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It is uncertain whether metformin use is associated with reduced risk of joint replacement in patients with type 2 diabetes mellitus. We aimed to establish whether metformin use was associated with a reduced risk of total knee replacement (TKR) or total hip replacement (THR) among these patients.We selected patients with type 2 diabetes mellitus that was diagnosed between 2000 and 2012 from the Taiwan National Health Insurance Research Database. We used prescription time-distribution matching and propensity-score matching to balance potential confounders between metformin users and nonusers. We assessed the risks of TKR or THR using Cox proportional hazards regression.We included 20 347 participants who were not treated with metformin and 20 347 who were treated with metformin, for a total of 40 694 participants (mean age 63 yr, standard deviation 11 yr; 49.8% were women) after prescription time-distribution matching. Compared with participants who did not use metformin, those who used metformin had lower risks of TKR or THR (adjusted hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.60-0.81 for TKR or THR; adjusted HR 0.71, 95% CI 0.61-0.84 for TKR; adjusted HR 0.61, 95% CI 0.41-0.92 for THR) after adjustment for covariates. Propensity-score matching analyses (10 163 participants not treated with metformin v. 10 163 treated with metformin) and sensitivity analyses using inverse probability of treatment weighting and competing risk regression showed similar results.Metformin use in patients with type 2 diabetes mellitus was associated with a significantly reduced risk of total joint replacement. Randomized controlled clinical trials in patients with osteoarthritis are warranted to determine whether metformin is effective in decreasing the need for joint replacement.

Objective To investigate the therapeutic effect and mechanism of metformin on knee OA in normal diet (ND) mice or high-fat diet (HFD)-induced obese mice. Methods Destabilization of the medial meniscus surgery was performed in ND mice or HFD mice, and metformin was administrated in drinking water or not. The changes of OA joint structure, infiltration and polarization of synovial macrophages and circulating and local levels of leptin and adiponectin were evaluated. In vitro, the effects of metformin on chondrocytes and macrophages, and of conditioned mediums derived from mouse abdominal fat on murine chondrogenic cell line ATDC5 and murine macrophage cell line RAW264.7, were detected. Results Metformin showed protective effects on OA, characterized by reductions on OARSI score [2.00, 95% CI (1.15, 2.86) for ND mice and 3.17, 95% CI (2.37, 3.96) for HFD mice] and synovitis score [1.17, 95% CI (0.27, 2.06) for ND mice and 2.50, 95% CI (1.49, 3.51) for HFD mice] after 10 weeks of treatment, and the effects were more significant in HFD mice than in ND mice. Mechanistically, in addition to decreasing apoptosis and matrix-degrading enzymes expression in chondrocytes as well as infiltration and pro-inflammatory differentiation of synovial macrophages, metformin reduced leptin secretion by adipose tissue in HFD mice. Conclusions Metformin protects against knee OA which could be through reducing apoptosis and catabolism of chondrocytes, and suppressing infiltration and pro-inflammatory polarization of synovial macrophages. For obese mice, metformin has a greater protective effect in knee OA additionally through reducing leptin secretion from adipose tissue.

OBJECTIVETo investigate the association of both individual and combined healthy lifestyle factors with the risk of all-cause mortality among patients with osteoarthritis (OA).DESIGNProspective population-based cohort study.SETTINGUK biobank and US National Health and Nutrition Examination Survey (US NHANES, 2007-2018)PARTICIPANTS104, 142 UK participants with OA aged 39-72 years and 3, 472 US participants with OA aged 20-80 years.EXPOSURESIndividual healthy lifestyle factors and a combined healthy lifestyle score were constructed from body mass index (BMI) and self-reported information on diet, sleep duration, physical activity, sedentary time, social connection, smoking and alcohol drinking.MAIN OUTCOME MEASURESAll-cause mortality was the primary outcome in both studies. Secondary outcomes included cause-specific mortalities (cardiovascular, cancer, digestive and respiratory). Hazard ratios were adjusted for age, sex, economic situation, race, education and employment (UK biobank only).RESULTSUK Biobank documented 9,914 deaths during a median follow-up of 12.7 years, and US NHANES documented 463 deaths during a mean follow-up of 6.01 years. For all-cause mortality using restricted cubic spline graph (RCS) models, sleep duration had a U-shaped (with a nadir at 7 hours/day), moderate physical activity (MPA) had an L-shaped (with a turning point at 550 minutes/week), while BMI, vigorous physical activity (VPA) and sedentary time had J-shaped (with turning points at 28 kg/m2, 240 minutes/week and 5 hours/day, respectively) associations in the UK biobank. Similar results were observed in US NHANES. In multivariable Cox models, each healthy lifestyle factor was significantly associated with all-cause mortality (hazard ratio [HRs] range 0.49 to 0.84 for UK biobank, and 0.26 to 0.73 for US NHANES), and HRs (95% CI) for associations with combined healthy lifestyle score (scoring 6-8 vs. 0-2) were 0.38 (0.35, 0.41) in UK biobank and healthy lifestyle score (scoring 5-7 vs. 0-1) were 0.20 (0.13, 0.31) in US NHANES for all-cause mortality. The results for cause-specific mortality were largely similar and consistent across two cohorts.CONCLUSIONSThe nonlinear relationships suggested patients with OA had the lowest risk of all-cause mortality when BMI was 28 kg/m2, sleep was 7 hours/day, VPA was 240 minutes/week, sedentary time was less than 5 hours/day, MPA was more than 550 minutes/week. The newly constructed healthy lifestyle score for OA population was associated with a significantly lower risk of all-cause mortality.WHAT IS ALREADY KNOWN ON THIS TOPICHealthy lifestyles are thought to reduce the risk of multiple causes of mortality in the general population.People with osteoarthritis (OA) are at higher risk of mortality than the general population. However, evidence of associations between combined healthy lifestyle and risks of all-cause and cause-specific mortality among OA patients are lacking.Whether and what kind of healthy lifestyles in patients with OA could offset the risk of mortality are unknown.WHAT THIS STUDY ADDSBy using two nationwide cohort studies in UK and US, a comprehensive healthy lifestyle pattern that integrates 8 or 7 lifestyle factors was established among OA individuals for the first time.People who had the highest combined healthy lifestyle score were significantly associated with 62% to 80% lower risk of all-cause mortality compared with those who had the lowest score in both the UK and US OA populations.

Objective To explore the longitudinal association of quantitative infrapatellar fat pad (IPFP) signal intensity alteration with OA-related biomarkers. Methods Eighteen OA-related biochemical biomarkers of 600 knee OA participants in the Foundation for the National Institutes of Health OA Biomarkers Consortium (FNIH) study were extracted. The quantitative IPFP signal intensity measures were acquired based on magnetic resonance imaging, including mean value [Mean (IPFP)] and standard deviation [sDev (IPFP)] of the whole IPFP signal intensity, median value [Median (H)] and upper quartile value [UQ (H)] of high signal intensity, the ratio of volume of high signal intensity to volume of whole IPFP signal intensity [Percentage (H)] and Clustering factor (H). The linear mixed-effect model was applied to determine the longitudinal associations between IPFP signal intensity alteration and biochemical biomarkers over 2 years. Results All IPFP measures except for Clustering factor (H) were positively associated with urine collagenase-cleaved type II collagen neoepitope (uC2C), urine C-terminal cross-linked telopeptide of type II collagen (uCTX-II), urine C-terminal cross-linked telopeptide of type I collagen-α (uCTX-Iα) and urine N-terminal cross-linked telopeptide of type I collagen (uNTX-I). Mean (IPFP), Median (H) and Percentage (H) were positively associated with the nitrated form of an epitope located in the triple helix of type II collagen (Coll2-1 NO2). Mean (IPFP), Median (H) and UQ (H) were positively associated with sCTX-I and uCTX-Iβ. Positive associations between sDev (IPFP), Percentage (H) and serum hyaluronic acid (sHA) were found. Conclusion Our results suggest a role of IPFP signal intensity alteration in joint tissue remodelling on a molecular level.

Objective: The objective of this study is to investigate whether quantitatively measured infrapatellar fat pad (IPFP) signal intensity alteration is associated with joint effusion-synovitis in people with knee osteoarthritis (OA) over two years. Methods: Among 255 knee OA patients, IPFP signal intensity alteration represented by four measurement parameters [standard deviation of IPFP signal intensity (IPFP sDev), upper quartile value of IPFP high signal intensity region (IPFP UQ (H)), ratio of IPFP high signal intensity region volume to whole IPFP volume (IPFP percentage (H)), and clustering factor of IPFP high signal intensity (IPFP clustering factor (H))] was measured quantitatively at baseline and two-year follow-up using magnetic resonance imaging (MRI). Effusion-synovitis of the suprapatellar pouch and other cavities were measured both quantitatively and semi-quantitatively as effusion-synovitis volume and effusion-synovitis score at baseline and two-year follow-up using MRI. Mixed effects models assessed the associations between IPFP signal intensity alteration and effusion-synovitis over two years. Results: In multivariable analyses, all four parameters of IPFP signal intensity alteration were positively associated with total effusion-synovitis volume and effusion-synovitis volumes of the suprapatellar pouch and of other cavities over two years (all P＜0.05). They were also associated with the semi-quantitative measure of effusion-synovitis except for IPFP percentage (H) with effusion-synovitis in other cavities. Conclusion: Quantitatively measured IPFP signal intensity alteration is positively associated with joint effusion-synovitis in people with knee OA, suggesting that IPFP signal intensity alteration may contribute to effusion-synovitis and a coexistent pattern of these two imaging biomarkers could exist in knee OA patients.

This study aimed to investigate the biochemical effects of osteoarthritic infrapatellar fat pad (IPFP) on cartilage and the underlying mechanisms. Human IPFP and articular cartilage were collected from end-stage osteoarthritis (OA) patients during total knee arthroplasty. IPFP-derived fat-conditioned medium (FCM) was used to stimulate human primary chondrocytes and cartilage explants. Functional effect of osteoarthritic IPFP was explored in human primary chondrocytes and articular cartilage in vitro and ex vivo. Activation of relative pathways and its effects on chondrocytes were assessed through immunoblotting and inhibition experiments, respectively. Neutralization test was performed to identify the main factors and their associated pathways responsible for the effects of IPFP. Osteoarthritic IPFP-derived FCM significantly induced extracellular matrix (ECM) degradation in both human primary chondrocytes and cartilage explants. Several pathways, such as NF-κB, mTORC1, p38MAPK, JNK, and ERK1/2 signaling, were significantly activated in human chondrocytes with osteoarthritic IPFP-derived FCM stimulation. Interestingly, inhibition of p38MAPK and ERK1/2 signaling pathway could alleviate the detrimental effects of FCM on chondrocytes, while inhibition of other signaling pathways had no similar results. In addition, IL-1β and TNF-α instead of IL-6 in osteoarthritic IPFP-derived FCM played key roles in cartilage degradation via activating p38MAPK rather than ERK1/2 signaling pathway. Osteoarthritic IPFP induces the degradation and inflammation of cartilage via activation of p38MAPK and ERK1/2 pathways, in which IL-1β and TNF-α act as the key factors. Our study suggests that modulating the effects of IPFP on cartilage may be a promising strategy for knee OA intervention.

To determine whether pericruciate fat pad (PCFP) signal intensity alteration and maximal area are associated with incident radiographic osteoarthritis (ROA) over 4 years in the Osteoarthritis Initiative (OAI) study. Participants were from the Osteoarthritis Initiative (OAI) study. Case knees (n = 355) were defined by incident ROA between 12 and 48 months visits and were matched by sex, age, and radiographic status with control knees (n = 355). Magnetic resonance images (MRIs) were used to assess PCFP signal intensity alteration and PCFP maximal area at P0 (time of onset of ROA), P-1 (1 year prior to P0), and baseline. Conditional logistic regression analyses were applied to assess associations between PCFP measures and the risk of incident ROA. The mean age of participants was 60.1 years and 66.9% were women. In multivariable analyses, PCFP signal intensity alteration measured at three time points (OR [95%CI]: 1.28 [1.10–1.50], 1.52 [1.30–1.78], 1.50 [1.27–1.76], respectively) and PCFP maximal area (OR [95%CI]: 1.21 [1.03–1.42], 1.27 [1.07–1.52], 1.37 [1.15–1.62], respectively) were significantly associated with incident ROA. PCFP signal intensity alteration and maximal area were associated with incident ROA over 4 years, implying that they may have roles to play in ROA. • Pericruciate fat pad signal intensity alteration and maximal area were associated with incident ROA, implying that they may have roles to play in ROA.

Objective To investigate the longitudinal associations of serum inflammatory markers and adipokines with joint symptoms and structures in participants with knee OA. Methods Two hundred participants (46.5% female, mean age 63.1 years, mean BMI 29.5 kg/m2) from Tasmania, part of the VIDEO (Vitamin D Effect on OA) study, were randomly selected in the current study. Serum levels of 19 biomarkers, scores of WOMAC and MRI-assessed knee structures were evaluated at baseline and month 24. The patterns of biomarkers were derived from principal component analysis and their association with knee symptoms and structures were examined using adjusted generalized estimating equations. Results Five components explained 78% of the total variance. IL-1β, -2, -4, -6, -8, -17 A, -17 F, -21, -22 and -23 loaded the highest on the first component, which was associated with increased bone marrow lesions (BMLs) and WOMAC dysfunction score. IL-10, -12 and GM-CSF loaded on the second component, which was associated with increased cartilage volume, and decreased effusion synovitis and WOMAC scores. Leptin, adipsin and CRP loaded on the third component, which was positively associated with WOMAC scores. Resistin loaded on the fourth component, which was associated with increased BMLs and cartilage defects. Apelin-36 and adiponectin loaded on the fifth component, which was associated with increased BMLs. Conclusion Various inflammatory and metabolic components were associated differently with joint symptoms and structural changes in knee OA, suggesting a complex inflammatory and metabolic interrelationship in the pathogenesis of knee OA.

Objective The present study was undertaken to determine whether vitamin D supplementation or maintaining sufficient vitamin D level reduces foot pain over 2 years in patients with symptomatic knee osteoarthritis (OA). Methods A post hoc study was conducted from a randomized, double-blind, placebo-controlled trial named the Vitamin D Effect on Osteoarthritis (VIDEO) study. Symptomatic knee OA patients with serum 25-hydroxyvitamin D levels between 12.5 nmoles/liter and 60 nmoles/liter were included and randomly allocated to either monthly vitamin D3 or placebo treatment (1:1) for 2 years. Manchester Foot Pain and Disability Index (MFPDI) was used to evaluate foot pain and disabling foot pain was defined as at least 1 of the 10 functional limitation items (items 1-9 and 11) being documented as on "most/every day(s)" in the last month. A repeated-measures, mixed-effects model was used to analyze the change of MFPDI scores between groups adjusting for potential confounders. Results A total of 413 patients with a mean age of 63.2 years (49.7% males) were enrolled and 340 completed the study. The mean MFPDI score was 22.8 ± 7.3, with 23.7% of participants having disabling foot pain at baseline. There were significant differences in MFPDI scores change between groups over 2 years, with more improvements in the vitamin D group than in the placebo group (-0.03 versus 1.30; P = 0.013) and more improvement in those maintaining sufficient vitamin D levels (n = 226) than those who did not (n = 114) (-0.09 versus 2.19; P = 0.001). Conclusion Vitamin D supplementation and maintenance of sufficient vitamin D levels may improve foot pain in those with knee OA.

Inflammatory cytokine–induced activation of nuclear factor κB (NF-κB) signaling plays a critical role in the pathogenesis of osteoarthritis (OA). We identified PILA as a long noncoding RNA (lncRNA) that enhances NF-κB signaling and OA. The abundance of PILA was increased in damaged cartilage from patients with OA and in human articular chondrocytes stimulated with the proinflammatory cytokine tumor necrosis factor (TNF). Knockdown of PILA inhibited TNF-induced NF-κB signaling, extracellular matrix catabolism, and apoptosis in chondrocytes, whereas ectopic expression of PILA promoted NF-κB signaling and matrix degradation. PILA promoted PRMT1-mediated arginine methylation of DExH-box helicase 9 (DHX9), leading to an increase in the transcription of the gene encoding transforming growth factor β–activated kinase 1 (TAK1), an upstream activator of NF-κB signaling. Furthermore, intra-articular injection of an adenovirus vector encoding PILA triggered spontaneous cartilage loss and exacerbated posttraumatic OA in mice. This study provides insight into the regulation of NF-κB signaling in OA and identifies a potential therapeutic target for this disease.

To investigate associations of dietary vitamin K intake with changes in knee symptoms and structures in patients with knee OA.Participants with symptomatic knee OA were enrolled (n=259) and followed up for 2 years (n=212). Baseline dietary vitamin K intake was calculated from a validated food frequency questionnaire. Knee symptoms were assessed by using the Western Ontario and McMaster University Index of osteoarthritis (WOMAC) scores. Knee cartilage defects, bone marrow lesions and effusion-synovitis volume were measured from MRI scans. Univariable and multivariable linear regressions were used for analyses.Higher vitamin K intake quartile was significantly associated with greater decrease in total WOMAC score and dysfunction score over 24 months. The subgroup analyses showed in patients with severe baseline VAS pain, higher vitamin K intake quartile was associated with more improvement in all WOMAC scores. There were no overall significant associations between vitamin K intake and changes in MRI features. In sub-group analysis, vitamin K intake was negatively associated with changes in tibiofemoral, patellar and total cartilage defects in participants with severe baseline radiographic grade, and was negatively associated with change in total and patellar cartilage defects in participants with severe baseline VAS pain and in female patients.The association of higher vitamin K intake with decreased knee symptoms over 24 months in patients with knee OA suggests that clinical trials examining the effect of vitamin K supplementation for knee OA symptoms are warranted. Whether there is an effect on knee structure is unclear. This article is protected by copyright. All rights reserved.

ObjectiveTo determine the association of quantitative infrapatellar fat pad (IPFP) signal intensity alteration with knee osteoarthritis (OA) progression.MethodThis study was performed based on the Foundation for the National Institutes of Health OA Biomarkers Consortium study, a nested case–control study consisting of 600 participants. The IPFP signal intensity alterations were quantitatively measured at baseline, 12 months and 24 months. The associations of baseline and time-integrated values over 12 and 24 months of IPFP signal intensity measures with knee OA progression over 48 months were evaluated with adjustment for baseline confounders.ResultsThe baseline level of clustering effect of high signal intensity (Clustering factor (H)) was predictive of clinically relevant progression (both radiographic and pain progression) (OR 1.22). The time-integrated values of all IPFP signal intensity measures, except for mean value of IPFP signal intensity (Mean (IPFP)) over 24 months (ORs ranging from 1.23 to 1.39) as well was all except for Mean (IPFP) and mean value of IPFP high signal intensity (Mean (H)) over 12 months (ORs ranging from 1.20 to 1.31), were positively associated with clinically relevant progression. When the associations of quantitative IPFP signal intensity measures with radiographic and pain progression were examined separately, more IPFP signal intensity measures with stronger effect sizes were associated with radiographic progression compared with pain progression.ConclusionThe associations of short-term alteration in quantitative IPFP signal intensity measures with long-term knee OA progression suggest that these measures might serve as efficacy of intervention biomarkers of knee OA.

Purpose To investigate whether acquiring basic knee arthroscopic skills via a spaced retraining schedule could prevent skills deterioration and achieve further skills improvement. Methods In the learning phase, 16 residents with no previous hands-on experience in practicing arthroscopic skills were asked to perform basic arthroscopic tasks on a simulator until they attained perfect scores in each task. Immediately after completing the learning phase, a pretest was performed to assess their performance. Next, they were randomly assigned into 2 groups. The spaced retraining group, which undertook a spaced repetitive training phase with a fixed-time interval, returned on days 2, 4 and 6 to repeat the same tasks for 20 minutes per day, whereas the control group did nothing. On day 7, all participants performed a posttest. A 2 × 2 mixed analysis of variance model was used for statistical analysis. Results Significant differences between the 2 groups were found in task completion time (P = .003) and camera path length (P = .043) but not cartilage injury (P = .186). Residents in the spaced retraining group decreased their task completion time (163.2 ± 23.9 seconds) whereas the task time in the control group increased (351.3 ± 25.5 seconds). The same pattern was found with the camera path length. Conclusions Implementing a spaced retraining schedule in 1 week resulted in a reduced task completion time and camera path length but no significant reduction in cartilage injury. It appears that introducing a spaced retraining schedule to retain arthroscopic skills acquired through massed learning may be advantageous. Clinical Relevance In consideration of the training time available to residents and the trend toward massed learning, this spaced retraining schedule may offer a cost-effective and convenient way for residents to maintain and improve their basic arthroscopic skills with no significant increase in time invested.

Summary Objective To determine if qualitative and quantitative measures of prefemoral fat pad (PFP) and quadriceps fat pad (QFP) are associated with incident radiographic osteoarthritis (iROA) over 4 years in the Osteoarthritis Initiative (OAI) study. Design Participants in this nested case–control study were selected from the OAI study with knees that had Kellgren Lawrence grades (KLG) of 0 or 1 at baseline. Case knees were defined by iROA (KLG≥ 2) over 4 years. Control knees without iROA were matched 1:1 with case knees. Magnetic resonance images (MRIs) were read at P0 (time of onset of iROA), P-1 (1 year prior to P0) and baseline, and used to assess PFP (i.e., prefemoral hyperintensity alteration, patellofemoral hyperintensity alteration, maximum axial area) and QFP (i.e., hyperintensity alteration, mass effect, maximum axial area). Conditional logistic regression analyses were performed to study the associations between PFP/QFP measures and iROA, after adjustment for covariates. Results 354 case knees with iROA were matched to 354 control knees. 66.9% of the participants were female, with an average age of 60.1 years. PFP prefemoral hyperintensity alteration measured at three time points (OR [95%CI]: 1.46 [1.18–1.82], 1.50 [1.20–1.88], 1.52 [1.22–1.89] respectively), PFP maximum axial area (OR [95%CI]: 1.07 [1.01–1.14], 1.08 [1.01–1.15], 1.08 [1.02–1.15] respectively) and QFP hyperintensity alteration (OR [95%CI]: 1.59 [1.27–2.00], 1.44 [1.13–1.82], 1.38 [1.09–1.73] respectively) were significantly associated with iROA in multivariable conditional logistic analyses. QFP mass effect measured at BL and P-1 (OR [95%CI]: 1.42 [1.11–1.82], 1.33 [1.01–1.73] respectively) were significantly associated with iROA. Conclusions Qualitative and quantitative measures of PFP and QFP are associated with increased iROA over 4 years.

Background: Abnormal infrapatellar fat pad (IPFP) plays a detrimental role in knee osteoarthritis (OA) by producing pro-inflammatory cytokines. IPFP may interact with synovium because of their adjacent anatomical positions; however, whether abnormal IPFP can contribute to effusion-synovitis in knee OA is unclear.Methods: Among 255 knee OA patients, IPFP signal intensity alteration represented by four measurement parameters [standard deviation of IPFP signal intensity (IPFP sDev), upper quartile value of IPFP high signal intensity region (IPFP UQ (H)), ratio of IPFP high signal intensity region volume to whole IPFP volume (IPFP percentage (H)), and clustering factor of IPFP high signal intensity (IPFP clustering factor (H))] was measured quantitatively at baseline and two-year follow-up using magnetic resonance imaging (MRI). Effusion-synovitis of the suprapatellar pouch and other cavities were measured both quantitatively and semi-quantitatively as effusion-synovitis volume and effusion-synovitis score at baseline and two-year follow-up using MRI. Mixed-effects models were used to assess the associations between IPFP signal intensity alteration and effusion-synovitis over two years.Results: In multivariable analyses, all four parameters of IPFP signal intensity alteration were positively associated with total effusion-synovitis volume and effusion-synovitis volumes of the suprapatellar pouch and of other cavities over two years (all P＜0.05). They were also associated with the semi-quantitative measure of effusion-synovitis except for IPFP percentage (H) with effusion-synovitis in other cavities. Conclusion: Quantitatively measured IPFP signal intensity alteration is positively associated with joint effusion-synovitis in people with knee OA, suggesting that IPFP signal intensity alteration may contribute to effusion-synovitis and a coexistent pattern of these two imaging biomarkers could exist in knee OA patients.

The aim of this study was to investigate cross-sectional associations between serum levels of IL-8 and the above outcomes in patients with knee osteoarthritis (OA).A total of 160 subjects with clinical knee OA were included. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score and Lequesne index were used to assess the joint symptom. Magnetic resonance imaging was used to measure knee structural abnormalities including infrapatellar fat pad (IPFP) signal intensity alternation. Knee radiographic OA was assessed by radiography using the Kellgren-Lawrence (K-L) grading system. Enzyme-linked immunosorbent assay was used to measure the serum levels of IL-8 and cartilage or bone biomarkers.In multivariable analyses, serum IL-8 was positively associated with WOMAC weight-bearing pain (β 2.85, P = 0.028), WOMAC physical dysfunction (β 12.71, P = 0.048), and Lequesne index (β 1.65, P = 0.015), and had positive associations with IPFP signal intensity alteration (OR 3.18, P = 0.011) and serum levels of N-telopeptide of type I collagen (NTXI), N-terminal procollagen III propeptide (PIIINP), matrix metalloproteinase (MMP)3, and MMP13 (β 0.24-1.44, all P 0.05) in patients with clinical knee OA. Furthermore, there were positive associations between IL-8 and WOMAC score (β 22.49, P = 0.037), K-L grades (OR 3.88, P = 0.013), and IPFP signal intensity alteration (OR 3.20, P = 0.033) in patients with radiographic OA.Serum levels of IL-8 were positively associated with increased knee symptoms, IPFP signal intensity alteration, and serum levels of bone and/or cartilage biomarkers, suggesting that IL-8 may have a role to play in knee OA.Key Point• This study systemically investigates the associations between serum IL 8 and knee symptoms, joint structures, and cartilage or bone biomarkers in patients with knee osteoarthritis, and some significant associations have been found, suggesting that IL 8 may have a role to play in knee OA.

Summary Objective To describe associations between presence of patellar tendon enthesis (PTE) abnormalities and symptoms, structural abnormalities, and total knee replacement (TKR) in older adult cohort. Methods PTE abnormalities (presence of abnormal bone signal and/or bone erosion), were measured on T2-weighted magnetic resonance (MR) images at baseline in 961 community-dwelling older adults. Knee pain and function limitation were assessed using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Bone marrow lesions (BMLs), cartilage volume and defects score, and infrapatellar fat pad (IPFP) area were measured using validated methods. Incidence of TKR was determined by data linkage. Results Participants with abnormal PTE bone signal and/or erosion was 20%. Cross-sectionally, presence of PTE abnormalities was associated with greater pain intensity while going up and down stairs (β = 0.22 (95% confidence interval (CI); 0.03, 0.41)), greater risk of femoral BMLs (RR = 1.46 (1.12, 1.90)) and worse tibial cartilage defects score (RR = 1.70 (1.16, 2.47), and smaller IPFP area (β = −0.27 (−0.47, −0.06) cm2), after adjustment of confounders. Longitudinally, presence of baseline PTE abnormalities was associated with a deleterious increase in tibial BML size (RR = 1.52 (1.12, 2.05)) over 10.7 years but not symptoms, other structural changes, or TKR. Conclusion PTE abnormalities are common in older adults. Presence of cross-sectional but not longitudinal associations suggests they are commonly co-exist with other knee structural abnormalities but may not play a major role in symptom development or structural change, excepting tibial BMLs.

Summary Objectives To validate a method to measure the morphological parameters of the proximal tibiofibular joint (PTFJ) in patients with knee osteoarthritis (OA). Methods 408 participants were examined in this cross-sectional subject-based study. We calculated the fibular contacting area of PTFJ (S) and its projection areas onto the horizontal plane (load-bearing area, Sτ), the sagittal plane (lateral stress-bolstering area, Sφ) and the coronal plane (posterior stress-bolstering area, Sυ). Joint space narrowing (JSN) and osteophyte was measured using radiographs. Cartilage defects, bone marrow lesions (BMLs) and cartilage volume were evaluated using magnetic resonance imaging (MRI). Results The average PTFJ fibular contacting area was 2.4 cm2 (SD, ±0.7 cm2). Intra-observer and inter-observer reliabilities of measures of PTFJ morphological parameters were excellent (≥0.90). S, Sτ and Sφ were significantly associated with JSN in the medial tibiofemoral compartment (PR: 1.40, 95% CI 1.10–1.78; PR: 1.65, 95% CI 1.25–2.18 and PR: 0.53, 95% CI 0.29–0.97, respectively). There was a significantly positive association between S, Sτ and medial and/or femoral tibial cartilage defects. S, Sτ and Sυ were significantly and positively associated with medial and/or femoral tibial BMLs (PR: 1.36, 95% CI 1.12–1.64; PR: 1.47, 95% CI 1.17–1.83; and PR: 1.39, 95% CI 1.06–1.82, respectively) after adjustment. S and Sτ were significantly and negatively associated with medial tibial cartilage volume. Conclusions This novel method to assess the morphological parameters of PTFJ in MRI is reproducible. These parameters are associated with knee radiographic and MRI-based OA-related structural abnormalities, suggesting clinical construct validity. Its predictive validity needs to be examined in future longitudinal studies.

Background: Although existing studies have suggested the involvement of the infrapatellar fat pad (IPFP) during the development of knee osteoarthritis (OA), the role of IPFP is still controversial. This study aimed to investigate the biochemical effects of osteoarthritic IPFP on cartilage and the underlying mechanisms.Methods: Human IPFP and articular cartilage were collected from end-stage OA patients during total knee arthroplasty. IPFP derived fat-conditioned medium (FCM) was used to stimulate human primary chondrocytes and cartilage explants. CCK8 was used to detect the viability of human chondrocyte. qRT-PCR and western blotting was performed to evaluate the balance of extracellular matrix (ECM) catabolism and anabolism in human chondrocytes with FCM stimulation. Functional effect of osteoarthritic IPFP was also demonstrated in human articular cartilage by ex vivo assay. Activation of relative pathways and its effects on chondrocytes were assessed through immunoblotting and inhibition experiments, respectively. Neutralization test was performed to identify the main factors and their associated pathways responsible for the effects of IPFP. Results: Osteoarthritic IPFP-derived FCM significantly induced extracellular matrix (ECM) degradation in both human primary chondrocytes and cartilage explants. Several pathways, such as NF-κB, mTORC1, p38MAPK, JNK, and ERK1/2 signaling were significantly activated in human chondrocytes with osteoarthritic IPFP-derived FCM stimulation. Interestingly, inhibition of p38MAPK and ERK1/2 signaling pathway could alleviate the detrimental effects of FCM on chondrocytes while inhibition of other signaling pathways had no similar results. In addition, IL-1β and TNF-α instead of IL-6 in osteoarthritic IPFP-derived FCM played a key role in cartilage degradation via activating p38MAPK rather than ERK1/2 signaling pathway.Conclusions: Osteoarthritic IPFP induces the degradation and inflammation of cartilage via activation of p38MAPK and ERK1/2 pathways, in which IL-1β and TNF-α act as the key factors. Our study suggests that modulating the effects of IPFP on cartilage may be a promising strategy for knee OA intervention.

Lysine acetylation (Kac) as an important posttranslational modification of histones is essential for the regulation of gene expression in hepatocellular carcinoma (HCC). However, the atlas of whole acetylated proteins in HCC tissues and the difference in protein acetylation between normal human tissues and HCC tissues are unknown. In this report, we characterized the proteome and acetyl proteome (acetylome) profile of normal, paracancerous, and HCC liver tissues in human clinical samples by quantitative proteomics techniques. We identified 6781 acetylation sites of 2582 proteins and quantified 2492 acetylation sites of 1190 proteins in normal, paracancerous, and HCC liver tissues. Among them, 15 proteins were multiacetylated with more than 10 lysine residues. The histone acetyltransferases p300 and CBP were found to be hyperacetylated in hepatitis B virus pathway. Moreover, we found that 250 Kac sites of 214 proteins were upregulated and 662 Kac sites of 451 proteins were downregulated in HCC compared with normal liver tissues. Additionally, the acetylation levels of lysine 120 in histone H2B (H2BK120ac), lysine 18 in histone H3.3 (H3.3K18ac), and lysine 77 in histone H4 (H4K77ac) were increased in HCC. Interestingly, the higher levels of H2BK120ac, H3.3K18ac, and H4K77ac were significantly associated with worse prognosis, such as poorer survival and higher recurrence in an independent clinical cohort of HCC patients. Overall, this study lays a foundation for understanding the functions of acetylation in HCC and provides potential prognostic factors for the diagnosis and therapy of HCC., Our analysis showed a landscape of lysine acetylation in HCC. And we clearly identified significantly altered acetylated sites in normal, paracancerous and HCC liver tissues and validated the clinical significance of three histone acetylation sites using an independent cohort.

To determine whether pericruciate fat pad (PCFP) signal intensity alteration and maximal area are associated with incident radiographic osteoarthritis (ROA) over 4 years in the Osteoarthritis Initiative (OAI) study.Participants were from the Osteoarthritis Initiative (OAI) study. Case knees (n = 355) were defined by incident ROA between 12 and 48 months visits and were matched by sex, age, and radiographic status with control knees (n = 355). Magnetic resonance images (MRIs) were used to assess PCFP signal intensity alteration and PCFP maximal area at P0 (time of onset of ROA), P-1 (1 year prior to P0), and baseline. Conditional logistic regression analyses were applied to assess associations between PCFP measures and the risk of incident ROA.The mean age of participants was 60.1 years and 66.9% were women. In multivariable analyses, PCFP signal intensity alteration measured at three time points (OR [95%CI]: 1.28 [1.10-1.50], 1.52 [1.30-1.78], 1.50 [1.27-1.76], respectively) and PCFP maximal area (OR [95%CI]: 1.21 [1.03-1.42], 1.27 [1.07-1.52], 1.37 [1.15-1.62], respectively) were significantly associated with incident ROA.PCFP signal intensity alteration and maximal area were associated with incident ROA over 4 years, implying that they may have roles to play in ROA.• Pericruciate fat pad signal intensity alteration and maximal area were associated with incident ROA, implying that they may have roles to play in ROA.

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Background To describe demographic and clinical factors associated with the presence and incidence of depression and explore the temporal relationship between depression and joint symptoms in patients with symptomatic knee osteoarthritis (OA). Methods Three hundred ninety-seven participants were selected from a randomized controlled trial in people with symptomatic knee OA and vitamin D deficiency (age 63.3 ± 7.1 year, 48.6% female). Depression severity and knee joint symptoms were assessed using the patient health questionnaire (PHQ-9) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), respectively, at baseline and 24 months. Results The presence and incidence of depression was 25.4 and 11.2%, respectively. At baseline, having younger age, a higher body mass index (BMI), greater scores of WOMAC pain (PR: 1.05, 95%CI:1.03, 1.07), dysfunction (PR: 1.02, 95%CI:1.01, 1.02) and stiffness (PR: 1.05, 95%CI: 1.02, 1.09), lower education level, having more than one comorbidity and having two or more painful body sites were significantly associated with a higher presence of depression. Over 24 months, being female, having a higher WOMAC pain (RR: 1.05, 95%CI: 1.02, 1.09) and dysfunction score (RR: 1.02, 95%CI: 1.01, 1.03) at baseline and having two or more painful sites were significantly associated with a higher incidence of depression. In contrast, baseline depression was not associated with changes in knee joint symptoms over 24 months. Conclusion Knee OA risk factors and joint symptoms, along with co-existing multi-site pain are associated with the presence and development of depression. This suggests that managing common OA risk factors and joint symptoms may be important for prevention and treatment depression in patients with knee OA. Trial registration ClinicalTrials.gov identifier: NCT01176344. Anzctr.org.au identifier: ACTRN12610000495022.

Background Osteoarthritis (OA) is a common chronic disease in older adults. Currently, there are no effective therapies to reduce disease severity and progression of knee OA (KOA), particularly in mid- to late-stages. This study aims to examine the effect of methotrexate (MTX) on knee effusion-synovitis and pain in symptomatic patients with mid- to late-stage KOA. Methods/design This protocol describes a multicentre randomised placebo-controlled clinical trial aiming to recruit 200 participants with mid- to late-stage symptomatic KOA and with effusion-synovitis grade of ≥ 2. Participants will be randomly allocated to the MTX group (start from 5 mg per week for the first 2 weeks and increase to 10 mg per week for the second 2 weeks and 15 mg per week for the remaining period if tolerated) or the placebo group. Primary outcomes are effusion-synovitis size measured by magnetic resonance imaging (MRI) and knee pain assessed by visual analogue scale (VAS). Secondary outcomes are signal intensity alteration within infrapatellar fat pad (IPFP) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score and subscores, and the Outcome Measures in Rheumatology Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) responders. Both intention-to-treat and per-protocol analyses will be performed. Discussion If MTX intervention can relieve symptoms and reduce inflammation in patients with mid- to late-stage KOA, it has the potential for significant clinical and public health impact as this low-cost and commonly used intervention would delay the time to knee replacement, leading to substantial cost savings and improve quality of life. Trial registration ClinicalTrials.gov NCT03815448. Registered on 21 January 2019.

Summary Background & aims The evidence of benefiting from a high-quality diet for knee osteoarthritis (OA) joint structures, symptoms, and systemic abnormalities is limited. Clarifying the relationship between diet quality and knee OA could provide useful information for knee OA management. To investigate the associations between diet quality and knee joint structures, symptoms, lower limb muscle strength, depressive symptoms, and quality of life in people with knee OA. Methods This study was a post-hoc, exploratory analysis using data from a randomized controlled trial in symptomatic knee OA participants with a follow-up time of 24 months. In brief, eligible participants of the original study were aged 50–79 years, had symptomatic knee OA, and had a pain of 20–80 mm on a 100-mm visual analog scale. After excluding the patients without information on diet quality, 392 participants were included in this post-hoc analysis. Diet quality was assessed at baseline using the Australian Recommended Food Score (ARFS) which includes subscores of vegetable, fruit, grain, dairy products, fat, and alcohol. Knee joint structures (including cartilage volume, cartilage defect, bone marrow lesions, and effusion-synovitis volume assessed by magnetic resonance imaging), OA symptoms, lower limb muscle strength, depressive symptoms, and quality of life were assessed at baseline and follow up. Mixed-effects models were used to assess the associations of diet quality with those outcomes. Results Diet quality mainly reflect diet variety within the core food was not associated with knee structures and OA symptoms, but was associated with greater lower limb muscle strength (β = 0.66, P = 0.001), lower depressive symptom (β = -0.08, P = 0.001), and better quality of life (β = -0.06, P = 0.002). In further analyses of food group-based sub-scores, only the vegetable sub-score had the similar associations with lower limb muscle strength (β = 1.03, P = 0.004), depressive symptom (β = -0.17, P Conclusions Higher diet quality, mainly vegetable diet quality, is associated with greater lower limb muscle strength, less depressive symptoms, and higher quality of life in knee OA patients, suggesting higher diet quality may have protective effects on knee OA.

A newly identified coronavirus, 2019-nCoV, has been posing significant threats to public health since December 2019. ACE2, the host cell receptor for severe acute respiratory syndrome coronavirus (SARS), has recently been demonstrated in mediating 2019-nCoV infection. Interestingly, besides the respiratory system, substantial proportion of SARS and 2019-nCoV patients showed signs of various degrees of liver damage, the mechanism and implication of which have not yet been determined. Here, we performed an unbiased evaluation of cell type specific expression of ACE2 in healthy liver tissues using single cell RNA-seq data of two independent cohorts, and identified specific expression in cholangiocytes. The results indicated that virus might directly bind to ACE2 positive cholangiocytes but not necessarily hepatocytes. This finding suggested the liver abnormalities of SARS and 2019-nCoV patients may not be due to hepatocyte damage, but cholangiocyte dysfunction and other causes such as drug induced and systemic inflammatory response induced liver injury. Our findings indicate that special care of liver dysfunction should be installed in treating 2019-nCoV patients during the hospitalization and shortly after cure.

Summary Objective To investigate cross-sectional associations between serum level of Matrix metalloproteinase (MMP)13 and knee structural measures and circulating inflammatory factors in patients with symptomatic knee osteoarthritis (OA). Design A total of 149 subjects with symptomatic knee OA were included. Magnetic resonance imaging was used to measure infrapatellar fat pad (IPFP) volume, IPFP signal intensity alternation, cartilage volume and cartilage defects. Knee radiography was used to assess radiographic OA using the Kellgren-Lawrence (K-L) grading system. Enzyme-linked immunosorbent assay was used to measure the serum levels of inflammatory factors and MMP13. Results In multivariable analyses, serum MMP13 was negatively associated with cartilage volume at patellar site (β: −32.94 mm3 per 10 ng/ml, P Conclusions Serum level of MMP13 was associated with knee structural abnormalities as well as serum inflammatory factors. These suggest that systemic MMP13 may play a role in knee OA, and could be regulated by inflammatory factors.

Knee osteoarthritis (OA) is the most common joint disease. Body adipose tissue has been shown to be related to the development and progression of knee OA. Among systemic adipose tissues, subcutaneous adipose tissue is significantly and negatively associated with muscle mass and forces, and could be related to the presence and progression of knee OA. Visceral adipose tissue is associated with increased cartilage loss and production of pro-inflammatory cytokines. Intra-muscular adipose tissue is associated with knee osteoarthritic changes, but it remains controversial if inter-muscular adipose tissue has a role to play in the pathogenesis for knee OA. Knee local adipose tissue such as infrapatellar fat pad (IPFP) can interact with neighbouring tissues, and may have a biphasic effect in knee OA. The underlying mechanisms for the roles of the systemic and local fat in knee OA could be related to biomechanical, metabolic, inflammatory factors and fat fibrosis, which may have a separated or combined effect on OA. Tissue engineering from systemic or local adipose tissue is a new research direction, and adipose tissue-derived stem cells from systemic or local adipose tissue may be beneficial for OA cartilage repair. Research on systemic and local adipose tissue would provide novel approaches for prevention and treatment of knee OA, but further studies are required to explore the roles of different adipose tissues in knee OA and the effects of stem cells derived from different adipose tissues on knee OA.

Summary Objectives To describe prevalence of osteophytes (OPs) detected only by magnetic resonance imaging (MRI) but not by standard X-ray in older adults and to evaluate longitudinal associations with knee structural changes. Methods 837 participants were randomly selected from the local community and had MRI scans to assess knee OPs and other structures. OPs detected only by MRI but not by standard X-ray were defined as MRI-detected early OPs (MRI-OPs for short). OPs detected by both MRI and X-ray were defined as established-OPs. Results The prevalence of MRI-OPs was 50% while the prevalence of established-OPs was 10% and no-OPs was 40% at total tibiofemoral (TF) compartment at baseline. Compared with no-OPs, participants with MRI-OPs had greater risks of increased cartilage defects in all TF compartments (RR 1.37, 95%CI 1.07–1.74) and bone marrow lesions (BMLs) only in medial TF compartment (RR 1.49, 95%CI 1.06–2.11), after adjustment for age, sex, BMI, cartilage defects, BMLs and/or joint space narrowing; participants with established-OPs had greater cartilage volume loss at total (β −2.02, 95%CI −3.86, −0.17) and lateral tibial sites (β −5.63, 95%CI −9.93, −1.32), greater risks of increased cartilage defects in total (RR 1.66, 95%CI 1.15–2.40) and medial TF compartments (RR 1.49, 95%CI 1.20–1.69) and BMLs in all TF compartments (RR 1.88, 95%CI 1.22–2.89), after adjustment for covariates. Conclusion MRI-OPs were associated with changes in knee structures, and the associations were similar but not as prominent as those for established-OPs. These suggest MRI-OPs may have a role to play in knee early-stage osteoarthritic progression.

Summary Objective To develop a measure of knee joint effusion-synovitis volume and to examine the effect of vitamin D supplementation on effusion-synovitis in people with knee osteoarthritis (OA) and low vitamin D levels over 24 months. Method Symptomatic knee OA patients with low 25-(OH)D levels (12.5–60 nmol/l) were recruited for a multi-centre, randomised, placebo-controlled and double-blind trial. Participants (age 63 ± 7 years, 208 females) were allocated to either 50,000 IU monthly vitamin D 3 ( n = 209) or placebo ( n = 204) for 24 months. Knee effusion-synovitis volume in suprapatellar and other regions was measured on magnetic resonance imaging (MRI) using OsiriX software. The intra-class correlation coefficients (ICCs) were used to test inter- and intra-rater reliabilities. The least significant change criterion was used to define the increase/decrease in effusion-synovitis volume. Result The reproducibilities of effusion-synovitis volume measurement were high with ICCs ranging from 0.93 to 0.99. Over 24 months, effusion-synovitis volume remained stable in the vitamin D group but increased in placebos with a significant between-group difference (−1.94 ml, 95% confidence interval (CI): −3.54, −0.33). This effect was evident in those with baseline effusion-synovitis and with suprapatellar effusion-synovitis. The proportion with an increase in effusion-synovitis volume was lower in the vitamin D group than placebo (risk ratio (RR): 0.87, 95% CI: 0.77, 0.97). Conclusion This highly reproducible effusion-synovitis volume measurement could be a promising outcome measure in OA trials. Vitamin D supplementation could retard the progression of effusion-synovitis which can potentially benefit people with an inflammatory OA phenotype.

Summary Objective To describe cross-sectional and longitudinal associations between serum levels of interleukin (IL) - 6, IL-17A, IL-17F, IL-23 and knee bone marrow lesions (BMLs) in patients with knee osteoarthritis (OA). Design Patients ( n = 192) with symptomatic knee OA (mean 63 years, range 50–79, female 53%) were assessed at baseline and after 24 months. At each time point, serum IL-6, IL-17A, IL-17F and IL-23 were measured using Bio-Plex ® Multiplex Immunoassays with Luminex xMAP technology. Knee BMLs were scored using the modified whole organ MRI score (WORMS) from T2 weighted fat-suppressed fast spin echo magnetic resonance imaging (MRI). Multivariable linear regression and log binominal regression were used to determine the associations between cytokines and BMLs. Results Baseline IL-6 (quarters) were significantly associated with total knee BMLs ( P P = 0.05 for the trend), after adjustment for confounders. Baseline IL-17F and IL-23 (highest quarters vs others) was associated with an increase in BML score in females ( P = 0.04 for IL-17F; P = 0.01 for IL-23), but not in males, in multivariable analyses. In contrast, IL-17A was not significantly associated with BMLs in either females or males. Conclusion IL-6 is associated with increased knee BMLs in both females and males with OA. Serum IL-17F and IL-23 predicted increased knee BML scores in females only, suggesting that inflammation is involved in BML pathogenesis in knee OA, especially in women. Trail registration ClinicalTrials.gov identifier: NCT01176344; Australian New Zealand Clinical Trials Registry: ACTRN12610000495022.