The expression of proinflammatory cytokines and matrix metalloproteinases in the synovial membranes of patients with osteoarthritis compared with traumatic knee disorders.

PURPOSE: The aim of this study was to evaluate a subset of matrix metalloproteinases (MMPs) and proinflammatory cytokines within the synovium, from traumatic knee disorders (TKDs) and nontraumatic osteoarthritis (OA). METHODS: MMP-1, MMP-3, interleukin 1beta, and tumor necrosis factor (TNF) alpha gene expression was quantified by use of TaqMan-based real-time polymerase chain reaction (Applied Biosystems, Foster City, CA) in synovial tissue samples obtained from 12 patients with OA and 32 with TKDs. In addition, the levels of serum inflammatory parameter C-reactive protein (CRP) were recorded. At arthroscopy, the amount of chondral damage was graded based on the Outerbridge classification. RESULTS: Quantitative analysis showed no significant differences in the expression levels of MMPs, interleukin 1beta, or TNF-alpha messenger RNA between the synovial tissues of patients with OA and TKD, but CRP level was significantly increased in the OA group. A significant correlation was also seen regarding the gene expression levels between MMP-1 and -3, as well as between CRP and MMPs tested. Furthermore, significant relations between TNF-alpha and MMP-1 plus MMP-3 were observed in the OA synovial tissue. The level of TNF-alpha in the synovial tissue correlated with the time after injury as well as chondral damage in patients with TKD. CONCLUSIONS: This study shows similar changes in the inflammatory patterns of synovial tissue of TKD and OA suggesting a likely disease progression. Moreover, the correlation between CRP and MMP expression levels indicates their essential role in joint degeneration in synovial tissue of primary OA patients. CLINICAL RELEVANCE: TNF-alpha could provide a factor to quantify individual risk for the development of OA.

Effect of COX-2 inhibition on tendon-to-bone healing and PGE2 concentration after anterior cruciate ligament reconstruction.

BACKGROUND: Non-steroidal anti-inflammatory drugs are commonly used to reduce pain and inflammation in orthopaedic patients. Selective cyclooxygenase-2 (COX-2) inhibitors have been developed to minimize drug-specific side effects. However, they are suspected to impair both bone and tendon healing. The objective of this study is to evaluate the effect of COX-2 inhibitor administration on tendon-to-bone healing and prostaglandin E (PGE2) concentration. METHODS: Thirty-two New Zealand white rabbits underwent reconstructions of the anterior cruciate ligaments and were randomized into four groups: Two groups postoperatively received a selective COX-2 inhibitor (Celecoxib) on a daily basis for 3 weeks, the two other groups received no postoperative COX-2 inhibitors at all and were examined after three or 6 weeks. The PGE2 concentration of the synovial fluid, the osseous integration of the tendon graft at tunnel aperture and midtunnel section, as well as the stability of the tendon graft were examined via biomechanic testing. RESULTS: After 3 weeks, the PGE2 content of the synovial fluid in the COX-2 inhibitor recipients was significantly lower than that of the control group (p = 0.018). At the same time, the COX-2 inhibitor recipients had a significantly lower bone density and lower amount of new bone formation than the control group (p = 0.020; p = 0.028) in the tunnel aperture. At the 6-week examination, there was a significant increase in the PGE2 content within synovial fluid of the COX-2 inhibitor recipients (p = 0.022), whose treatment with COX-2 inhibitors had ended 3 weeks earlier; in contrast, the transplant stability decreased and was reduced by 37% compared to the controls. CONCLUSIONS: Selective COX-2 inhibitors cause impaired tendon-to-bone healing, weaken mechanical stability and decrease PGE2 content of the synovial fluid. The present study suggests a reluctant use of COX-2 inhibitors when tendon-to-bone healing is intended.

The NQO1 C609T polymorphism is associated with risk of secondary malignant neoplasms after treatment for childhood acute lymphoblastic leukemia: a matched-pair analysis from the ALL-BFM study group.

In a matched-pair study, we analyzed the association of a phenotypically relevant NQO1 polymorphism (C609T) with risk of secondary malignant neoplasms (SMN) after treatment for childhood acute lymphoblastic leukemia. Patients carrying a variant low-activity NQO1 allele had a significantly increased risk of developing a SMN. The observed effect was restricted to solid tumors.

Tendon healing in a bone tunnel differs at the tunnel entrance versus the tunnel exit: an effect of graft-tunnel motion?

BACKGROUND: Motion between a tendon graft and bone tunnel may impair graft incorporation and lead to tunnel widening. HYPOTHESIS: Healing of a tendon graft in a bone tunnel is inhibited by graft-tunnel motion. STUDY DESIGN: Controlled laboratory study. METHODS: Anterior cruciate ligament reconstruction was performed in 5 cadaveric rabbit limbs, and 3-dimensional graft-tunnel motion was measured using micro-computed tomography. The authors then performed bilateral anterior cruciate ligament reconstruction in 15 rabbits and used histomorphometry to compare tendon-to-bone healing between the tunnel aperture, midtunnel, and tunnel exit and between the anterior and posterior aspects of the tunnel. RESULTS: Graft-tunnel motion was greatest at the tunnel apertures and least at the tunnel exit in cadaveric testing. Healing of the graft was slowest at the tunnel apertures. Tendon-bone interface width was greater at the aperture than at the tunnel exit for the femoral tunnel (P = .04). There was an inverse correlation between time zero graft-tunnel motion and healing in the femoral tunnel (P = .005). There was closer apposition of new bone to the tendon graft in the posterior half of the interface (P < .05). Osteoclasts were found at the tunnel apertures. CONCLUSION: Although graft-tunnel motion was only measured in cadaveric animals, results suggest that healing may be affected by the local mechanical environment, as graft healing in the femoral tunnel was inversely proportional to the magnitude of graft-tunnel motion. CLINICAL RELEVANCE: Graft-tunnel motion may impair early graft incorporation and may lead to osteoclast-mediated bone resorption, contributing to tunnel widening. Early, aggressive postoperative rehabilitation may have detrimental effects on graft-to-bone healing.

Macrophages accumulate in the early phase of tendon-bone healing.

A scar tissue interface forms rather than a normal ligament insertion site following attachment of a tendon graft to bone. The specific cell types that initiate the process of tendon-to-bone healing are unknown. We hypothesized that inflammatory cell accumulation following tendon-to-bone repair results in this scar interface. We used a rodent model to examine the temporal and spatial pattern of accumulation of hematopoietic lineage cells in the early phase of tendon-to-bone healing. Thirty-six Lewis rats underwent anterior cruciate ligament (ACL) reconstruction in the left knee using a flexor digitorum longus tendon graft. Six animals were sacrificed at 4, 7, 11, 14, 21, and 28 days after surgery. Serial sections were analyzed for proliferating cells (PCNA), recruited macrophages (ED1), resident macrophages (ED2), neutrophils, T-lymphocytes (CD3), mast cells, immature progenitor cells/pericytes (expressing the NG2 cell-surface chondroitin sulfate proteoglycan), and newly-formed blood vessels (Factor VIII). Neutrophils, ED1(+) and ED2(+) macrophages accumulated sequentially in the healing tendon graft, with progressive cell ingrowth from the interface towards the inner tendon. Neutrophils and ED1(+) cells were seen in the tendon-bone interface at 4 days after surgery, while ED2(+) macrophages were not identified until 11 days. These cells progressively repopulated the tendon graft. NG2-positive progenitor cells were found along the edge of the bone tunnel in the interface, but these cells did not invade the tendon. Occasional T-lymphocytes and mast cells were seen in the tendon-bone interface. There was no proliferation of intrinsic tendon cells, indicating that the tendon does not directly contribute to healing. We hypothesize that cytokines produced by infiltrating macrophages are likely to contribute to the formation of a fibrous scar tissue interface rather than a normal insertion site.

Diverse expression of selected cytokines and proteinases in synovial fluid obtained from osteoarthritic and healthy human knee joints.

BACKGROUND: Osteoarthritis (OA) is defined by signs and symptoms of inflammation within the affected joint. The aim of this study is to determine the mRNA expression levels of selected cytokines and matrix-metalloproteinases of cells found in synovial fluid (SF) obtained from osteoarthritic knee joints compared to healthy controls. METHODS: SF was obtained from 40 patients undergoing total knee arthroplasty due to evident OA and from 10 healthy controls. Expression of TNF-α, IL-1ß, MMP-1 and MMP-3 was assayed among both groups by performing qPCR. Patients were configured concerning age, gender and BMI. RESULTS: IL-1ß, MMP-1 and MMP-3 showed significantly higher expression among the OA group compared to control (P < 0.001). Strong correlation appeared between expression of MMP-1 and MMP-3 among OA patients (r = 0.856); no correlation was found between age, gender or BMI and cytokine/proteinase expression. Expression of IL-1ß, MMP-1 and MMP-3 within SF was elevated in OA-patients. CONCLUSION: Consequently, cells within SF expressing cytokines and proteinases may play a relevant role in the progression of joint destruction. Considering the fact that SF in an OA joint comprises abnormal amounts of detrimental bioactive proteins, temporary clearance, dilution or suppression/modulation by means of lavage or disease-modifying medication may be promising to constitute interim relief or even postpone disease progression due to decreased inflammatory and/or degrading activity within the articular environment.