Osteoarthritis Susceptibility Research Articles

Identification of key hub genes in knee osteoarthritis through integrated bioinformatics analysis.

Knee osteoarthritis (KOA) is a common chronic joint disease globally. Synovial inflammation plays a pivotal role in its pathogenesis, preceding cartilage damage. Identifying biomarkers in osteoarthritic synovial tissues holds promise for early diagnosis and targeted interventions. Gene expression profiles were obtained from the Gene Expression Omnibus database. Subsequent analyses included differential expression gene (DEG) analysis and weighted gene co-expression network analysis (WGCNA) on the combined datasets. We performed functional enrichment analysis on the overlapping genes between DEGs and module genes and constructed a protein-protein interaction network. Using Cytoscape software, we identified hub genes related to the disease and conducted gene set enrichment analysis on these hub genes. The CIBERSORT algorithm was employed to evaluate the correlation between hub genes and the abundance of immune cells within tissues. Finally, Mendelian randomization analysis was utilized to assess the potential of these hub genes as biomarkers. We identified 46 differentially expressed genes (DEGs), comprising 20 upregulated and 26 downregulated genes. Using WGCNA, we constructed a gene co-expression network and selected the most relevant modules, resulting in 24 intersecting genes with the DEGs. KEGG enrichment analysis of the intersecting genes identified the IL-17 signaling pathway, associated with inflammation, as the most significant pathway. Cytoscape software was utilized to rank the candidate genes, with JUN, ATF3, FOSB, NR4A2, and IL6 emerging as the top five based on the Degree algorithm. A nomogram model incorporating these five genes, supported by ROC curve analysis, validated their diagnostic efficacy. Immune infiltration and correlation analysis revealed that macrophages were significantly associated with JUN (p < 0.01), FOSB (p < 0.01), and NR4A2 (p < 0.05). Additionally, T follicular helper cells showed significant associations with ATF3 (p < 0.05), FOSB (p < 0.05), and JUN (p < 0.05). Mendelian randomization analysis provided strong evidence linking JUN (IVW: OR = 0.910, p = 0.005) and IL6 (IVW: OR = 1.024, p = 0.026) with KOA. Through the utilization of various bioinformatics analysis methods, we have pinpointed key hub genes relevant to knee osteoarthritis. These findings hold promise for advancing pre-symptomatic diagnostic strategies and enhancing our understanding of the biological underpinnings behind knee osteoarthritis susceptibility genes.

PIEZO1 variants that reduce open channel probability are associated with familial osteoarthritis.

The synovial joints senses and responds to a multitude of physical forces to maintain joint homeostasis. Disruption of joint homeostasis results in development of osteoarthritis (OA), a disease characterized by loss of joint space, degeneration of articular cartilage, remodeling of bone and other joint tissues, low-grade inflammation, and pain. How changes in mechanosensing in the joint contribute to OA susceptibility remains elusive. PIEZO1 is a major mechanosensitive cation channel in the joint directly regulated by mechanical stimulus. To test whether altered PIEZO1 channel activity causes increased OA susceptibility, we determined whether variants affecting PIEZO1 are associated with dominant inheritance of age-associated familial OA. We identified four rare coding variants affecting PIEZO1 that are associated with familial hand OA. Single channel analyses demonstrated that all four PIEZO1 mutant channels act in a dominant-negative manner to reduce the open probability of the channel in response to pressure. Furthermore, we show that a GWAS mutation in PIEZO1 associated with reduced joint replacement results in increased channel activity when compared with WT and the mutants. Our data support the hypothesis that reduced PIEZO1 activity confers susceptibility to age-associated OA whereas increased PIEZO1 activity may be associated with reduced OA susceptibility.

Genetic polymorphisms of LMX1B and MLXIP are associated with hip osteoarthritis in the Chinese population.

Aims: A large genome-wide analyses of UK Biobank data reported 15 novel loci associated with the susceptibility of hip osteoarthritis (HOA). We aimed to replicate the association of these loci with HOA in the Chinese population.Methods: A total of 13 Single Nucleotide Polymorphismswere genotyped in 892 HOA patients and 1123 healthy controls.Results: The risk allele frequency of rs62578127 and rs11059094 was significantly higher in the patients than in the controls. The mRNA expression of LMX1B (p=0.01) and MLXIP (p=0.001) were significantly increased in HOA tissues.Conclusion: We successfully replicated two novel susceptible loci of HOA and further characterized two potential causative genes.

α7-nAChR/P300/NLRP3-regulated pyroptosis mediated poor articular cartilage quality induced by prenatal nicotine exposure in female offspring rats

Nicotine is developmentally toxic. Prenatal nicotine exposure (PNE) affects the development of multiple fetal organs and causes susceptibility to a variety of diseases in offspring. In this study, we aimed to investigate the effect of PNE on cartilage development and osteoarthritis susceptibility in female offspring rats. Wistar rats were orally gavaged with nicotine on days 9–20 of pregnancy. The articular cartilage was obtained at gestational day (GD) 20 and postnatal week (PW) 24, respectively. Further, the effect of nicotine on chondrogenic differentiation was explored by the chondrogenic differentiation model in human Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs). The PNE group showed significantly shallower Safranin O staining and lower Collagen 2a1 content of articular cartilage in female offspring rats. Further, we found that PNE activated pyroptosis in the articular cartilage at GD20 and PW24. In vitro experiments revealed that nicotine inhibited chondrogenic differentiation and activated pyroptosis. After interfering with nod-like receptors3 (NLRP3) expression by SiRNA, it was found that pyroptosis mediated the chondrogenic differentiation inhibition of WJ-MSCs induced by nicotine. In addition, we found that α7-nAChR antagonist α-BTX reversed nicotine-induced NLRP3 and P300 high expression. And, P300 SiRNA reversed the increase of NLRP3 mRNA expression and histone acetylation level in its promoter region induced by nicotine. In conclusion, PNE caused chondrodysplasia and poor articular cartilage quality in female offspring rats. PNE increased the histone acetylation level of NLRP3 promoter region by α7-nAChR/P300, which resulting in the high expression of NLRP3. Further, NLRP3 mediated the inhibition of chondrogenic differentiation by activating pyroptosis.

The potential impact of polymorphisms in METTL3 gene on knee osteoarthritis susceptibility

ObjectiveThis study was aimed to explore the correlation between METTL3 polymorphisms and susceptibility to knee osteoarthritis (KOA). MethodsThe relationship of five single nucleotide polymorphisms (SNPs) in the METTL3 gene with the susceptibility of KOA was analyzed through multinomial logistic regression analysis in this a case-control study. Genotyping was performed on 228 KOA patients and 252 unaffected individuals from South China based on the TaqMan method. The MDR software (version 3.0.2) was utilized for the analysis of SNP interactions. ResultsOut of the five SNPs examined, the T > G change in the METTL3 gene at the rs1061026 locus increased the risk of KOA, while rs1139130 A > G and rs1263802 C > T variants were found to be linked with a reduced risk of developing KOA with statistical significance. The rs1061027 A > C and rs1263801 C > G variants did not show significant association (p＞0.05). The rs1061026 TG/GG genotype showed a significant correlation with an increased risk of KOA in the following subgroups: the males, individuals with a BMI ranging from 24 to 28, smokers, those who were not engaged in physical exercise (PE), patients who had experienced KOA symptoms for eight years or longer, and those without a family history of the disease or reported swelling. On the other hand, the rs1139130 AG/GG genotype demonstrated a protective effect against KOA among the females, individuals with a BMI greater than or equal to 24, a unilateral KOA, or a KOA duration of 8 years or less, non-smokers, non-alcohol drinkers, those who were not engaged in PE, and those who had no injury or family history, or no experience of knee swelling. Additionally, it was observed that the rs1263802 CT/TT genotypes showed a protective effect among patients without a history of injury. Furthermore, individuals with the haplotypes GAT, GGC, TAT, and TGC were found to have a significantly lower susceptibility to KOA compared to the reference haplotype TAC. ConclusionsThe METTL3 gene variant rs1061026 could increase the risk of KOA, whereas the variants of rs1139130 as well as rs1263802 might exert a protective effect against KOA. These variants could potentially function as susceptibility markers for KOA among the population from South China.

Relation of STAT3 rs1053005 Variation and miR-452-3p with Osteoarthritis Susceptibility and Severity and the Clinical Response to High-Molecular-Weight Hyaluronic Acid Injection in Osteoarthritis Patients

Polymorphisms in the 3′ untranslated region of STAT3 mRNA can derange STAT3 gene expression via modifying the microRNA-binding site. This study aimed to examine the impact of STAT3 rs1053005 variation and miR-452-3p expression on osteoarthritis (OA) susceptibility and severity and the efficacy of intra-articular high-molecular-weight hyaluronic acid (HMW-HA) injection as a therapy option for knee OA. Two hundred and fifty-eight OA patients and 200 healthy controls were enrolled in the study. STAT3 genotyping and STAT3 and miR-452-3p expression were carried out using allelic-discrimination PCR and quantitative real-time PCR. Functional assessment and pain evaluation were performed for all patients. Eighty-three patients received HMW-HA injections, and multiple follow-up visits were performed. STAT3 mRNA was upregulated, and expression was positively associated with plasmin, TNF-α, MMP-3, and STAT3 serum levels, whereas miR-452-3p was downregulated and negatively associated with the previously mentioned parameters in OA patients. Osteoarthritis patients had a lower prevalence of the minor allele of the rs1053005 variant (p &lt; 0.001). Plasmin, TNF, MMP-3, and STAT3 mRNA and protein levels were significantly decreased, and miR-452-3p expression was significantly increased in the GG genotype compared to AG and AA genotypes. HMW-HA injection improved OA patients’ clinical scores with concomitant decreased STAT3 levels and enhanced expression of miR-452-3p. More efficient improvement was observed in rs1053005 AG + GG genotype carriers vs. AA genotype carriers. The G allele of STAT3 rs1053005 (A/G) polymorphism was associated with decreased OA susceptibility and severity and enhanced clinical response to HMW-HA injection, possibly via enhancing miR-452-3p binding and a subsequent decrease in STAT3 expression.

OA susceptibility in mice is partially mediated by the gut microbiome, is transferrable via microbiome transplantation and is associated with immunophenotype changes

ObjectivesThe Murphy Roths Large (MRL)/MpJ ‘superhealer’ mouse strain is protected from post-traumatic osteoarthritis (OA), although no studies have evaluated the microbiome in the context of this protection. This study characterised...

Inhibition of miR-6215 rescued low subchondral bone mass caused by maternal exposure to dexamethasone in female offspring rats

Osteoporotic osteoarthritis is primarily associated with low subchondral bone mass. However, the mechanisms and therapeutic targets of osteoporotic osteoarthritis caused by prenatal dexamethasone exposure (PDE) in offspring remain unclear. In this study, pregnant Wistar rats were injected with dexamethasone to obtain bone tissue from fetal and postnatal rat offspring for analysis. Bone marrow mesenchymal stem cells (BMSCs) were isolated in vitro to elucidate the underlying molecular mechanisms. We determined in vivo that PDE reduced subchondral bone mass in adult female rat offspring, which originated from dysplasia of the subchondral bone. PDE led to a continuous increase in miR-6215 expression, accompanied by a decrease in FERM domain-containing protein 6 (FRMD6) expression. In vitro, dexamethasone upregulated miR-6215 expression through the glucocorticoid receptor, thereby inhibiting FRMD6 expression, promoting the translocation of yes-associated protein 1 (YAP1) into the nucleus of BMSCs, and downregulating downstream osteogenic marker genes. Finally, the rAAV-miR-6215 inhibitor rescued the low subchondral bone mass and osteoarthritis susceptibility caused by PDE in rat offspring. In conclusion, increased expression of miR-6215 mediates low subchondral bone mass caused by PDE through FRMD6/YAP1 signaling. Therefore, miR-6215 is a promising therapeutic target for PDE-induced low subchondral bone mass in offspring.

The Role of Genetics and Epigenetic Regulation in the Pathogenesis of Osteoarthritis.

Osteoarthritis (OA) is progressive disease characterised by cartilage degradation, subchondral bone remodelling and inflammation of the synovium. The disease is associated with obesity, mechanical load and age. However, multiple pro-inflammatory immune mediators regulate the expression of metalloproteinases, which take part in cartilage degradation. Furthermore, genetic factors also contribute to OA susceptibility. Recent studies have highlighted that epigenetic mechanisms may regulate the expression of OA-associated genes. This review aims to present the mechanisms of OA pathogenesis and summarise current evidence regarding the role of genetics and epigenetics in this process.

Matrix metalloproteinases in rheumatoid arthritis and osteoarthritis: a state of the art review.

Although the pathological mechanisms involved in osteoarthritis (OA) and rheumatoid arthritis (RA) are different, the onset and progression of both diseases are associated with several analogous clinical manifestations, inflammation, and immune mechanisms. In both diseases, cartilage destruction is mediated by matrix metalloproteinases (MMPs) synthesized by chondrocytes and synovium fibroblasts. This review aims to summarize recent articles regarding the role of MMPs in OA and RA, as well as the possible methods of targeting MMPs to alleviate the degradation processes taking part in OA and RA. The novel experimental MMP-targeted treatments in OA and RA are MMP inhibitors eg. 3-B2, taraxasterol, and naringin, while other treatments aim to silence miRNAs, lncRNAs, or transcription factors. Additionally, other recent MMP-related developments include gene polymorphism of MMPs, which have been linked to OA susceptibility, and the MMP-generated neoepitope of CRP, which could serve as a biomarker of OA progression.

A shared genetic contribution to osteoarthritis and COVID-19 outcomes: a large-scale genome-wide cross-trait analysis.

Patients with osteoarthritis (OA) are exposed to an increased risk of adverse outcomes of COVID-19, and they tend to experience disruption in access to healthcare services and exercise facilities. However, a deep understanding of this comorbidity phenomenon and the underlying genetic architecture of the two diseases is still unclear. In this study, we aimed to untangle the relationship between OA and COVID-19 outcomes by conducting a large-scale genome-wide cross-trait analysis. Genetic correlation and causal relationships between OA and COVID-19 outcomes (critical COVID-19, COVID-19 hospitalization, and COVID-19 infection) were estimated by linkage disequilibrium score regression and Mendelian Randomization approaches. We further applied Multi-Trait Analysis of GWAS and colocalization analysis to identify putative functional genes associated with both OA and COVID-19 outcomes. Significant positive genetic correlations between OA susceptibility and both critical COVID-19 (rg=0.266, P=0.0097) and COVID-19 hospitalization (rg=0.361, P=0.0006) were detected. However, there was no evidence to support causal genetic relationships between OA and critical COVID-19 (OR=1.17[1.00-1.36], P=0.049) or OA and COVID-19 hospitalization OR=1.08[0.97-1.20], P=0.143). These results were robustly consistent after the removal of obesity-related single nucleotide polymorphisms (SNPs). Moreover, we identified a strong association signal located near the FYCO1 gene (lead SNPs: rs71325101 for critical COVID-19, Pmeta=1.02×10-34; rs13079478 for COVID-19 hospitalization, Pmeta=1.09×10-25). Our findings further confirmed the comorbidity of OA and COVID-19 severity, but indicate a non-causal impact of OA on COVID-19 outcomes. The study offers an instructive perspective that OA patients did not generate negative COVID-19 outcomes during the pandemic in a causal way. Further clinical guidance can be formulated to enhance the quality of self-management in vulnerable OA patients.

Circulating leptin level in osteoarthritis and associations between leptin receptor polymorphisms and disease susceptibility: A meta-analysis.

This study aimed to systemically review the evidence on the relationship between the circulating leptin levels and osteoarthritis (OA), and the association between leptin and leptin receptor (LEPR) polymorphisms and OA susceptibility. To find relevant papers (up to February 2023) examining the association between circulating leptin levels, LEPR polymorphisms, and OA, the PUBMED, EMBASE, and Cochrane databases were searched. We performed a meta-analysis to examine the levels of synovial and serum/plasma leptin in OA patients compared with healthy controls, as well as the relationship between OA and LEPR polymorphisms. Data from 15 investigations, totaling 2197 patients with OA and 2546 controls, were included in the meta-analysis. There were statistically significant differences in the levels of circulating leptin between the OA and control groups (standardized mean difference [SMD] 2.178, 95% confidence interval [CI] 1.208-3.139, P = 0.001). Leptin levels were also substantially greater in European, Asian, and Arab groups among OA patients. After adjusting for age, sex, and/or body mass index, the leptin levels of patients with OA were significantly higher. Similarly, regardless of sample size (n < 100 and n ≥ 100) or year of publication, leptin levels were considerably higher in the OA group. In addition, the synovial leptin level was greater in the OA group than in the control group (SMD 0.783; 95% CI 0.247-1.319, P = 0.004). In the LEPR rs1137101 polymorphism, the OA and AA genotypes were significantly associated (odds ratio 0.282, 95% CI 0.126-0.629, P = 0.002), according to the meta-analysis. Ethnic stratification revealed an association between OA and the LEPR rs1137101 AA genotype in Asian and Arab populations. The results of this meta-analysis indicate that patients with OA had considerably greater levels of circulating leptin than did control individuals. In addition, synovial leptin levels were greater in OA patients than in healthy individuals, and the LEPR rs1137101 polymorphism was linked to an increased risk of developing OA. These results imply that leptin participates in the onset and progression of OA.

Potential Impact of Polymorphisms in Toll-like Receptors 2, 3, 4, 7, 9, miR-146a, miR-155, and miR-196a Genes on Osteoarthritis Susceptibility.

Osteoarthritis (OA) is a progressive inflammatory disease of synovial joints and a leading cause of disability among adults. Inflammation-related genes, including genes for Toll-like receptors (TLRs), are tightly controlled by several microRNAs that, in addition to their pivotal role in the epigenetic regulation of target genes, are ligands for TLR activation and downstream signaling. Thus, we evaluated the association between OA risk and genetic variants in TLR2, TLR3, TLR4, TLR7, TLR9, and microRNAs that regulate TLRs signaling miR146a, miR155, and miR196a2. Our study group consisted of 95 surgically treated OA patients and a control group of 104 healthy individuals. Genetic polymorphisms were determined using TaqMan real-time PCR assays (Applied Biosystems). Adjusted logistic regression analysis demonstrated that polymorphisms in TLR4 rs4986790 (OR = 2.964, p = 0.006), TLR4 rs4986791 (OR = 8.766, p = 0.00001), and TLR7 rs385389 (OR = 1.579, p = 0.012) increased OA risk, while miR-196a2 rs11614913 (OR = 0.619, p = 0.034) was significantly associated with decreased OA risk. Our findings indicate that polymorphisms in the TLR4 and TLR7 genes might increase OA risk and suggest a novel association of miR-196a2 polymorphism with decreased OA susceptibility. The modulation of TLRs and miRNAs and their cross-talk might be an attractive target for a personalized approach to OA management.

3D profiling of mouse epiphyses across ages reveals new potential imaging biomarkers of early spontaneous osteoarthritis.

Worldwide research groups and funding bodies have highlighted the need for imaging biomarkers to predict osteoarthritis (OA) progression and treatment effectiveness. Changes in trabecular architecture, which can be detected with non-destructive high-resolution CT imaging, may reveal OA progression before apparent articular surface damage. Here, we analysed the tibial epiphyses of STR/Ort (OA-prone) and CBA (healthy, parental control) mice at different ages to characterise the effects of mouse age and strain on multiple bony parameters. We isolated epiphyseal components using a semi-automated method, and measured the total epiphyseal volume; cortical bone, trabecular bone and marrow space volumes; mean trabecular and cortical bone thicknesses; trabecular volume relative to cortical volume; trabecular volume relative to epiphyseal interior (trabecular BV/TV); and the trabecular degree of anisotropy. Using two-way ANOVA (significance level ≤0.05), we confirmed that all of these parameters change significantly with age, and that the two strains were significantly different in cortical and trabecular bone volumes, and trabecular degree of anisotropy. STR/Ort mice had higher cortical and trabecular volumes and a lower degree of anisotropy. As the two mouse strains reflect markedly divergent OA predispositions, these parameters have potential as bioimaging markers to monitor OA susceptibility and progression. Additionally, significant age/strain interaction effects were identified for total epiphyseal volume, marrow space volume and trabecular BV/TV. These interactions confirm that the two mouse strains have different epiphyseal growth patterns throughout life, some of which emerge prior to OA onset. Our findings not only propose valuable imaging biomarkers of OA, but also provide insight into ageing 3D epiphyseal architecture bone profiles and skeletal biology underlying the onset and development of age-related OA in STR/Ort mice.

DNA methylation as a mediator of epigenetic regulation in the pathogenesis and precision medicine of osteoarthritis: An updated review

The pathophysiology of osteoarthritis (OA) is multifactorial, with the primary risk factors being obesity, age, environmental variables, and genetic predisposition. The available evidence suggests that genetic diversity does not adequately account for all clinical characteristics and heterogeneity of OA. Genetics has emerged as a nascent and crucial area of research in OA. The epigenetic module presents a potential link between genetic and environmental risk factors and the susceptibility and pathogenesis of OA. As a critical epigenetic alteration, DNA methylation has been shown to have an important role in the etiology of OA and is a viable biomarker for predicting disease progression and medication response, as shown in this research. This review aims to update knowledge in the field of DNA methylation associated with OA to better identify the essential features of OA subtypes and pathological conditions, hence accelerating individualized treatment and precision medicine.

Identification of susceptibility modules and hub genes of osteoarthritis by WGCNA analysis.

Osteoarthritis (OA) is a major cause of pain, disability, and social burden in the elderly throughout the world. Although many studies focused on the molecular mechanism of OA, its etiology remains unclear. Therefore, more biomarkers need to be explored to help early diagnosis, clinical outcome measurement, and new therapeutic target development. Our study aimed to retrieve the potential hub genes of osteoarthritis (OA) by weighted gene co-expression network analysis (WGCNA) and assess their clinical utility for predicting OA. Here, we integrated WGCNA to identify novel OA susceptibility modules and hub genes. In this study, we first selected 477 and 834 DEGs in the GSE1919 and the GSE55235 databases, respectively, from the Gene Expression Omnibus (GEO) website. Genes with p-value<0.05 and | log2FC | > 1 were included in our analysis. Then, WGCNA was conducted to build a gene co-expression network, which filtered out the most relevant modules and screened out 23 overlapping WGCNA-derived hub genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses elucidated that these hub genes were associated with cell adhesion molecules pathway, leukocyte activation, and inflammatory response. In addition, we conducted the protein-protein interaction (PPI) network in 23 hub genes, and the top four upregulated hub genes were sorted out (CD4, SELL, ITGB2, and CD52). Moreover, our nomogram model showed good performance in predicting the risk of OA (C-index = 0.76), and this model proved to be efficient in diagnosis by ROC curves (AUC = 0.789). After that, a single-sample gene set enrichment (ssGSEA) analysis was performed to discover immune cell infiltration in OA. Finally, human primary synoviocytes and immunohistochemistry study of synovial tissues confirmed that those candidate genes were significantly upregulated in the OA groups compared with normal groups. We successfully constructed a co-expression network based on WGCNA and found out that OA-associated susceptibility modules and hub genes, which may provide further insight into the development of pre-symptomatic diagnosis, may contribute to understanding the molecular mechanism study of OA risk genes.

Association of rs1800795 and rs1800796 polymorphisms in interleukin-6 gene and osteoarthritis risk: evidence from a meta-analysis

Multiple studies have investigated the association of interleukin-6 (IL-6) gene polymorphisms and osteoarthritis (OA) risk, but failed to reach a consistent conclusion. Therefore, this study was designed to elucidate the association of IL-6 polymorphisms and OA by a meta-analysis approach. Literature retrieval was carried out on PubMed, EMBASE, Web of Science, CNKI, and Wanfang databases. The strength of association was appraised by odds ratios (ORs) and 95% confidence intervals (95%CIs) in five genetic models. The data were merged by using RevMan 5.3 software. Ten studies with 4944 cases and 4651 controls were analyzed. Overall, no significant association was identified between rs1800795 polymorphism and OA. Subgroup analysis by ethnicity and OA site also suggested rs1800795 polymorphism was not associated with OA. For rs1800796 polymorphism, G-allele and GG-genotype carriers appeared to have an increased risk to OA (G vs. C, OR = 1.66, 95%CI 1.30-1.96, P < 0.01; GG vs. CC, OR = 1.75, 95%CI 1.07-2.84, P = 0.03; GG vs. GC + CC, OR = 1.82, 95%CI 1.42-2.34, P < 0.01). Findings of this study indicate that the rs1800795 polymorphism is not correlated to OA susceptibility, regardless of ethnicity or OA site. However, rs1800796 polymorphism trends to be associated with susceptibility to OA.

Association between Common Variants in VEGFA Gene and the Susceptibility of Primary Knee Osteoarthritis.

This study aimed to analyze the relationship between vascular endothelial growth factor A (VEGFA) gene polymorphisms, plasma VEGFA, and the susceptibility of knee osteoarthritis (OA). A total of 404 subjects, 202 knee OA subjects and 202 healthy volunteers, were enrolled into the study. Four distinct polymorphisms of the VEGFA gene were evaluated using polymerase chain reaction-restriction fragment length polymorphism: -2578C/A (rs699947), -1154G/A (rs1570360), -634C/G (rs2010963), and +936C/T (rs3025039). Plasma VEGFA levels were analyzed using enzyme-linked immunosorbent assay. The most common nucleotides in both knee OA subjects and healthy controls were CC for -2578C/A, GG for -1154G/A, CG for -634C/G, and CC for +936C/T in the VEGFA gene. Genotype distribution and allele frequencies of VEGFA -2578C/A, -1154G/A, -634C/G, and +936C/T single nucleotide polymorphisms did not differ between OA patients and the controls. Plasma VEGFA levels showed no difference between OA patients and the controls. In contrast, plasma VEGFA levels of -634C/C genotype were significantly higher in OA patients than in the controls (P = 0.035). According to the -2578A/A genotype, patients with early stage OA had a higher odds ratio than those with advanced stage OA (P = 0.023). VEGFA -2578C/A (rs699947), -1154G/A (rs1570360), -634C/G (rs2010963), and +936C/T (rs3025039) polymorphisms may not be responsible for OA susceptibility in the Thai population. However, the OA patients with A/A genotype at the -2578C/A seemed to have a lower potential risk of developing severe OA than those with the C/A and C/C genotypes. These findings would help elucidate and facilitate a better understanding of the genetic fundamentals of OA.

Common variants in GNL3 gene contributed the susceptibility of hand osteoarthritis in Han Chinese population

Osteoarthritis (OA) is one of the most popular degenerative joint diseases. The nucleolar GTP binding protein 3 (GNL3) gene encodes guanine nucleotide binding protein-like 3, which is related in cell proliferation, differentiation, and cell cycle regulation. Our study aimed to examine the contribution of GNL3 gene polymorphisms to the risk of hand OA and its related clinical features. A total of 3387 study participants including 1160 patients with hand OA and 2227 controls were recruited in this study. Eleven SNPs in GNL3 gene were selected for genotyping. Genetic association signals were examined using Plink. Relationships between significant SNPs and clinical features of hand OA were also explored. SNP rs11177 was found to be strongly associated with susceptibility of hand OA (P = 4.32 × 10–5). The minor allele of rs11177 was associated with increased susceptibility of hand OA. In addition, significant associations were also identified between genotypes of rs11177 and clinical features of hand OA patients including K-L grade (P < 0.01) and categorized pain scores (P < 0.01). Significant eQTL signals for rs11177 on GNL3 in multiple types of human tissues were also identified in GTEx database. Our results have established the link between GNL3 gene and susceptibility of hand OA.

Increased Wnt/β-catenin signaling contributes to autophagy inhibition resulting from a dietary magnesium deficiency in injury-induced osteoarthritis

BackgroundDietary magnesium deficiency, which is common in modern diet, has been associated with osteoarthritis (OA) susceptibility. Despite this clinical association, no study has addressed if dietary magnesium deficiency accelerates OA development, especially at molecular level. This study aimed to explore aggravating effects of dietary magnesium deficiency on cartilage damage in an injury-induced murine OA model and to determine the underlying mechanism.MethodsTwelve-week-old C57BL/6J mice subject to injury-induced OA modeling were randomized into different diet groups in which the mice were fed a diet with daily recommended magnesium content (500 mg/kg) or diets with low magnesium content (100 or 300 mg/kg). Articular cartilage damage was evaluated using the OARSI score. To determine molecular mechanisms in vitro, mouse chondrocytes were treated with media of low magnesium conditions at 0.1 and 0.4 mM, compared with normal magnesium condition at 0.7 mM as control. Anabolic and catabolic factors, autophagy markers, β-catenin, Wnt ligands, and a magnesium channel transient receptor potential cation channel subfamily member 7 (TRPM7) were analyzed by quantitative real-time PCR and immunoblotting. Autolysosomes were detected by DALGreen staining via fluorescence microscopy and autophagosomes were evaluated by transmission electron microscopy. Autophagy markers, β-catenin, and TRPM7 were assessed in vivo in the mouse cartilage, comparing between dietary magnesium deficiency and normal diet, by immunohistochemistry.ResultsDietary magnesium deficiency aggravated injury-induced cartilage damage, indicated by significant higher OARSI scores. Autophagy markers LC3-II and Beclin-1 were decreased both in low magnesium diet-fed mice and low magnesium-treated chondrocytes. The number of autolysosomes and autophagosomes was also reduced under low magnesium conditions. Moreover, magnesium deficiency induced decreased anabolic and increased catabolic effect of chondrocytes which could be restored by autophagy activator rapamycin. In addition, reduced autophagy under low magnesium conditions is mediated by activated Wnt/β-catenin signaling. The expression of TRPM7 also decreased in low magnesium diet-fed mice, indicating that downstream changes could be regulated through this channel.ConclusionsDietary magnesium deficiency contributes to OA development, which is mediated by reduced autophagy through Wnt/β-catenin signaling activation. These findings indicated potential benefits of adequate dietary magnesium for OA patients or those individuals at high risk of OA.