IntroductionOsteoarthritis (OA) is a degenerative disease characterized by cartilage breakdown in the synovial joints. The presence of low-grade inflammation in OA joints is receiving increasing attention, with synovitis shown to be present even in the early stages of the disease. How the synovial inflammation arises is unclear, but proteins in the synovial fluid of affected joints could conceivably contribute. We therefore surveyed the proteins present in OA synovial fluid and assessed their immunostimulatory properties.MethodsWe used mass spectrometry to survey the proteins present in the synovial fluid of patients with knee OA. We used a multiplex bead-based immunoassay to measure levels of inflammatory cytokines in serum and synovial fluid from patients with knee OA and from patients with rheumatoid arthritis (RA), as well as in sera from healthy individuals. Significant differences in cytokine levels between groups were determined by significance analysis of microarrays, and relations were determined by unsupervised hierarchic clustering. To assess the immunostimulatory properties of a subset of the identified proteins, we tested the proteins' ability to induce the production of inflammatory cytokines by macrophages. For proteins found to be stimulatory, the macrophage stimulation assays were repeated by using Toll-like receptor 4 (TLR4)-deficient macrophages.ResultsWe identified 108 proteins in OA synovial fluid, including plasma proteins, serine protease inhibitors, proteins indicative of cartilage turnover, and proteins involved in inflammation and immunity. Multiplex cytokine analysis revealed that levels of several inflammatory cytokines were significantly higher in OA sera than in normal sera, and levels of inflammatory cytokines in synovial fluid and serum were, as expected, higher in RA samples than in OA samples. As much as 36% of the proteins identified in OA synovial fluid were plasma proteins. Testing a subset of these plasma proteins in macrophage stimulation assays, we found that Gc-globulin, α1-microglobulin, and α2-macroglobulin can signal via TLR4 to induce macrophage production of inflammatory cytokines implicated in OA.ConclusionsOur findings suggest that plasma proteins present in OA synovial fluid, whether through exudation from plasma or production by synovial tissues, could contribute to low-grade inflammation in OA by functioning as so-called damage-associated molecular patterns in the synovial joint.

No abstract

This study tested the effects of variable-stiffness shoes on knee adduction moment, pain, and function in subjects with symptoms of medial compartment knee osteoarthritis over 6 months. Patients were randomly and blindly assigned to a variable-stiffness intervention or constant-stiffness control shoe. The Western Ontario and McMaster Universities (WOMAC) score served as the primary outcome measure. Joint loading, the secondary outcome measure, was assessed using the external knee adduction moment. Peak external knee adduction moment, total WOMAC, and WOMAC pain scores were assessed at baseline and after 6 months. The total WOMAC and WOMAC pain scores for the intervention group were reduced from baseline to 6 months (p ¼ 0.017 and p ¼ 0.002, respectively), with no significant reductions for the control group. There was no difference between groups in magnitude of the reduction in total WOMAC (p ¼ 0.50) or WOMAC pain scores (p ¼ 0.31). The proportion of patients achieving a clinically important improvement in pain was greater in the intervention group than in the control group (p ¼ 0.012). The variable-stiffness shoes reduced the peak knee adduction moment (À6.6% vs. control, p < 0.001) in the 34 intervention subjects at 6 months. The adduction moment reduction significantly improved (p ¼ 0.03) from the baseline reduction. The constant-stiffness control shoe increased the peak knee adduction moment (þ6.3% vs. personal, p ¼ 0.004) in the 26 control subjects at 6 months. The results of this study showed that wearing the variable-stiffness shoe lowered the adduction moment, reduced pain, and improved functionality after 6 months of wear. The lower adduction moment associated with wearing this shoe may slow the rate of progression of osteoarthritis after long-term use. ß

External knee adduction moment can be reduced using footwear interventions, but the exact changes in in vivo medial joint loading remain unknown. An instrumented knee replacement was used to assess changes in in vivo medial joint loading in a single patient walking with a variable-stiffness intervention shoe. We hypothesized that during walking with a load modifying variable-stiffness shoe intervention: (1) the first peak knee adduction moment will be reduced compared to a subject's personal shoes; (2) the first peak in vivo medial contact force will be reduced compared to personal shoes; and (3) the reduction in knee adduction moment will be correlated with the reduction in medial contact force. The instrumentation included a motion capture system, force plate, and the instrumented knee prosthesis. The intervention shoe reduced the first peak knee adduction moment (13.3%, p = 0.011) and medial compartment joint contact force (12.3%; p = 0.008) compared to the personal shoe. The change in first peak knee adduction moment was significantly correlated with the change in first peak medial contact force (R 2 = 0.67, p = 0.007). Thus, for a single subject with a total knee prosthesis the variablestiffness shoe reduces loading on the affected compartment of the joint. The reductions in the external knee adduction moment are indicative of reductions in in vivo medial compressive force with this intervention. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J. Orthop. Res. 28: 1548Res. 28: -1553Res. 28: , 2010 Keywords: knee osteoarthritis; biomechanics; load-altering intervention; variable-stiffness shoes; walking gait Osteoarthritis (OA) of the knee afflicts more than 30% of the American population over the age of 65 1,2 with involvement of the medial compartment ten times more frequent than the lateral compartment. 3,4 The increased incidence of medial knee OA is due in part to the high percentage of loading transmitted across the medial aspect of the knee during both static and dynamic loading, ∼60-80% of the total transmitted load. [5][6][7][8] To reduce pain, improve function, and slow the rate of disease progression, surgical and mechanical interventions for OA often attempt to reduce medial compartment loading. Surgery such as high tibial osteotomy corrects malalignment of the knee and transfers loading from the affected medial compartment to the unaffected lateral compartment to relieve symptoms and slow the rate of cartilage breakdown. 9,10 While direct force measurements in the medial compartment after surgery are impossible under normal circumstances, reductions in the adduction moment, a surrogate external measure for medial compartment loading, have been reported to range from ∼19% 11 to 30% 7 following high tibial osteotomy. Clinical studies reported that the adduction moment during walking is associated with the presence, 12 severity, 13,14 rate of progression, 15 and treatment outcome 7 of medial compartment OA. Therefore, the external adduction moment has been used ...