SF.
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