Expression of mitochondrial TSPO and FAM173B is associated with inflammation and symptoms in patients with painful knee osteoarthritis.

OBJECTIVES: To characterize the expression profiles of two nuclear-encoded mitochondrial genes previously associated with chronic pain, the translocator protein (TSPO) and family with sequence similarity 173B (FAM173B), in different knee compartments from patients with painful knee OA. Also, to examine their association with the joint expression of inflammatory cytokines/chemokines and clinical symptoms. METHODS: The study was performed on 40 knee OA patients and 19 postmortem (PM) controls from which we collected the knee tissues: articular cartilage (AC), synovial membrane (SM) and subchondral bone (SB). Quantitative real-time polymerase chain reaction was used to determine the relative mRNA levels of TSPO, FAM173B, and inflammatory mediators IL6, IL8, IL10, IL12, MCP1, CCL11 and CCL17. OA patients rated their pain intensity (visual analogue scale), severity of knee-related outcomes (KOOS) and pain sensitivity assessed by pressure algometry. RESULTS: The gene expression of TSPO in SM was elevated in OA patients compared with control subjects while there were no group differences in AC and SB. Expression of FAM173B was reduced in SM but elevated in SB in OA patients compared with controls. The expression of TSPO and FAM173B in SM and SB was associated with the expression of inflammatory substances, but not in AC. Synovial expression of TSPO correlated with lower pain intensity and FAM173B with increased pressure pain sensitivity in OA. CONCLUSION: Our results suggest that altered expression of TSPO and FAM173B is associated with joint expression of inflammatory mediators and with clinical symptoms indicating the relevance for the pathophysiology of knee OA.

Activation of NF-κB in Synovium versus Cartilage from Patients with Advanced Knee Osteoarthritis: A Potential Contributor to Inflammatory Aspects of Disease Progression.

The aim was to assess the activation and association of the NF-κB system across synovial membrane (SM) and articular cartilage (AC) in patients with knee osteoarthritis (OA) and ascertain its potential effects on catabolic mediator expression in advanced OA. SM and AC were obtained from 40 OA patients undergoing total knee arthroplasty and from 19 postmortem control subjects. NF-κB subunit RelA in nuclear and cytosolic fractions and NF-κB1-DNA binding in nuclear extracts was assessed by ELISA, whereas NFKB1, RELA, IL-8, IL-6, and MMP3 gene expression were analyzed by reverse transcriptase-quantitative PCR in tissues. We observed higher SM nuclear RelA protein levels and upregulated NF-κB1-DNA binding in OA patients compared with postmortem controls. However, in AC, lower nuclear RelA levels were observed compared with cytosolic extracts in patients. Nuclear RelA levels correlated positively with NF-κB1-DNA binding in SM and AC in patients. SM RELA and MMP3 mRNA levels were upregulated, whereas IL-8 and IL-6 as well as AC RELA were downregulated in patients compared with controls. In SM, nuclear RelA levels correlated positively with MMP3 gene expression in patients. A negative correlation was observed between SM nuclear RelA levels and AC NF-κB1-DNA binding, and SM nuclear NF-κB1-DNA binding correlated negatively with AC MMP3 and NFKB1 mRNA levels in patients. These findings highlight NF-κB-triggered cross-talk and feedback mechanisms between SM and AC in OA. Further, our findings strongly support a role for an activated NF-κB system in the transcriptional mechanism of inflammatory processes, especially in SM of patients with advanced OA.

Lysophosphatidylcholine 16:0 mediates chronic joint pain associated to rheumatic diseases through acid-sensing ion channel 3.

ABSTRACT: Rheumatic diseases are often associated to debilitating chronic pain, which remains difficult to treat and requires new therapeutic strategies. We had previously identified lysophosphatidylcholine (LPC) in the synovial fluids from few patients and shown its effect as a positive modulator of acid-sensing ion channel 3 (ASIC3) able to induce acute cutaneous pain in rodents. However, the possible involvement of LPC in chronic joint pain remained completely unknown. Here, we show, from 2 independent cohorts of patients with painful rheumatic diseases, that the synovial fluid levels of LPC are significantly elevated, especially the LPC16:0 species, compared with postmortem control subjects. Moreover, LPC16:0 levels correlated with pain outcomes in a cohort of osteoarthritis patients. However, LPC16:0 do not appear to be the hallmark of a particular joint disease because similar levels are found in the synovial fluids of a second cohort of patients with various rheumatic diseases. The mechanism of action was next explored by developing a pathology-derived rodent model. Intra-articular injections of LPC16:0 is a triggering factor of chronic joint pain in both male and female mice, ultimately leading to persistent pain and anxiety-like behaviors. All these effects are dependent on ASIC3 channels, which drive sufficient peripheral inputs to generate spinal sensitization processes. This study brings evidences from mouse and human supporting a role for LPC16:0 via ASIC3 channels in chronic pain arising from joints, with potential implications for pain management in osteoarthritis and possibly across other rheumatic diseases.

Elevated inflammatory proteins in cerebrospinal fluid from patients with painful knee osteoarthritis are associated with reduced symptom severity.

Neuroinflammation and periphery-to-CNS neuroimmune cross-talk in patients with painful knee osteoarthritis (OA) are poorly understood. We utilized proximity extension assay to measure the level of 91 inflammatory proteins in CSF and serum from OA patients and controls. The patients had elevated levels of 48 proteins in CSF indicating neuroinflammation. Ten proteins were correlated between CSF and serum and potentially involved in periphery-to-CNS neuroimmune cross-talk. Seven CSF proteins, all with previously reported neuroprotective effects, were associated with lower pain intensity and milder knee-related symptoms. Our findings indicate that neuroinflammation in OA could be protective and associated with less severe symptoms.

Leg length discrepancy in total hip arthroplasty: comparison of two methods of measurement.

Measurement of leg length discrepancy is an important part in planning a successful total hip arthroplasty (THA). Many clinical and radiological methods with variable degrees of accuracy have been advocated to carry out this measurement. We studied the accuracy of a commonly used clinical method by comparing it to a well-known and reliable radiological method. A total of 139 patients aged 44-89 (mean: 67.5 years) scheduled to undergo THA were examined for clinical and radiological leg length discrepancy measurements before and after the operation by the same observers. There was a poor correlation between the clinical and radiological methods preoperatively [r = 0.21, intra-class correlation coefficient (ICC) = 0.33]. The correlation was better postoperatively (r = 0.45, ICC = 0.62). The clinical method used is not recommended for leg length discrepancy measurement preoperatively. Caution should even be taken when using this method postoperatively. The authors recommend using the radiological method when measuring leg length discrepancy as a part of planning for THA.

Hip joint load in relation to leg length discrepancy.

OBJECTIVE: Leg length discrepancy is common both in healthy subjects and after total hip arthroplasty (THA). Studies that evaluated leg length following THA have demonstrated a notable inconsistency in restoring leg length. The effects concerning joint load during gait is however not well known. The purpose of this study was to use three-dimensional (3D) gait analysis to evaluate joint load during gait with a simulated leg length discrepancy of 2 and 4 cm. Nine healthy subjects without any history of hip injury participated. METHOD: A 3D gait analysis (Vicon, Motion System, Oxford, England) was performed with 6 cameras and 2 force palates using a standard biomechanical gait model. Hip joint moments of force were calculated for all three degrees of motion freedom. ANOVA for repeated measurements was used for statistical calculations. RESULTS: Abduction peak moment was significantly increased at the short side (P < 0.05) but unaffected on the long side. The adduction moment decreased on the long side between 0 and 4 cm (P < 0.01) but was unaffected on the short side. The internal hip rotation moments were unchanged for both the long and the short side. The external rotation moment was unchanged on the short side and decreased between bare foot and 4 cm on the long side (P < 0.05). CONCLUSION: A leg length discrepancy of 2 cm or more creates biomechanical changes concerning hip joint load both on the long and the short side and that the effects are larger on the short side. The increased stress may cause problems in the long run.