Diagnostic biomarkers in knee osteoarthritis: Based on bioinformatics and experimental verification in vivo and in vitro.

BACKGROUND: Knee osteoarthritis (KOA) is a multifactorial whole-joint disease with a high rate of disability. Considering the complexity of KOA, there is an urgent need to discover new molecular pathological markers and multi-target treatment strategies. METHODS: Two datasets, GSE51588 and GSE57218, were downloaded from the Gene Expression Omnibus database and screened for differentially expressed genes (DEGs) using the Gene Expression Omnibus 2R (GEO2R). Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of DEGs were performed. A protein-protein interaction (PPI) network was constructed and hub genes were identified using Molecular Complex Detection (MCODE). Receiver-operating characteristic curves (ROC) were plotted for the genes, and their prognostic values were evaluated. The expression levels of the hub genes in the monosodium iodoacetate (MIA)-induced KOA rat model and lipopolysaccharide (LPS)-stimulated C28/I2 cells were verified using reverse transcription quantitative real-time PCR (RT-qPCR). RESULTS: Overall, 33 DEGs were up-regulated and 6 DEGs were down-regulated in the two datasets. A total of 12 hub genes were identified, including COL15A1, THY1, COL1A1, COL5A1, CTHRC1, MXRA5, FN1, COL1A2, COL3A1, SPARC, COL8A1, and COL2A1, which all could be used as biomarkers to differentiate KOA samples from healthy controls. More importantly, we found that THY1, CTHRC1, SPARC, and COL8A1 were significantly upregulated in vivo and in vitro compared with the controls (p < .01). CONCLUSIONS: The expression levels of THY1, CTHRC1, SPARC, and COL8A1 were elevated and had good prognostic values as biomarkers in KOA.

Functional Insights into the Sphingolipids C1P, S1P, and SPC in Human Fibroblast-like Synoviocytes by Proteomic Analysis.

The (patho)physiological function of the sphingolipids ceramide-1-phosphate (C1P), sphingosine-1-phosphate (S1P), and sphingosylphosphorylcholine (SPC) in articular joints during osteoarthritis (OA) is largely unknown. Therefore, we investigated the influence of these lipids on protein expression by fibroblast-like synoviocytes (FLSs) from OA knees. Cultured human FLSs (n = 7) were treated with 1 of 3 lipid species-C1P, S1P, or SPC-IL-1ß, or with vehicle. The expression of individual proteins was determined by tandem mass tag peptide labeling followed by high-resolution electrospray ionization (ESI) mass spectrometry after liquid chromatographic separation (LC-MS/MS/MS). The mRNA levels of selected proteins were analyzed using RT-PCR. The 3sphingolipids were quantified in the SF of 18 OA patients using LC-MS/MS. A total of 4930 proteins were determined using multiplex MS, of which 136, 9, 1, and 0 were regulated both reproducibly and significantly by IL-1ß, C1P, S1P, and SPC, respectively. In the presence of IL-1ß, all 3 sphingolipids exerted ancillary effects. Only low SF levels of C1P and SPC were found. In conclusion, the 3 lipid species regulated proteins that have not been described in OA. Our results indicate that charged multivesicular body protein 1b, metal cation symporter ZIP14, glutamine-fructose-6-P transaminase, metallothionein-1F and -2A, ferritin, and prosaposin are particularly interesting proteins due to their potential to affect inflammatory, anabolic, catabolic, and apoptotic mechanisms.

[Clinical advantage staging and underlying mechanisms of Wangbi Tablets against knee osteoarthritis based on "disease-formula" interaction network].

The clinical advantage staging and underlying mechanisms of Wangbi Tablets against knee osteoarthritis(KOA) were studied based on the "disease-formula" interaction network. Firstly, the clinical symptoms and related genes corresponding to Wangbi Tablets and KOA in the acute, remission, and recovery phases were collected from clinical guidelines/consensus and SoFDA database, and the putative targets of Wangbi Tablets were obtained from ETCM 2.0. Then, Jaccard similarity and cosine similarity were employed to assess the similarities of clinical symptoms, genes, and enriched pathways between Wangbi Tablets and KOA in different phases. The "disease-formula" interaction network of the drug targets and disease genes was constructed, and the key targets were screened by topological feature calculation. KEGG and Reactome database were used for the functional enrichment of the key targets, on the basis of which the functional characteristics of Wangbi Tablets against KOA in the acute, remission, and recovery phases were predicted. Finally, the SW1353 cells exposed to lipopolysaccharide were used to decipher the mechanism of Wangbi Tablets against KOA. The results showed that 92/3 921, 138/3 708, 139/3 800, and 196/3 946 clinical symptoms and the related genes corresponded to KOA in the acute, remission, and recovery phases and Wangbi Tablets were collected from SoFDA, and 260 putative targets of Wangbi Tablets were obtained from ETCM 2.0. Wangbi Tablets had highest similarity of clinical symptoms, genes, and enriched pathways with KOA in the remission phase and the secondary highest similarity with KOA in the recovery phase. The key targets of Wangbi Tablets mainly participated in the regulation of immunity-inflammation imbalance and exerted pain-relieving and bone-protecting effects to alleviate symptoms such as knee joint pain, joint swelling, soreness, fatigue, and dysfunction. Intriguingly, the key targets of Wangbi Tablets possessed antioxidant effects during KOA in the acute and remission phases, while they maintained material and energy metabolism homeostasis and protected vessels during KOA in the recovery phase. The cell experiment indicated that Wangbi Tablets down-regulated the expression of interleukin(IL)-6, IL-1ß, tumor necrosis factor-α(TNF-α), and Bcl-2-associated X protein(Bax)/B-cell lymphoma 2(Bcl-2) via regulating the phosphatidylinositol 3-kinase(PI3K)-protein kinase B(Akt) signaling pathway. The findings lay a theoretical foundation for further clarifying the clinical advantage stage and precise clinical application of Wangbi Tablets in treating KOA.

Mechanism of drug-pairs Astragalus Mongholicus-Largehead Atractylodes on treating knee osteoarthritis investigated by GEO gene chip with network pharmacology and molecular docking.

Investigations into the therapeutic potential of Astragalus Mongholicus (AM, huáng qí) and Largehead Atractylodes (LA, bái zhú) reveal significant efficacy in mitigating the onset and progression of knee osteoarthritis (KOA), albeit with an elusive mechanistic understanding. This study delineates the primary bioactive constituents and their molecular targets within the AM-LA synergy by harnessing the comprehensive Traditional Chinese Medicine (TCM) network databases, including TCMSP, TCMID, and ETCM. Furthermore, an analysis of 3 gene expression datasets, sourced from the gene expression omnibus database, facilitated the identification of differential genes associated with KOA. Integrating these findings with data from 5 predominant databases yielded a refined list of KOA-associated targets, which were subsequently aligned with the gene signatures corresponding to AM and LA treatment. Through this alignment, specific molecular targets pertinent to the AM-LA therapeutic axis were elucidated. The construction of a protein-protein interaction network, leveraging the shared genetic markers between KOA pathology and AM-LA intervention, enabled the identification of pivotal molecular targets via the topological analysis facilitated by CytoNCA plugins. Subsequent GO and KEGG enrichment analyses fostered the development of a holistic herbal-ingredient-target network and a core target-signal pathway network. Molecular docking techniques were employed to validate the interaction between 5 central molecular targets and their corresponding active compounds within the AM-LA complex. Our findings suggest that the AM-LA combination modulates key biological processes, including cellular activity, reactive oxygen species modification, metabolic regulation, and the activation of systemic immunity. By either augmenting or attenuating crucial signaling pathways, such as MAPK, calcium, and PI3K/AKT pathways, the AM-LA dyad orchestrates a comprehensive regulatory effect on immune-inflammatory responses, cellular proliferation, differentiation, apoptosis, and antioxidant defenses, offering a novel therapeutic avenue for KOA management. This study, underpinned by gene expression omnibus gene chip analyses and network pharmacology, advances our understanding of the molecular underpinnings governing the inhibitory effects of AM and LA on KOA progression, laying the groundwork for future explorations into the active components and mechanistic pathways of TCM in KOA treatment.

Genetic insights into serum cathepsins as diagnostic and therapeutic targets in knee and hip osteoarthritis.

Osteoarthritis (OA) is a chronic disease due to the deterioration of cartilage structure and function, involving the progressive degradation of the cartilage extracellular matrix. Cathepsins, lysosomal cysteine proteases, play pivotal roles in various biological and pathological processes, particularly in protein degradation. Excess cathepsins levels are reported to contribute to the development of OA. However, the causal relationship between the cathepsin family and knee and hip OA remains uncertain. Therefore, this study utilized bidirectional Mendelian Randomization (MR) analyses to explore this causal association. Our results indicated that elevated serum levels of cathepsin O increase the overall risk of knee OA, while increased serum levels of cathepsin H enhance the risk of hip OA. Conversely, the reverse MR analyses did not reveal a reverse causal relationship between them. In summary, OA in different anatomical locations may genetically result from pathological elevations in different serum cathepsin isoforms, which could be utilized as diagnostic and therapeutic targets in clinical practice.

Physical activity and the osteoarthritis of the knee: A Mendelian randomization study.

Previous studies have reported an association between physical activity and the occurrence and progression of knee osteoarthritis (KOA). However, the existing evidence remains limited and of low-quality. This study aimed to examine the causal relationship between different levels of physical activity and KOA. Instrumental variables, represented by single nucleotide polymorphisms (SNPs), were utilized to capture sedentary behavior, appropriate physical exercise, and excessive physical activity. Aggregated statistics from the UK Biobank genome-wide association study dataset were used to assess the impact of these SNPs on KOA. Causality was estimated using inverse variance weighting (IVW), MR Egger, simple model, weighted median, and weighted model approaches. The stability of the results was assessed through heterogeneity and sensitivity analyses. Mendelian randomization (MR) analysis revealed a strong association between sedentary behavior and KOA, with an odds ratio (OR) of 2.096 (95% CI: 1.506-2.917) and a P value of 1.14 × 10-5. Appropriate physical exercise behavior exhibited a strong negative association with KOA, with an OR of 0.147 (95% CI: 0.037-0.582) and a P value of 0.006. Conversely, excessive physical activity behavior showed a significant positive association with KOA, with an OR of 2.162 (95% CI: 1.327-3.521) and a P value of .002. Our findings indicate that sedentary behavior and excessive physical activity are identified as risk factors for KOA, whereas engaging in appropriate physical exercise emerges as a protective factor against the development of KOA.

Gene expression and immune infiltration analysis comparing lesioned and preserved subchondral bone in osteoarthritis.

Background: Osteoarthritis (OA) is a degenerative disease requiring additional research. This study compared gene expression and immune infiltration between lesioned and preserved subchondral bone. The results were validated using multiple tissue datasets and experiments. Methods: Differentially expressed genes (DEGs) between the lesioned and preserved tibial plateaus of OA patients were identified in the GSE51588 dataset. Moreover, functional annotation and protein-protein interaction (PPI) network analyses were performed on the lesioned and preserved sides to explore potential therapeutic targets in OA subchondral bones. In addition, multiple tissues were used to screen coexpressed genes, and the expression levels of identified candidate DEGs in OA were measured by quantitative real-time polymerase chain reaction. Finally, an immune infiltration analysis was conducted. Results: A total of 1,010 DEGs were identified, 423 upregulated and 587 downregulated. The biological process (BP) terms enriched in the upregulated genes included "skeletal system development", "sister chromatid cohesion", and "ossification". Pathways were enriched in "Wnt signaling pathway" and "proteoglycans in cancer". The BP terms enriched in the downregulated genes included "inflammatory response", "xenobiotic metabolic process", and "positive regulation of inflammatory response". The enriched pathways included "neuroactive ligand-receptor interaction" and "AMP-activated protein kinase signaling". JUN, tumor necrosis factor α, and interleukin-1ß were the hub genes in the PPI network. Collagen XI A1 and leucine-rich repeat-containing 15 were screened from multiple datasets and experimentally validated. Immune infiltration analyses showed fewer infiltrating adipocytes and endothelial cells in the lesioned versus preserved samples. Conclusion: Our findings provide valuable information for future studies on the pathogenic mechanism of OA and potential therapeutic and diagnostic targets.

Increased alcohol intake is associated with radiographic severity of knee and hand osteoarthritis in men.

Observational studies have shown controversial associations between alcohol intake and radiographic osteoarthritis (OA). This study investigated whether this association was causal using a Mendelian randomization (MR) study in a population-based cohort in Korean. The study enrolled 2429 subjects (1058 men, 1371 women) from the Dong-gu Study. X-rays of the hand and knee joints were scored using a semi-quantitative grading system to calculate the total score of the hand and knee joints. ALDH2 rs671 genotyping was performed by high-resolution melting analysis. MR instrumental variable analysis and observational multivariable regression analysis were used to estimate the association between genetically predicted alcohol intake and the radiographic severity of OA. Subjects with the G/G genotype had a higher current alcohol intake than those with the G/A and A/A genotypes in both men and women (all P < 0.001). Men with the G/G genotype had higher total knee (P < 0.001) and hand scores (P = 0.042) compared to those with the G/A and A/A genotypes after adjusting for age and body mass index, but not in women. In the observational multivariable regression analysis, each alcohol drink per day in men was associated with increased knee (P = 0.001) and hand joint scores (P = 0.013) after adjustment, but not in women. In our MR analysis, utilizing ALDH2 rs671 genotypes as instrumental variables for alcohol consumption, has shown a significant link between each additional daily alcohol drink and increased radiographic joint severity in men.

Single-cell RNA sequencing reveals different chondrocyte states in femoral cartilage between osteoarthritis and healthy individuals.

Background: Cartilage injury is the main pathological manifestation of osteoarthritis (OA). Healthy chondrocyte is a prerequisite for cartilage regeneration and repair. Differences between healthy and OA chondrocyte types and the role these types play in cartilage regeneration and OA progression are unclear. Method: This study conducted single-cell RNA sequencing (scRNA-seq) on the cartilage from normal distal femur of the knee (NC group) and OA femur (OA group) cartilage, the chondrocyte atlas was constructed, and the differences of cell subtypes between the two groups were compared. Pseudo-time and RNA velocity analysis were both performed to verify the possible differentiation sequence of cell subtypes. GO and KEGG pathway enrichment analysis were used to explore the potential functional characteristics of each cell subtype, and to predict the functional changes during cell differentiation. Differences in transcriptional regulation in subtypes were explored by single-cell regulatory network inference and clustering (SCENIC). The distribution of each cell subtype in cartilage tissue was identified by immunohistochemical staining (IHC). Result: A total of 75,104 cells were included, they were divided into 19 clusters and annotated as 11 chondrocyte subtypes, including two new chondrocyte subtypes: METRNL+ and PRG4+ subtype. METRNL+ is in an early stage during chondrocyte differentiation, and RegC-B is in an intermediate state before chondrocyte dedifferentiation. With cell differentiation, cell subtypes shift from genetic expression to extracellular matrix adhesion and collagen remodeling, and signal pathways shift from HIF-1 to Hippo. The 11 subtypes were finally classified as intrinsic chondrocytes, effector chondrocytes, abnormally differentiated chondrocytes and dedifferentiated chondrocytes. IHC was used to verify the presence and distribution of each chondrocyte subtype. Conclusion: This study screened two new chondrocyte subtypes, and a novel classification of each subtype was proposed. METRNL+ subtype is in an early stage during chondrocyte differentiation, and its transcriptomic characteristics and specific pathways provide a foundation for cartilage regeneration. EC-B, PRG4+ RegC-B, and FC are typical subtypes in the OA group, and the HippO-Taz pathway enriched by these cell subtypes may play a role in cartilage repair and OA progression. RegC-B is in the intermediate state before chondrocyte dedifferentiation, and its transcriptomic characteristics may provide a theoretical basis for intervening chondrocyte dedifferentiation.

Depression and risk of arthritis: A Mendelian randomization study.

INTRODUCTION: Observational studies have found that most patients with arthritis have depression. We aimed to determine the causal relationship between various types of arthritis and depression. METHODS: We conducted a two-sample bidirectional Mendelian randomized (MR) analysis to determine whether there was a significant causal relationship between depression and multiple types of arthritis. The data of our study were derived from the publicly released genome-wide association studies (GWASs) and the largest GWAS meta-analysis. MR analysis mainly used inverse-variance weighted method; supplementary methods included weighted median, weighted mode, and MR-Egger using MR pleiotropy residual sum and outlier to detect and correct for the presence of pleiotropy. RESULTS: After adjusting for heterogeneity and horizontal pleiotropy, we found that depression was associated with an increased risk of osteoarthritis (OA) (OR = 1.02, 95%CI: 1.01-1.02, p = 2.96 × E - 5). In the reverse analysis, OA was also found to increase the risk of depression (OR = 1.10, 95%CI: 1.04-1.15, p = .0002). Depression only increased the risk of knee OA (KOA) (OR = 1.25, 95%CI: 1.10-1.42, p = 6.46 × E - 4). Depression could potentially increase the risk of spondyloarthritis (OR = 1.52, 95%CI: 1.19-1.94, p ≤ 8.94 × E - 4). CONCLUSION: There is a bidirectional causal relationship of depression with OA. However, depression only augments the risk of developing KOA. Depression may increase the risk of spondyloarthritis and gout.

Exploring causal correlations between inflammatory cytokines and knee osteoarthritis: a two-sample Mendelian randomization.

Objectives: Knee osteoarthritis (KOA) and certain inflammatory cytokines (such as interleukin 1 [IL-1] and tumor necrosis factor alpha [TNF-a]) are related; however, the causal relationship remains unclear. Here, we aimed to assess the causal relationship between 41 inflammatory cytokines and KOA using Mendelian randomization (MR). Methods: Two-sample bidirectional MR was performed using genetic variation data for 41 inflammatory cytokines that were obtained from European Genome-Wide Association Study (GWAS) data (n=8293). KOA-related genetic association data were also obtained from European GWAS data (n=40,3124). Inverse variance weighting (IVW), MR, heterogeneity, sensitivity, and multiple validation analyses were performed. Results: Granulocyte colony-stimulating factor (G-CSF) or colony-stimulating factor 3 (CSF-3) levels were negatively associated with the risk of developing KOA (OR: 0.93, 95%CI:0.89-0.99, P=0.015). Additionally, macrophage inflammatory protein-1 alpha (MIP-1A/CCL3) was a consequence of KOA (OR: 0.72, 95%CI:0.54-0.97, P=0.032). No causal relationship was evident between other inflammatory cytokines and KOA development. Conclusion: This study suggests that certain inflammatory cytokines may be associated with KOA etiology. G-CSF exerts an upstream influence on KOA development, whereas MIP-1A (CCL-3) acts as a downstream factor.

Causal relationship between periodontal disease-related phenotype and knee osteoarthritis: A two-sample mendelian randomization analysis.

OBJECTIVE: This study aimed to explore the bidirectional causal relationship between periodontal disease-related phenotype (PDRP) and knee osteoarthritis (KOA) in a European population using a two-sample Mendelian Randomization (MR) approach. METHODS: We leveraged publicly available GWAS summary statistics for PDRP (n = 975) and KOA (n = 403,124), assessing their roles as both exposures and outcomes. Our comprehensive MR analysis employed various methods, including inverse variance weighting (IVW), weighted median, Egger regression, simple mode, and weighted mode, to enhance the robustness of our findings. To ensure the reliability of our instrumental variables, we implemented a rigorous screening process based on p-values and F-values, utilized Phenoscanner to investigate potential confounders, and conducted sensitivity analyses. RESULTS: Our analysis identified five SNPs associated with PDRP and three SNPs with KOA, all surpassing the genome-wide significance threshold, as instrumental variables. The IVW method demonstrated a significant causal relationship from PDRP to KOA (beta = 0.013, SE = 0.007, P = 0.035), without evidence of directional pleiotropy (MR-Egger regression intercept = 0.021, P = 0.706). No support was found for reverse causality from KOA to PDRP, as further MR analyses yielded non-significant P-values. Additionally, funnel plots and Cochran's Q test detected no significant heterogeneity or directional pleiotropy, confirming the robustness of our results. In multivariate analysis, when considering smoking, alcohol consumption, BMI collectively no direct causal relationship between KOA and PDRP. Conversely, smoking and higher BMI were independently associated with an increased risk of KOA. CONCLUSION: In conclusion, our analysis revealed no direct causal relationship from KOA to PDRP. However, a causal relationship from PDRP to KOA was observed. Notably, when adjusting for potential confounders like smoking, alcohol intake, and BMI, both the causal connection from PDRP to KOA and the inverse relationship were not substantiated.

Causal relationship between sarcopenia with osteoarthritis and the mediating role of obesity: a univariate, multivariate, two-step Mendelian randomization study.

BACKGROUND: Recent genetic evidence supports a causal role for sarcopenia in osteoarthritis, which may be mediated by the occurrence of obesity or changes in circulating inflammatory protein levels. Here, we leveraged publicly available genome-wide association study data to investigate the intrinsic causal relationship between sarcopenia, obesity, circulating inflammatory protein levels, and osteoarthritis. METHODS: In this study, we used Mendelian randomization analyses to explore the causal relationship between sarcopenia phenotypes (Appendicular lean mass [ALM], Low hand-grip strength [LHG], and usual walking pace [UWP]) and osteoarthritis (Knee osteoarthritis [KOA], and Hip osteoarthritis [HOA]). Univariable Mendelian randomization (UVMR) analyses were performed using the inverse variance weighted (IVW) method, MR-Egger, weighted median method, simple mode, and weighted mode, with the IVW method being the primary analytical technique. Subsequently, the independent causal effects of sarcopenia phenotype on osteoarthritis were investigated using multivariate Mendelian randomization (MVMR) analysis. To further explore the mechanisms involved, obesity and circulating inflammatory proteins were introduced as the mediator variables, and a two-step Mendelian randomization analysis was used to explore the mediating effects of obesity and circulating inflammatory proteins between ALM and KOA as well as the mediating proportions. RESULTS: UVMR analysis showed a causal relationship between ALM, LHG, UWP and KOA [(OR = 1.151, 95% CI: 1.087-1.218, P = 1.19 × 10-6, PFDR = 7.14 × 10-6) (OR = 1.215, 95% CI: 1.004-1.470; P = 0.046, PFDR = 0.055) (OR = 0.503, 95% CI: 0.292-0.867; P = 0.013, PFDR = 0.027)], and a causal relationship between ALM, UWP and HOA [(OR = 1.181, 95% CI: 1.103-1.265, P = 2.05 × 10-6, PFDR = 6.15 × 10-6) (OR = 0.438, 95% CI: 0.226-0.849, P = 0.014, PFDR = 0.022)]. In the MVMR analyses adjusting for confounders (body mass index, insomnia, sedentary behavior, and bone density), causal relationships were observed between ALM, LHG, UWP and KOA [(ALM: OR = 1.323, 95%CI: 1.224- 1.431, P = 2.07 × 10-12), (LHG: OR = 1.161, 95%CI: 1.044- 1.292, P = 0.006), (UWP: OR = 0.511, 95%CI: 0.290- 0.899, P = 0.020)], and between ALM and HOA (ALM: OR = 1.245, 95%CI: 1.149- 1.348, P = 7.65 × 10-8). In a two-step MR analysis, obesity was identified to play a potential mediating role in ALM and KOA (proportion mediated: 5.9%). CONCLUSIONS: The results of this study suggest that decreased appendicular lean mass, grip strength, and walking speed increase the risk of KOA and decreased appendicular lean mass increases the risk of HOA in patients with sarcopenia in a European population. Obesity plays a mediator role in the occurrence of KOA due to appendicular lean body mass reduction.

Association between angiotensin-converting enzyme (ACE) gene I/D polymorphism with the risk of knee OA: A systematic review, meta-analysis, and meta-regression.

Background: Previous studies have linked genetics to knee osteoarthritis. Angiotensin-converting enzyme (ACE) gene I/D polymorphism may cause OA. However, evidence remains inconsistent. This study examines knee OA risk and ACE gene I/D polymorphism. Methods: We explored Europe PMC, Medline, Scopus, and Cochrane Library using keywords. Three assessment bias factors were assessed using the Newcastle-Ottawa Scale (NOS). Criteria for inclusion: (1) Split the study population into knee OA patients and healthy controls; (2) Analysed the ACE gene I/D polymorphism; (3) Case-control or cross-sectional surveys. Studies with non-knee OA, incomplete data, and no full-text were excluded. The odds ratio (OR) and 95% confidence intervals (95% CI) were calculated using random-effect models. Results: A total of 6 case-control studies consist of 1,226 patients with knee OA and 1,145 healthy subjects as controls were included. Our pooled analysis revealed that a significant association between ACE gene I/D polymorphism and risk of knee OA was only seen in the dominant (DD + ID vs. II) [OR 1.69 (95% CI 1.14 - 2.50), p = 0.009, I2 = 72%], and ID vs. II [OR 1.37 (95% CI 1.01- 1.86), p = 0.04, I2 = 43%] genotype models. Other genotype models, including recessive (DD vs. ID + II), alleles (D vs. I), DD vs. ID, and DD vs. II models did not show a significant association with knee OA risk. Further regression analysis revealed that ethnicity and sex may influence those relationships in several genotype models. Conclusions: Dominant and ID vs. II ACE gene I/D polymorphism models increased knee OA risk significantly. More research with larger samples and different ethnic groups is needed to confirm our findings. After ethnicity subgroup analysis, some genetic models in our study showed significant heterogeneities, and most studies are from Asian countries with Asian populations, with little evidence on Arabs.

Acupotomy alleviates knee osteoarthritis in rabbit by regulating chondrocyte mitophagy Pink1-Parkin pathway.

OBJECTIVE: To investigate the effect of acupotomy, on mitophagy and the Pink1-Parkin pathway in chondrocytes from rabbits with knee osteoarthritis (KOA). METHODS: A KOA model was established via the modified Videman method. Rabbits were randomly divided into a control group (CON), KOA group and KOA + acupotomy group (Acu). Rabbits in the acupotomy group were subjected to acupotomy for 4 weeks after model establishment. The behavior of the rabbits before and after intervention was recorded. Cartilage degeneration was evaluated by optical microscopy and fluorescence microscopy. The level of mitophagy was evaluated by transmission electron microscopy, immunofluorescence and enzyme-linked immunosorbent assay (ELISA). The expression of phosphatase and tensin homolog (PTEN)-induced kinase 1 (Pink1)-Parkin mitophagy pathway components was evaluated by immunofluorescence, Western blotting and real-time polymerase chain reaction. RESULTS: In rabbits with KOA, joint pain, mobility disorders and cartilage degeneration were observed, the Mankin score was increased, collagen type Ⅱ (Col-Ⅱ) expression was significantly decreased, mitophagy was inhibited, mitochondrial function was impaired, and factors associated with the Pink1-Parkin pathway were inhibited. Acupotomy regulated the expression of Pink1-Parkin pathway-related proteins, the mitophagy-related protein microtubule-associated protein-1 light chain-3, the translocase of the outer membrane, and the inner mitochondrial membrane 23; increased the colocalization of mitochondria and autophagosomes; promoted the removal of damaged mitochondria; restored mitochondrial adenosine-triphosphate (ATP) production; and alleviated cartilage degeneration in rabbits with KOA. CONCLUSIONS: Acupotomy played a role in alleviating KOA in rabbits by activating mitophagy in chondrocytes via the regulation of proteins that are related to the Pink1-Parkin pathway.

Intrauterine hyperglycemia induces SIRT3-mediated mitochondrial dysfunction: the fetal origin pathogenesis of precocious osteoarthritis.

OBJECTIVE: Diabetes and other metabolic and inflammatory comorbidities are highly associated with osteoarthritis (OA). However, whether early-life hyperglycemia exposure affects susceptibility to long-term OA is still unknown. The purpose of this study was to explore the fetal origins of OA and provide insights into early-life safeguarding for individual health. METHOD: This study utilized streptozotocin to induce intrauterine hyperglycemia and performed destabilization of the medial meniscus surgery on the knee joints of the offspring mice to induce accelerated OA. Cartilage degeneration-related markers, as well as the expression levels of mitochondrial respiratory chain complexes and mitophagy genes in the adult offspring mice, were investigated. In vitro, mitochondrial function and mitophagy of chondrocyte C28/I2 cells stimulated under high glucose conditions were also evaluated. The methylation levels of the sirt3 gene promoter region in the articular cartilage of intrauterine hyperglycemia-exposed offspring mice were further analyzed. RESULTS: In this study, we found that the intrauterine hyperglycemic environment could lead to an increase in individual susceptibility to OA in late adulthood, mainly due to persistently low levels of Sirt3 expression. Downregulation of Sirt3 causes impaired mitophagy in chondrocytes and abnormal mitochondrial respiratory function due to a failure to clear aged and damaged mitochondria in a timely manner. Overexpressing Sirt3 at the cellular level or using Sirt3 agonists like Honokiol in mouse models can partially rescue mitophagy disorders caused by the hyperglycemic environment and thus alleviate the progression of OA. CONCLUSION: Our study revealed a significantly increased susceptibility to OA in the gestational diabetes mellitus offspring, which is partly attributed to exposure to adverse factors in utero and ultimately to the onset of disease via epigenetic modulation.

Ultra-processed food consumption, genetic susceptibility, and the risk of hip/knee osteoarthritis.

BACKGROUND: The associations between ultra-processed food (UPF) consumption, genetic susceptibility, and the risk of osteoarthritis (OA) remain unknown. This study was to examine the effect of UPF consumption, genetic susceptibility, and their interactions on hip/knee OA. METHODS: Cohort analyses included 163,987 participants from the UK Biobank. Participants' UPF consumption was derived from their 24-h dietary recall using a questionnaire. Genetic risk scores (GRSs) of 70 and 83 single nucleotide polymorphisms (SNPs) for hip and knee OA were constructed. FINDINGS: After 1,461,447 person-years of follow-up, 11,540 patients developed OA. After adjustments, compared to participants in the low quartile of UPF consumption, those in the high quartile had a 10 % (hazard ratio [HR], 1.10; 95% confidence interval [CI], 1.03-1.18) increased risk of knee OA. No significant association was found between UPF consumption and hip OA. Replacing 20% of UPF diet weight with an equivalent proportion of unprocessed or minimally processed food caused a 6% (HR, 0.94; 95% CI, 0.89-0.98) decreased risk of knee OA, respectively. A significant interaction was found between UPF consumption, genetic predisposition, and the risk of knee OA (P = 0.01). Participants with lower OA-GRS scores experienced higher knee OA risks due to UPF consumption. INTERPRETATION: UPF consumption was associated with a higher risk of knee OA but not hip OA, particularly in those with lower genetic susceptibility. These results highlight the importance of reducing UPF consumption to prevent knee OA.

Circulating cytokines levels and osteoarthritis: A Mendelian randomization study.

BACKGROUND: Previous traditional observational studies have suggested the contribution of several cytokines and growth factors to the development of osteoarthritis (OA). This study aimed to determine the association of circulating cytokine and growth factor levels with OA. METHODS: We used two-sample Mendelian randomization (MR) to explore the causality between circulating cytokine and growth factor levels and OA [including knee or hip OA (K/HOA), knee OA (KOA), and hip OA (HOA)]. Summary level data for circulating cytokine and growth factor levels were sourced from a genome-wide association study (GWAS) involving 8,293 participants of Finnish ancestry. Single-nucleotide polymorphisms related to K/HOA (39,427 cases and 378,169 controls), KOA (24,955 cases and 378,169 controls), and HOA (15,704 cases and 378,169 controls) were obtained from a previous GWAS. The inverse variance weighted (IVW) method was primarily used for our MR analysis. For exposures to only one relevant SNP as IV, we used the Wald ratio as the major method to assess causal effects. We also conducted a series of sensitivity analyses to improve the robustness of the results. RESULTS: Circulating vascular endothelial growth factor levels were suggestively associated with an increased risk of K/HOA (odds ratio (OR) = 1.034; 95 % confidence interval (CI) = 1.013-1.055; P = 0.001), KOA (OR = 1.034; 95 % CI = 1.014-1.065; P = 0.002), and HOA (OR = 1.039; 95 % CI = 1.003-1.067; P = 0.034). Circulating interleukin (IL)-12p70 levels was suggestively associated with K/HOA (OR = 1.047; 95 % CI = 1.018-1.077; P = 0.001), KOA (OR = 1.058; 95 % CI = 1.022-1.095; P = 0.001), and HOA (OR = 1.044; 95 % CI = 1.000-1.091; P = 0.048). Circulating IL-18 levels were suggestively associated with HOA (OR = 1.068; 95 % CI = 1.014-1.125; P = 0.012). However, limited evidence exists to support causal genetic relationships between other circulating cytokines, growth factor levels and K/HOA, KOA, and HOA. CONCLUSIONS: Our MR analysis provides suggestive evidence of causal relationships between circulating cytokines and growth factors levels and OA, providing new insights into the etiology of OA.

Causal analysis of body composition measurements in osteoarthritis knee: a two-sample mendelian randomization study.

BACKGROUND: To analyse the causal associations of different physical measures with osteoarthritis knee (KOA). METHODS: Exposure factors (weight, body mass index (BMI), body fat percentage, waist circumference, hip circumference, waist-hip ratio (WHR), and basal metabolic rate (BMR)), and outcome factor KOA were analyzed by inverse-variance weighted (IVW) method, along with heterogeneity test, sensitivity and pleiotropy analyses. Meta-analysis was used to combine the effect values of IVW methods in different data sources. RESULTS: Weight, BMI, body fat percentage, waist circumference, hip circumference and BMR analyses showed causal association with increased KOA risk, while WHR analysis indicated a reduction of the incidence of KOA. P-value for all the results was less than 0.05 and F-value large than 20. All results were negative for heterogeneity tests and sensitivity analyses, and there was pleiotropy in weight and BMR. Meta-analysis results showed that the results of Odds Ratios (95% Confidence Intervals) for Weight (1.43(1.35-1.51)), BMI (1.40(1.10-1.78)), body fat percentage (1.56(1.44-1.68)), waist circumference (1.40(1.10-1.78)), hip circumference (1.37(1.30-1.44)), WHR (0.86(0.71-1.04)) and BMR (1.36(1.27-1.46) were consistent with the ones by Mendelian randomization analyses. CONCLUSIONS: Body fat percentage may be a better indicator of KOA than BMI. In addition, weight and BMR may have a causal effect in KOA, but WHR does not have a causal relationship. BMI, body fat percentage, waist circumference, and hip circumference has a causal effect on KOA.

Assessing the causal associations of different types of statins use and knee/hip osteoarthritis: A Mendelian randomization study.

OBJECTIVE: This study comprehensively evaluated the causal relationship between different types of statins use and knee/hip osteoarthritis (OA) using a two-sample and multivariate Mendelian randomization (MR) method. METHODS: MR analysis was conducted using publicly available summary statistics data from genome-wide association studies (GWAS) to assess the causal associations between total statins use (including specific types) and knee/hip OA. The primary analysis utilized the inverse variance-weighted (IVW) method, with sensitivity analysis conducted to assess robustness. Multivariable MR (MVMR) analysis adjusted for low-density lipoprotein cholesterol (LDL-C), intermediate-density lipoprotein cholesterol (IDL-C), high-density lipoprotein cholesterol (HDL-C), and body mass index (BMI). RESULTS: The MR analysis revealed a significant inverse association between genetically predicted total statins use and the risk of knee OA (OR = 0.950, 95%CI: 0.920-0.982, p = 0.002) as well as hip OA (OR = 0.932, 95%CI: 0.899-0.966, p <0.001). Furthermore, this study highlighted a reduced risk of knee/hip OA with the use of atorvastatin and simvastatin. Rosuvastatin use was associated with a decreased risk of hip OA but showed no association with knee OA. MVMR results indicated no correlation between exposure factors and outcomes after adjusting for LDL-C or IDL-C. HDL-C may not significantly contribute to statin-induced osteoarthritis, while BMI may play an important role. CONCLUSION: This study provides compelling evidence of the close relationship between statin use and a reduced risk of knee/hip OA, particularly with atorvastatin and simvastatin. LDL-C and IDL-C may mediate these effects. These findings have important implications for the clinical prevention and treatment of knee/hip OA.