Molecular biomarker approaches to prevention of post-traumatic osteoarthritis.

Up to 50% of individuals develop post-traumatic osteoarthritis (PTOA) within 10 years following knee-joint injuries such as anterior cruciate ligament rupture or acute meniscal tear. Lower-extremity PTOA prevalence is estimated to account for ≥12% of all symptomatic osteoarthritis (OA), or approximately 5.6 million cases in the USA. With knowledge of the inciting event, it might be possible to 'catch PTOA in the act' with sensitive imaging and soluble biomarkers and thereby prevent OA sequelae by early intervention. Existing biomarker data in the joint-injury literature can provide insights into the pathogenesis and early risk trajectory related to PTOA and can help to elucidate a research agenda for preventing or slowing the onset of PTOA. Non-traumatic OA and PTOA have many clinical, radiological and genetic similarities, and efforts to understand early risk trajectories in PTOA might therefore contribute to the identification and classification of early non-traumatic OA, which is the most prevalent form of OA.

Immune system-related plasma extracellular vesicles in healthy aging.

Objectives: To identify age-related plasma extracellular vehicle (EVs) phenotypes in healthy adults. Methods: EV proteomics by high-resolution mass spectrometry to evaluate EV protein stability and discover age-associated EV proteins (n=4 with 4 serial freeze-thaws each); validation by high-resolution flow cytometry and EV cytokine quantification by multiplex ELISA (n=28 healthy donors, aged 18-83 years); quantification of WI-38 fibroblast cell proliferation response to co-culture with PKH67-labeled young and old plasma EVs. The EV samples from these plasma specimens were previously characterized for bilayer structure, intra-vesicle mitochondria and cytokines, and hematopoietic cell-related surface markers. Results: Compared with matched exo-EVs (EV-depleted supernatants), endo-EVs (EV-associated) had higher mean TNF-α and IL-27, lower mean IL-6, IL-11, IFN-γ, and IL-17A/F, and similar mean IL-1ß, IL-21, and IL-22 concentrations. Some endo-EV and exo-EV cytokine concentrations were correlated, including TNF-α, IL-27, IL-6, IL-1ß, and IFN-γ, but not IL-11, IL-17A/F, IL-21 or IL-22. Endo-EV IFN-γ and exo-EV IL-17A/F and IL-21 declined with age. By proteomics and confirmed by flow cytometry, we identified age-associated decline of fibrinogen (FGA, FGB and FGG) in EVs. Age-related EV proteins indicated predominant origins in the liver and innate immune system. WI-38 cells (>95%) internalized similar amounts of young and old plasma EVs, but cells that internalized PKH67-EVs, particularly young EVs, underwent significantly greater cell proliferation. Conclusion: Endo-EV and exo-EV cytokines function as different biomarkers. The observed healthy aging EV phenotype reflected a downregulation of EV fibrinogen subpopulations consistent with the absence of a pro-coagulant and pro-inflammatory condition common with age-related disease.

An osteoarthritis pathophysiological continuum revealed by molecular biomarkers.

We aimed to identify serum biomarkers that predict knee osteoarthritis (OA) before the appearance of radiographic abnormalities in a cohort of 200 women. As few as six serum peptides, corresponding to six proteins, reached AUC 77% probability to distinguish those who developed OA from age-matched individuals who did not develop OA up to 8 years later. Prediction based on these blood biomarkers was superior to traditional prediction based on age and BMI (AUC 51%) or knee pain (AUC 57%). These results identify a prolonged molecular derangement of joint tissue before the onset of radiographic OA abnormalities consistent with an unresolved acute phase response. Among all 24 protein biomarkers predicting incident knee OA, the majority (58%) also predicted knee OA progression, revealing the existence of a pathophysiological "OA continuum" based on considerable similarity in the molecular pathophysiology of the progression to incident OA and the progression of established OA.

IL-1ra gene therapy in equine osteoarthritis improves physiological, anatomical, and biological outcomes of joint degeneration.

OBJECTIVE: To evaluate the effects of a gene transfer approach to IL-1ß inhibition in an equine osteochondral chip fragment model of joint injury using a self-complementary adeno-associated virus with interleukin receptor antagonist transgene cassette (scAAVIL-1ra), as posttraumatic osteoarthritis in horses, similar to people, is a significant clinical problem. ANIMALS: 16 horses were utilized for the study. METHODS: All horses had an osteochondral chip fragment induced arthroscopically in one middle carpal joint while the contralateral joint was sham operated. Eight horses received either scAAVIL-1ra or saline in the osteoarthritis joint. Horses were evaluated over 70 days clinically (lameness, imaging, and biomarker analysis) and euthanized at 70 days and evaluated grossly, with imaging and histopathology. RESULTS: The following findings were statistically significant. Injection of scAAVIL-1ra resulted in high synovial fluid levels of IL-1ra (0.5 to 9 µg/mL) throughout the duration of the experiment (70 days). Over the duration, we observed scAAVIL-1ra to improve lameness (lameness score relative improvement of 1.2 on a scale of 0 to 5), cause suppression of prostaglandin E2 (a relative decline of 30 pg/mL), and result in histological improvement in articular cartilage (decreased chondrocyte loss and chondrone formation) and subchondral bone (less osteochondral splitting and osteochondral lesions). Within the synovial membrane of scAAVIL-1ra-treated joints, we also observed perivascular infiltration with CD3-positive WBCs, suggesting lymphocytic T-cell perivascular infiltration commonly observed with viral transduction. CLINICAL RELEVANCE: These data provide support for further evaluation and optimization of scAAVIL-1ra gene therapy to treat equine osteoarthritis.

Body mass index, waist circumference, and mortality in subjects older than 80 years: a Mendelian randomization study.

BACKGROUND AND AIMS: Emerging evidence has raised an obesity paradox in observational studies of body mass index (BMI) and health among the oldest-old (aged ≥80 years), as an inverse relationship of BMI with mortality was reported. This study was to investigate the causal associations of BMI, waist circumference (WC), or both with mortality in the oldest-old people in China. METHODS: A total of 5306 community-based oldest-old (mean age 90.6 years) were enrolled in the Chinese Longitudinal Healthy Longevity Survey (CLHLS) between 1998 and 2018. Genetic risk scores were constructed from 58 single-nucleotide polymorphisms (SNPs) associated with BMI and 49 SNPs associated with WC to subsequently derive causal estimates for Mendelian randomization (MR) models. One-sample linear MR along with non-linear MR analyses were performed to explore the associations of genetically predicted BMI, WC, and their joint effect with all-cause mortality, cardiovascular disease (CVD) mortality, and non-CVD mortality. RESULTS: During 24 337 person-years of follow-up, 3766 deaths were documented. In observational analyses, higher BMI and WC were both associated with decreased mortality risk [hazard ratio (HR) 0.963, 95% confidence interval (CI) 0.955-0.971 for a 1-kg/m2 increment of BMI and HR 0.971 (95% CI 0.950-0.993) for each 5 cm increase of WC]. Linear MR models indicated that each 1 kg/m2 increase in genetically predicted BMI was monotonically associated with a 4.5% decrease in all-cause mortality risk [HR 0.955 (95% CI 0.928-0.983)]. Non-linear curves showed the lowest mortality risk at the BMI of around 28.0 kg/m2, suggesting that optimal BMI for the oldest-old may be around overweight or mild obesity. Positive monotonic causal associations were observed between WC and all-cause mortality [HR 1.108 (95% CI 1.036-1.185) per 5 cm increase], CVD mortality [HR 1.193 (95% CI 1.064-1.337)], and non-CVD mortality [HR 1.110 (95% CI 1.016-1.212)]. The joint effect analyses indicated that the lowest risk was observed among those with higher BMI and lower WC. CONCLUSIONS: Among the oldest-old, opposite causal associations of BMI and WC with mortality were observed, and a body figure with higher BMI and lower WC could substantially decrease the mortality risk. Guidelines for the weight management should be cautiously designed and implemented among the oldest-old people, considering distinct roles of BMI and WC.

Serum proteomic biomarkers diagnostic of knee osteoarthritis.

OBJECTIVE: To better understand the pathogenesis of knee osteoarthritis (OA) through identification of serum diagnostics. DESIGN: We conducted multiple reaction monitoring mass spectrometry analysis of 107 peptides in baseline sera of two cohorts: the Foundation for National Institutes of Health (NIH) (n = 596 Kellgren-Lawrence (KL) grade 1-3 knee OA participants); and the Johnston County Osteoarthritis Project (n = 127 multi-joint controls free of radiographic OA of the hands, hips, knees (bilateral KL=0), and spine). Data were split into (70%) training and (30%) testing sets. Diagnostic peptide and clinical data predictors were selected by random forest (RF); selection was based on association (p < 0.05) with OA status in multivariable logistic regression models. Model performance was based on area under the curve (AUC) of receiver operating characteristic (ROC) and precision-recall (PR) curves. RESULTS: RF selected 23 peptides (19 proteins) and body mass index (BMI) as diagnostic of OA. BMI weakly diagnosed OA (ROC-AUC 0.57, PR-AUC 0.812) and only symptomatic OA cases. ACTG was the strongest univariable predictor (ROC-AUC 0.705, PR-AUC 0.897). The final model (8 serum peptides) was highly diagnostic (ROC-AUC 0.833, 95% confidence interval [CI] 0.751, 0.905; PR-AUC 0.929, 95% CI 0.876, 0.973) in the testing set and equally diagnostic of non-symptomatic and symptomatic cases (AUCs 0.830-0.835), and not significantly improved with addition of BMI. The STRING database predicted multiple high confidence interactions of the 19 diagnostic OA proteins. CONCLUSIONS: No more than 8 serum protein biomarkers were required to discriminate knee OA from non-OA. These biomarkers lend strong support to the involvement and cross-talk of complement and coagulation pathways in the development of OA.

Association between regular proton pump inhibitors use and cardiovascular outcomes: A large prospective cohort study.

BACKGROUND: Proton pump inhibitors (PPIs) are widely prescribed for gastroesophageal reflux disease and peptic ulcer disease. However, the association between the regular PPIs use and the risk of cardiovascular disease (CVD) outcomes remains unclear. We aimed to determine whether regular proton pump inhibitors (PPIs) use is associated with an altered incidence of cardiovascular disease (CVD) in the general population. METHODS: This prospective cohort study included 459,207 participants (mean [SD] age, 56.2 [8.1] years) from the UK Biobank study without prevalent CVD who enrolled between 2006 and 2010 and were followed until 2018. Hazard ratios (HRs) and 95% confidence intervals (CIs) for incident CVD and its components (coronary heart disease [CHD], stroke, heart failure, atrial fibrillation, and venous thromboembolism) were obtained using Cox proportional hazards models with adjustment for potential confounding factors, including demographic factors, lifestyle behaviors, prevalent comorbidities, and clinical indicators for PPIs use. RESULTS: During the follow-up period, we recorded 26,346 incident CVD events (including 13,749 CHD events, 4144 stroke events, 5812 atrial fibrillation events, 1159 heart failure events, and 4206 venous thromboembolism events). The fully adjusted HRs (and 95% CIs) associated with PPIs users compared to nonusers were 1.44 (95% CI 1.39-1.50) for incident CVD, 1.65 (95% CI 1.57-1.74) for CHD, 1.21 (95% CI 1.09-1.33) for stroke, 1.17 (95% CI 1.08-1.28) for atrial fibrillation, 1.61 (95% CI 1.37-1.89) for heart failure, and 1.36 (95% CI 1.24-1.50) for venous thromboembolism. CONCLUSIONS: Regular PPIs use was associated with higher risk of CVD outcomes. Clinicians should therefore exercise caution when prescribing PPIs.

Serum proteomic panel validated for prediction of knee osteoarthritis progression.

Objective: To further validate a serum proteomics panel for predicting radiographic (structural) knee OA progression. Design: Serum peptides were targeted by multiple-reaction-monitoring mass spectrometry in the New York University cohort (n â€‹= â€‹104). Knee OA progression was defined as joint space narrowing ≥1 in the tibiofemoral compartment of one knee per study participant over a 24-month follow-up. The discriminative ability of an 11-peptide panel was evaluated by multivariable logistic regression and area under the receiver operating characteristic curve (AUC), without and with demographic characteristics of age, sex, and body mass index. The association of each peptide with OA progression was assessed by odds ratios (OR) in multivariable logistic regression models adjusted for demographics. Results: The cohort included 46 (44%) knee OA progressors. The panel of 11 peptides alone yielded AUC â€‹= â€‹0.66 (95% CI [0.55, 0.77]) for discriminating progressors from non-progressors; demographic traits alone yielded AUC â€‹= â€‹0.66 (95% CI [0.55, 0.77]). Together the 11 peptides and demographics yielded AUC â€‹= â€‹0.72 (95% CI [0.62, 0.83]). CRAC1 had the highest odds for predicting OA progression (OR 2.014, 95% CI [0.996, 4.296], p â€‹= â€‹0.058). Conclusions: We evaluated a parsimonious serum proteomic panel and found it to be a good discriminator of knee radiographic OA progression from non-progression. Since these biomarkers are quantifiable in serum, they could be deployed relatively easily to provide a simple, cost-effective strategy for identifying and monitoring individuals at high risk of knee OA progression.

Arthritis Foundation/HSS Workshop on Hip Osteoarthritis, Part 2: Detecting Hips at Risk: Early Biomechanical and Structural Mechanisms.

Far more publications are available for osteoarthritis of the knee than of the hip. Recognizing this research gap, the Arthritis Foundation (AF), in partnership with the Hospital for Special Surgery (HSS), convened an in-person meeting of thought leaders to review the state of the science of and clinical approaches to hip osteoarthritis. This article summarizes the recommendations gleaned from 5 presentations given in the "early hip osteoarthritis" session of the 2023 Hip Osteoarthritis Clinical Studies Conference, which took place on February 17 and 18, 2023, in New York City. It also summarizes the workgroup recommendations from a small-group discussion on clinical research gaps.

Comprehensive characterization of pathogenic synovial fluid extracellular vesicles from knee osteoarthritis.

Synovial fluid (SF) extracellular vesicles (EVs) play a pathogenic role in osteoarthritis (OA). However, the surface markers, cell and tissue origins, and effectors of these EVs are largely unknown. We found that SF EVs contained 692 peptides that were positively associated with knee radiographic OA severity; 57.4% of these pathogenic peptides were from 46 proteins of the immune system, predominantly the innate immune system. CSPG4, BGN, NRP1, and CD109 are the major surface markers of pathogenic SF EVs. Genes encoding surface marker CSPG4 and CD109 were highly expressed by chondrocytes from damaged cartilage, while VISG4, MARCO, CD163 and NRP1 were enriched in the synovial immune cells. The frequency of CSPG4+ and VSIG4+ EV subpopulations in OA SF was high. We conclude that pathogenic SF EVs carry knee OA severity-associated proteins and specific surface markers, which could be developed as a new source of diagnostic biomarkers or therapeutic targets in OA.

Synergistic roles of CBX4 chromo and SIM domains in regulating senescence of primary human osteoarthritic chondrocytes.

BACKGROUND: Cellular senescence is a critical factor contributing to osteoarthritis (OA). Overexpression of chromobox homolog 4 (CBX4) in a mouse system was demonstrated to alleviate post-traumatic osteoarthritis (PTOA) by reducing cellular senescence. Additionally, replicative cellular senescence of WI-38 fibroblasts can be attenuated by CBX4. However, the mechanisms underlying this senomorphic function of CBX4 are not fully understood. In this study, we aimed to investigate the role of CBX4 in cellular senescence in human primary osteoarthritic chondrocytes and to identify the functional domains of CBX4 necessary for its function in modulating senescence. METHODS: Chondrocytes, isolated from 6 individuals undergoing total knee replacement for OA, were transduced with wild-type CBX4, mutant CBX4, and control lentiviral constructs. Senescence-related phenotypic outcomes included the following: multiple flow cytometry-measured markers (p16INK4A, senescence-associated ß-galactosidase [SA-ß-gal] activity and dipeptidyl peptidase-4 [DPP4], and proliferation marker EdU), multiplex ELISA-measured markers in chondrocyte culture media (senescence-associated secretory phenotypes [SASPs], including IL-1ß, IL-6, IL-8, TNF-α, MMP-1, MMP-3, and MMP-9), and PCR array-evaluated senescence-related genes. RESULTS: Compared with control, CBX4 overexpression in OA chondrocytes decreased DPP4 expression and SASP secretion and increased chondrocyte proliferation confirming CBX4 senomorphic effects on primary human chondrocytes. Point mutations of the chromodomain domain (CDM, involved in chromatin modification) alone were sufficient to partially block the senomorphic activity of CBX4 (p16INK4A and DPP4 increased, and EdU decreased) but had minimal effect on SASP secretion. Although having no effect on p16INK4A, DPP4, and EdU, deletion of two small-ubiquitin-like-modifier-interaction motifs (CBX4 ΔSIMs) led to increased SASP secretion (IL-1ß, TNF-α, IL-8). The combination CBX4 CDMΔSIMs altered all these measures adversely and to a greater degree than the single domain mutants. Deletion of the C-terminal (CBX4 ΔC-box) involved with transcriptional silencing of polycomb group proteins increased IL-1ß slightly but significantly but altered none of the other senescence outcome measures. CONCLUSIONS: CBX4 has a senomorphic effect on human osteoarthritic chondrocytes. CDM is critical for CBX4-mediated regulation of senescence. The SIMs are supportive but not indispensable for CBX4 senomorphic function while the C-box is dispensable.

Dietary Diversity Changes and Cognitive Frailty in Chinese Older Adults: A Prospective Community-Based Cohort Study.

Evidence for the effects of dietary diversity changes and cognitive frailty (CF) in the older adults is not clear. This study aimed to investigate the relationship between dietary diversity changes and CF in older adults Chinese. A total of 14,382 participants (mean age: 82.3 years) were enrolled. Dietary diversity scores (DDSs) were collected and calculated using a food frequency questionnaire. DDS changes between baseline and first follow-up were categorized into nine patterns. The associations between DDS changes and the incidence of CF were estimated using Cox proportional hazards models. During an 80,860 person-year follow-up, 3023 CF cases were identified. Groups with a decrease in DDS had increased CF risk compared with the high-to-high DDS group, with adjusted hazard ratios (HRs; 95% confidence intervals (Cis)) of 1.30 (1.06, 1.59), 2.04 (1.51, 2.74), and 1.81 (1.47, 2.22) for high-to-medium, high-to-low, and medium-to-low groups, respectively. Lower overall DDS groups were associated with greater CF risks, with HRs (95% CIs) of 1.49 (1.19, 1.86) for the low-to-medium group and 1.96 (1.53, 2.52) for the low-to-low group. Compared with the high-to-high group, significant associations with CF were found in other DDS change groups; HRs ranged from 1.38 to 3.12 for the plant-based DDS group and from 1.24 to 1.32 for the animal-based DDS group. Additionally, extreme and moderate declines in overall DDS increased CF risk compared with stable DDS, with HRs (95% CIs) of 1.67 (1.50, 1.86) and 1.13 (1.03, 1.24), respectively. In conclusion, among older adults, a declining or persistently low DDS and a moderately or extremely declining DDS were linked to higher incident CF. Plant-based DDS changes correlated more strongly with CF than animal-based DDS changes.

Leisure Activities, Genetic Risk, and Frailty: Evidence from the Chinese Adults Aged 80 Years or Older.

INTRODUCTION: About half of adults aged ≥80 years suffer from frailty. Exercise is considered effective in preventing frailty but may be inapplicable to adults aged ≥80 years due to physical limitations. As an alternative, we aimed to explore the association of leisure activities with frailty and identify potential interaction with established polygenic risk score (PRS) among adults aged ≥80 years. METHODS: Analyses were performed in a prospective cohort study of 7,471 community-living older adults aged ≥80 years who were recruited between 2002 and 2014 from 23 provinces in China. Leisure activity was assessed using a seven-question leisure activity index and frailty was defined as a frailty index ≥0.25 using a validated 39-item health-related scale. The PRS was constructed using 59 single-nucleotide polymorphisms associated with frailty in a subsample of 2,541 older adults. Cox proportional hazards models were used to explore the associations of leisure activities, PRS with frailty. RESULTS: The mean age of participants was 89.4 ± 6.6 years (range: 80-116). In total, 2,930 cases of frailty were identified during 42,216 person-years of follow-up. Each 1 unit increase in the leisure activity index was associated with 12% lower risk of frailty (hazard ratio: 0.88 [95% confidence interval, 0.85-0.91]). Participants with high genetic risk (PRS >2.47 × 10-4) suffered from 26% higher risk of frailty. Interaction between leisure activity and genetic risk was not observed. CONCLUSION: Evidence is presented for the independent association of leisure activities and genetic risk with frailty. Engagement in leisure activities is suggested to be associated with lower risk of frailty across all levels of genetic risk among adults aged ≥80 years.

Development and Validation of a Lifespan Prediction Model in Chinese Adults Aged 65 Years or Older.

OBJECTIVES: Previous studies investigated factors associated with mortality. Nevertheless, evidence is limited regarding the determinants of lifespan. We aimed to develop and validate a lifespan prediction model based on the most important predictors. DESIGN: A prospective cohort study. SETTING AND PARTICIPANTS: A total of 23,892 community-living adults aged 65 years or older with confirmed death records between 1998 and 2018 from 23 provinces in China. METHODS: Information including demographic characteristics, lifestyle, functional health, and prevalence of diseases was collected. The risk prediction model was generated using multivariate linear regression, incorporating the most important predictors identified by the Lasso selection method. We used 1000 bootstrap resampling for the internal validation. The model performance was assessed by adjusted R2, root mean square error (RMSE), mean absolute error (MAE), and intraclass correlation coefficient (ICC). RESULTS: Twenty-one predictors were included in the final lifespan prediction model. Older adults with longer lifespans were characterized by older age at baseline, female, minority race, living in rural areas, married, with healthier lifestyles and more leisure engagement, better functional status, and absence of diseases. The predicted lifespans were highly consistent with observed lifespans, with an adjusted R2 of 0.893. RMSE was 2.86 (95% CI 2.84-2.88) and MAE was 2.18 (95% CI 2.16-2.20) years. The ICC between observed and predicted lifespans was 0.971 (95% CI 0.971-0.971). CONCLUSIONS AND IMPLICATIONS: The lifespan prediction model was validated with good performance, the web-based prediction tool can be easily applied in practical use as it relies on all easily accessible variables.

Population Attributable Fractions for Modifiable Factors of Longevity and Healthy Longevity Among the Late-Elderly Aged 75 Years or Older - China, 1998-2018.

What is already known about this topic?: Limited evidence on healthy longevity was provided in the world, and no studies investigated the fractions of healthy longevity attributed to modifiable factors. What is added by this report?: Incidences of longevity and healthy longevity in China are provided. It reveals that the total weighted population attributable fractions for lifestyles and all modifiable factors were 32.8% and 83.7% for longevity, respectively, and 30.4% and 73.4% for healthy longevity, respectively. What are the implications for public health practice?: China has a high potential for longevity and healthy longevity. Strategies may be targeted at education and residence in early life as well as healthy lifestyles, disease prevention, and functional optimization in late life.

Dietary diversity and frailty among older Chinese people: evidence from the Chinese Longitudinal Healthy Longevity Study.

BACKGROUND: Dietary diversity is widely advocated as a means to promote health, but little is known regarding whether the beneficial effects still apply in older adults. OBJECTIVE: To examine the association between the dietary diversity score (DDS) and frailty among older Chinese adults. METHODS: A total of 13,721 adults aged ≥65 y without frailty at baseline were enrolled. The DDS at baseline was constructed based on 9 items of a food frequency questionnaire. We used 39 self-reported health items to construct a frailty index (FI), with FI ≥ 0.25 indicating frailty. Cox models with restricted cubic splines were used to evaluate the dose-response relationships of DDS (continuous) with frailty. In addition, Cox proportional hazard models were used to examine the association between DDS (categorized as scores ≤4, 5-6, 7, and ≥8) and frailty. RESULTS: During the mean follow-up of 5.94 y, 5250 participants met the criteria for frailty. Each 1-unit increase in DDS corresponded to a 5% lower risk of frailty (hazard ratio [HR]; 0.95; 95% CI: 0.94, 0.97]. Compared with participants with DDS ≤4 points, those with a DDS of 5-6, 7, and ≥8 points exhibited a lower frailty risk, with HRs of 0.79 (95% CI: 0.71, 0.87), 0.75 (95% CI: 0.68, 0.83), and 0.74 (95% CI: 0.67, 0.81), respectively (P-trend < 0.001). Protein-rich food items, such as meat; eggs; and beans, were associated with protective effects against frailty. In addition, a significant association was observed between higher consumption of 2 high-frequency foods, tea and fruits, and lower risk of frailty. CONCLUSIONS: A higher DDS was associated with a lower risk of frailty among older Chinese adults. This study highlights the importance of a diverse diet as a potential modifiable behavioral factor for preventing frailty in older Chinese adults.

Association of Dipeptidylpeptidase 4 (CD26) With Chondrocyte Senescence and Radiographic Progression in Knee Osteoarthritis.

OBJECTIVE: To evaluate the association of dipeptidylpeptidase 4 (DPP-4; also known as CD26) with cellular senescence of human cartilage and progression of knee osteoarthritis (OA). METHODS: Articular cartilage sections and chondrocytes were acquired from 35 individuals undergoing total knee replacement for OA to evaluate the following: 1) the association between OA severity and established senescence markers (senescence-associated ß-galactosidase activity and p16), which was quantified using immunohistochemistry and flow cytometry (n = 19 samples); 2) the coexpression of DPP-4 with established senescence markers, which was assessed using flow cytometry; and 3) expression levels of anabolic and catabolic genes, senescence-related genes, and senescence-associated secretory phenotypes in DPP-4+ and DPP-4- cells, which were isolated using fluorescence-activated cell sorting or magnetic-activated cell sorting (n = 16 samples). The concentration of soluble DPP-4 was measured in samples of synovial fluid and samples of plasma from the Prediction of Osteoarthritis Progression cohort and then evaluated for association with the severity of radiographic knee OA at baseline (n = 65 samples) and the progression of structural radiographic OA (n = 57 samples) over a 3-year period. RESULTS: DPP-4 expression was associated with higher senescence-associated ß-galactosidase activity, p16 expression, senescence-related gene and catabolic gene (ADAMTS5, MMP13, IL6, and IL8) expression, higher senescence-associated secretory phenotype secretion, and lower anabolic gene (COL2A1 and ACAN) expression in primary chondrocytes. Synovial fluid DPP-4 concentration was associated with radiographic OA progression (odds ratio 105.32; P = 0.015), proteases (synovial fluid matrix metalloproteinase 1 and matrix metalloproteinase 3), aggrecan degradation (synovial fluid sulfated glycosaminoglycan), indicators of activated macrophages (synovial fluid CD14 and CD163), and inflammation (synovial fluid interleukin-6). CONCLUSION: Our study identifies DPP-4 as a key surface marker in senescent chondrocytes and a predictor of radiographic OA progression.

A "best-in-class" systemic biomarker predictor of clinically relevant knee osteoarthritis structural and pain progression.

We aimed to identify markers in blood (serum) to predict clinically relevant knee osteoarthritis (OA) progression defined as the combination of both joint structure and pain worsening over 48 months. A set of 15 serum proteomic markers corresponding to 13 total proteins reached an area under the receiver operating characteristic curve (AUC) of 73% for distinguishing progressors from nonprogressors in a cohort of 596 individuals with knee OA. Prediction based on these blood markers was far better than traditional prediction based on baseline structural OA and pain severity (59%) or the current "best-in-class" biomarker for predicting OA progression, urinary carboxyl-terminal cross-linked telopeptide of type II collagen (58%). The generalizability of the marker set was confirmed in a second cohort of 86 individuals that yielded an AUC of 70% for distinguishing joint structural progressors. Blood is a readily accessible biospecimen whose analysis for these biomarkers could facilitate identification of individuals for clinical trial enrollment and those most in need of treatment.

Association of physical activity and air pollution exposure with the risk of type 2 diabetes: a large population-based prospective cohort study.

BACKGROUND: The interplay between physical activity (PA) and air pollution in relation to type 2 diabetes (T2D) remains largely unknown. Based on a large population-based cohort study, this study aimed to examine whether the benefits of PA with respect to the risk of T2D are moderated by exposure to air pollution. METHODS: UK Biobank participants (n = 359,153) without diabetes at baseline were included. Information on PA was obtained using the International Physical Activity Questionnaire short form. Exposure to air pollution, including PM2.5, PMcoarse (PM2.5-10), PM10, and NO2, was estimated from land use regression models. Cox regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (95% CIs). RESULTS: During a median of 8.9 years of follow-up, 13,706 T2D events were recorded. Compared with a low PA level, the HRs for the risk of T2D among individuals with moderate and high PA were 0.82 (95% CI, 0.79-0.86) and 0.73 (95% CI, 0.70-0.77), respectively. Compared with low levels of air pollution, the HRs for risk of T2D for high levels of air pollution (PM2.5, PMcoarse, PM10, and NO2) were 1.19 (1.14-1.24), 1.06 (1.02-1.11), 1.13 (1.08-1.18), and 1.19 (1.14-1.24), respectively. There was no effect modification of the associations between PA and T2D by air pollution (all P-interactions > 0.05). The inverse associations between PA and T2D in each air pollution stratum were generally consistent (all P for trend < 0.05). CONCLUSION: A higher PA and lower air pollution level were independently associated with a lower risk of T2D. The beneficial effects of PA on T2D generally remained stable among participants exposed to different levels of air pollution. Further studies are needed to replicate our findings in moderately and severely polluted areas.