Conditional Macrophage Depletion Increases Inflammation and Does Not Inhibit the Development of Osteoarthritis in Obese Macrophage Fas-Induced Apoptosis-Transgenic Mice.

OBJECTIVE: To investigate whether short-term, systemic depletion of macrophages can mitigate osteoarthritis (OA) following injury in the setting of obesity. METHODS: CSF-1R-GFP+ macrophage Fas-induced apoptosis (MaFIA)-transgenic mice that allow conditional depletion of macrophages were placed on a high-fat diet and underwent surgery to induce knee OA. A small molecule (AP20187) was administrated to deplete macrophages in MaFIA mice. The effects of macrophage depletion on acute joint inflammation, OA severity, and arthritic bone changes were evaluated using histology and micro-computed tomography. Immunohistochemical analysis was performed to identify various immune cells. The levels of serum and synovial fluid cytokines were also measured. RESULTS: Macrophage-depleted mice had significantly fewer M1 and M2 macrophages in the surgically operated joints relative to controls and exhibited decreased osteophyte formation immediately following depletion. Surprisingly, macrophage depletion did not attenuate the severity of OA in obese mice; instead, it induced systemic inflammation and led to a massive infiltration of CD3+ T cells and particularly neutrophils, but not B cells, into the injured joints. Macrophage-depleted mice also demonstrated a markedly increased number of proinflammatory cytokines including granulocyte colony-stimulating factor, interleukin-1ß (IL-1ß), IL-6, IL-8, and tumor necrosis factor in both serum and joint synovial fluid, although the mice showed a trend toward decreased levels of insulin and leptin in serum after macrophage depletion. CONCLUSION: Our findings indicate that macrophages are vital for modulating homeostasis of immune cells in the setting of obesity and suggest that more targeted approaches of depleting specific macrophage subtypes may be necessary to mitigate inflammation and OA in the setting of obesity.

Altered gait mechanics and elevated serum pro-inflammatory cytokines in asymptomatic patients with MRI evidence of knee cartilage loss.

OBJECTIVE: To test if sagittal plane gait mechanics parameters and serum inflammation levels differ between healthy asymptomatic subjects and asymptomatic subjects with magnetic resonance imaging (MRI) evidence of cartilage loss. DESIGN: Gait mechanics and resting serum tumor necrosis factor-α (TNFα) concentrations were measured for two groups of asymptomatic subjects recruited for a previous study: Pre-Osteoarthritis (OA) subjects had MRI evidence of partial- or full-thickness knee cartilage loss in at least one compartment (n = 52 (30 female), 1.7 ± 0.1 m, 85.3 ± 18.9 kg, 44 ± 11 years); Control subjects had no MRI features of cartilage loss, osteophytes, bone marrow lesions, nor meniscal pathology in either knee (n = 26 (13 female), 1.7 ± 0.1 m, 74.6 ± 14.9 kg, 34 ± 10 years). Discrete measures of sagittal plane gait kinematics and kinetics were compared between subject groups and adjusted for age and body mass index (BMI) using analysis of covariance (ANCOVA). Serum TNFα concentrations were compared between groups using bootstrap t-test. RESULTS: The Pre-OA group had less extended knees (P = 0.021) and decreased maximum external knee extension moment (P = 0.0062) in terminal stance during gait, as well as increased resting serum TNFα concentration (P = 0.040) as compared to Control subjects. There were no group differences in heel strike flexion angle (P = 0.14), in maximum knee flexion moment (P = 0.91), nor in first peak knee adduction moment (KAM) (post-hoc analysis, P = 0.39). CONCLUSIONS: The finding that asymptomatic subjects with cartilage loss had gait and inflammatory characteristics similar to those previously reported in symptomatic OA patients supports the idea that there are specific mechanical and biological factors that precede the onset of knee pain in the pathogenesis of OA.

Quantification and Impact of Secondary Osteoarthritis in Patients With Anti-Citrullinated Protein Antibody-Positive Rheumatoid Arthritis.

OBJECTIVE: To search for evidence of secondary osteoarthritis (OA) in patients with rheumatoid arthritis (RA) in a cross-sectional and longitudinal setting, and to relate osteophyte formation to functional outcome. METHODS: Anti-citrullinated protein antibody (ACPA)-positive RA patients underwent high-resolution peripheral quantitative computed tomography of the hand. Cross-sectional and longitudinal measurements were performed. The number and size (volume) of osteophytes as well as bone erosions were documented. The relationship of osteophytes to bone erosions and to demographic and disease-specific data was evaluated by multiple logistic regression models. RESULTS: A total of 202 ACPA-positive RA patients were enrolled in the cross-sectional part of the study, and a total of 77 ACPA-positive RA patients were enrolled in the longitudinal analysis (interval of 1.5 years between baseline and follow-up assessment). The mean ± SD number of osteophytes per patient was 1.3 ± 2.3, and the mean ± SD osteophyte volume per patient was 2.6 ± 4.9 mm(3) . The total number of erosions was significantly correlated with the total number of osteophytes (P < 0.001), and the total volume of erosions was significantly correlated with the total volume of osteophytes (P < 0.001). Moreover, the number of osteophytes was related to age (P < 0.001) and disease duration (P = 0.001), while the volume of osteophytes was related to age (P = 0.001), disease duration (P < 0.001), and function as measured by the Health Assessment Questionnaire (P = 0.013). Multivariate regression analyses showed an independent association between osteophytes and erosions. In the longitudinal analysis, the mean number (P = 0.033) and volume (P < 0.001) of osteophytes increased significantly in RA patients during their disease course. CONCLUSION: Age, disease duration, and bone erosions are associated with osteophytes, indicating development of secondary OA in patients with RA.

Increased levels of soluble cytokine receptors in the synovial fluid of temporomandibular joint disorders in relation to joint effusion on magnetic resonance images.

PURPOSE: The purpose of this study is to clarify the significance of joint effusion (JE) on T2-weighted magnetic resonance images of the temporomandibular joint (TMJ) in comparison to various soluble cytokine receptors in the synovial fluid of patients with temporomandibular disorders (TMDs). PATIENTS AND METHODS: Magnetic resonance imaging of 55 TMJs of 55 patients with TMD was performed, and synovial fluid samples were obtained on the same day. The grade of JE was evaluated on a scale from 0 to 3, with grade 0 indicating the absence of JE and grades 1 to 3 indicating the presence of JE. Correlations were measured between JE and the concentrations of soluble tumor necrosis factor receptors I and II, interleukin (IL) 6 soluble receptor, IL-1 soluble receptor type II, and IL-1 receptor antagonist and protein in the synovial fluid samples. RESULTS: The mean concentrations of cytokine receptors in the synovial fluid were significantly higher in the 30 joints with JE than in the 25 joints without JE. There were no correlations between the JE grade and the level of any mediators. CONCLUSION: Increased levels of cytokine receptors are likely to influence the expression of JE and may play important roles in the pathogenesis of TMD. These results also suggest that JE may reflect synovial inflammation of the TMJ.