The Negative Impacts of Sarcopenia on Primary Total Knee Arthroplasty under the Enhanced Recovery after Surgery Protocol.

OBJECTIVE: Sarcopenia, as an emerging public health concern, has been associated with postoperative adverse outcomes in various surgical procedures. However, the evidence regarding the impacts of sarcopenia on total knee arthroplasty (TKA) remained limited. This study aimed to assess the impacts of sarcopenia on primary TKA based on the enhanced recovery after surgery (ERAS) protocol. METHODS: This retrospective study included 291 patients who received unilateral TKA from October 2017 to May 2018 in our institution. Sarcopenia was diagnosed based on the algorithm of Asian Working Group for Sarcopenia 2019. The handgrip strength was measured using a handheld dynamometer and the muscle mass was estimated by a previously validated anthropometric equation. Patients were classified into sarcopenia group and non-sarcopenia group. The outcomes included complications, postoperative length of stay (LOS), total hospitalization cost, operative time, total estimated blood loss, blood transfusion rate, and the 12-item forgotten joint score (FJS-12) at the follow-up. The propensity score matching (PSM) was used to adjust confounding factors. We compared continuous variables using Student's t-test and the Wilcoxon Mann-Whitney U test for normal and non-normal distributions, respectively, and categorical variables with chi-square tests. RESULTS: Of the 291 patients, 58 (19.9%) patients were identified as having sarcopenia. After PSM, each group matched 42 patients. All matched patients were followed-up at least 5 years. Patients with sarcopenia had higher rates of surgical complications compared to the non-sarcopenia group (p = 0.019), and no significant difference was observed in 30-day readmission, and periprosthetic joint infection. The sarcopenia group had significantly longer LOS (p = 0.038), higher total hospitalization (p = 0.015) than the non-sarcopenia group. For the FJS-12 scores at follow-up, patients with sarcopenia had significantly higher scores than the non-sarcopenia group (p = 0.024). CONCLUSION: Our findings indicated sarcopenia may be a risk factor for postoperative complications, prolonged LOS, increased hospitalization cost and reduced patient satisfaction.

Association between handgrip strength weakness and asymmetry with incident hip fracture among older Chinese adults.

BACKGROUND: To evaluate the association between handgrip strength (HGS) weakness and asymmetry with incident hip fracture among older Chinese adults. METHODS: Data was obtained from the 2011 and 2015 waves of the China Health and Retirement Longitudinal Study (CHARLS). HGS weakness was defined as maximal HGS 〈 28 kg in men and < 18 kg in women. HGS asymmetry was defined as the HGS ratio < 0.9 or 〉 1.1. Participants were categorized into normal HGS, weakness only, asymmetry only, and both weakness and asymmetry. Given the sex differences in HGS, the association between HGS weakness and asymmetry was analyzed by sex using the multivariable logistic regression models. RESULTS: A total of 4789 participants aged ≥ 60 years old without hip fracture at baseline were included in the final analysis. Over the four-year follow-up, there were 152 (3.17 %) participants having incident hip fractures, of which 69 (2.90 %) were men and 83 (3.45 %) were women. Compared to the normal group, men with both weakness and asymmetry had a significantly higher risk of incident hip fracture in the fully adjusted model (adjusted odds ratio (OR): 2.31, 95 % confidence interval (CI):1.17-4.52). There was no significant association between HGS asymmetry and weakness with hip fracture in women. CONCLUSIONS: Our findings indicated that among the Chinese population, men with both HGS weakness and asymmetry were associated with increased odds of hip fracture, while no significant association was observed in women.

Association between nighttime sleep duration and quality with knee osteoarthritis in middle-aged and older Chinese: A longitudinal cohort study.

BACKGROUND: The association between nighttime sleep duration and sleep quality with the risk of knee osteoarthritis (OA) remains unclear. This study aimed to examine the longitudinal association among middle-aged and older adults in China. METHODS: The data used in this study were obtained from the China Health and Retirement Longitudinal Study (CHARLS) surveys conducted in 2011 and 2015. Nighttime sleep duration was categorized into five groups: <6 h, 6 to <7 h, 7 to <8 h, 8 to <9 h, and ≥9 h/night. Sleep quality was assessed by restless days in the past week (<1, 1-2, 3-4, and 5-7 days/week). Multivariate logistic regression models were used to assess the association between sleep duration and quality with incident knee OA. RESULTS: A total of 11,114 participants who did not have knee OA at baseline were enrolled in this study. After 4 years of follow-up, the overall incidence of knee OA was 8.07 %. Compared to 7 to <8 h of sleep duration, short sleep duration (<6 h/night) was associated with a significantly increased risk of incident knee OA in the fully adjusted model [odds ratio (OR) =1.73, 95 % confidence interval (CI): 1.33-2.25]. Additionally, participants with 5-7 sleep restless days/week were associated with significantly increased risk of incident knee OA (OR = 1.88, 95 % CI: 1.48-2.38). CONCLUSIONS: Short nighttime sleep duration and poor sleep quality are associated with increased risk of incident knee OA.

Longitudinal Association between Uric Acid and Incident Sarcopenia.

BACKGROUND: Sarcopenia has emerged as a significant public health concern. Uric acid (UA), as a metabolite with excellent antioxidant capacity, has been found to be associated with sarcopenia. However, the casual effects of UA on incident sarcopenia still remain unclear. Our study aimed to explore the longitudinal association between UA and incident sarcopenia among middle-aged and older adults. METHOD: A total of 5086 participants aged ≥45 years old without sarcopenia at baseline were included from the China Health and Retirement Longitudinal Study (CHARLS). Due to the sex differences, the UA levels were analyzed by categorizing into sex-specific quartiles or by using UA levels as a continuous variable (per 1 mg/dL). The longitudinal association between UA and incident sarcopenia was evaluated using Cox proportional hazards regression models. RESULTS: During the 4-year follow-up period, 552 (10.85%) participants with incident sarcopenia were identified, of which 370 cases were males and 182 cases were females. Compared to the first quartile (Q1) UA levels, the Q3 and Q4 UA levels were significantly associated with lower risk of incident sarcopenia in males (Q3: adjusted hazard ratio (HR), 0.72; 95% CI (confidence interval), 0.54-0.97; Q4: HR, 0.57; 95% CI, 0.41-0.80). When UA was as a continuous variable (per 1 mg/dL), the association in males remained significant (HR: 0.87; 95% CI: 0.79-0.97). No significant association was observed in females. CONCLUSION: Our findings indicated that UA was negatively associated with incident sarcopenia in males but not in females among middle-aged and older Chinese.

Does diabetes mellitus impair the clinical results of total knee arthroplasty under enhanced recovery after surgery?

BACKGROUND: Diabetes mellitus (DM) and osteoarthritis (OA) are common diseases that are predicted to increase in prevalence, and DM is a risk factor for OA progression and has a negative impact on the outcome. However, the evidence remains unclear on how it affects patients' clinical results of total knee arthroplasty (TKA) under enhanced recovery after surgery (ERAS). METHODS: A retrospective single-center study was conducted comparing diabetic and non-diabetic patients who underwent TKA in West China Hospital of Sichuan University between September 2016 to December 2017 under ERAS. Consecutive propensity score matching (PSM) was conducted by 1:1 (DM: non-DM) matching analysis with all baselines as covariates. The primary clinical results were the improvement of knee joint function, the incidence of postoperative complications, and the FJS-12 sensory results 5 years after the operation between DM and Non-DM groups. The secondary clinical results were the postoperative length of stay (LOS), postoperative blood test and total blood loss (TBL). RESULT: After PSM, the final analysis included 84 diabetic patients and 84 non-diabetic patients. Diabetic patients were more likely to experience early postoperative complications (21.4% vs. 4.8%, P = 0.003), of which wound complications are the most significant (10.7% vs. 1.2%, P = 0.022). Diabetic patients experienced longer postoperative LOS with a significant increase in patients with LOS exceeding 3 days (66.7% vs. 50%, P = 0.028) and showed less postoperative range of motion (ROM) (106.43 ± 7.88 vs. 109.50 ± 6.33 degrees, P = 0. 011). Diabetic patients also reported lower Forgotten joint score (FJS-12) than non-diabetic patients (68.16 + 12.16 vs. 71.57 + 10.75, P = 0.020) in the 5-year follow-up and were less likely to achieve a forgotten knee joint (10.7% vs. 1.2%, P = 0.022). In additional, Compared with non-diabetics, diabetic patients showed lower hemoglobin (Hb) (P < 0.001) and hematocrit (HCT) (P < 0.001) and were more likely to suffer from hypertension before TKA (P < 0.001). CONCLUSION: Diabetic patients show increased risk for postoperative complications, and have lower lower postoperative ROM and lower FJS-12 compared with non-diabetic patients after TKA under ERAS. More perioperative protocols are still needed to be investigated and optimized for diabetic patients.

Regional versus general anesthesia in older patients for hip fracture surgery: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The optimal anesthesia technique for older patients undergoing hip fracture surgery remains controversial. We performed a systematic review and meta-analysis of updated randomized controlled trials (RCTs) to assess whether regional anesthesia was superior to general anesthesia in hip fracture surgery. METHODS: We searched PubMed, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials from January 2000 until April 2022. RCTs directly comparing regional and general anesthesia in hip fracture surgery were included in the analysis. The incidence of delirium and mortality were the primary outcomes and other perioperative outcomes including complications were secondary outcomes. RESULTS: Thirteen studies involving 3736 patients were included in this study. There was no significant difference in the incidence of delirium (odds ratio [OR] 1.09; 95% confidence interval [CI] 0.86, 1.37) and mortality (OR 1.08; 95% CI 0.71, 1.64) between the two groups. Patients receiving regional anesthesia in hip fracture surgery were associated with a reduction in operative time (weighted mean difference [WMD]: - 4.74; 95% CI - 8.85, - 0.63), intraoperative blood loss (WMD: - 0.25; 95% CI - 0.37, - 0.12), postoperative pain score (WMD: - 1.77; 95% CI - 2.79, - 0.74), length of stay (WMD: - 0.10; 95% CI - 0.18, - 0.02), and risk of acute kidney injury (AKI) (OR 0.56; 95% CI 0.36, 0.87). No significant difference was observed in the other perioperative outcomes. CONCLUSIONS: For older patients undergoing hip fracture surgery, RA did not significantly reduce the incidence of postoperative delirium and mortality compared to GA. Due to the limitations of this study, the evidence on delirium and mortality was still inconclusive and further high-quality studies are needed.

YY1/miR-140-5p/Jagged1/Notch axis mediates cartilage progenitor/stem cells fate reprogramming in knee osteoarthritis.

Osteoarthritis is a multifactorial disease characterized by cartilage degeneration, while cartilage progenitor/stem cells (CPCs) are responsible for endogenous cartilage repair. However, the relevant regulatory mechanisms of CPCs fate reprogramming in OA are rarely reported. Recently, we observed fate disorders in OA CPCs and found that microRNA-140-5p (miR-140-5p) protects CPCs from fate changes in OA. This study further mechanistically investigated the upstream regulator and downstream effectors of miR-140-5p in OA CPCs fate reprogramming. As a result, luciferase reporter assay and validation assays revealed that miR-140-5p targets Jagged1 and inhibits Notch signaling in human CPCs, and the loss-/gain-of-function experiments and rescue assays discovered that miR-140-5p improves OA CPCs fate, but this effect can be counteracted by Jagged1. Moreover, increased transcription factor Ying Yang 1 (YY1) was associated with OA progression, and YY1 could disturb CPCs fate via transcriptionally repressing miR-140-5p and enhancing the Jagged1/Notch signaling. Finally, the relevant changes and mechanisms of YY1, miR-140-5p, and Jagged1/Notch signaling in OA CPCs fate reprogramming were validated in rats. Conclusively, this study identified a novel YY1/miR-140-5p/Jagged1/Notch signaling axis that mediates OA CPCs fate reprogramming, wherein YY1 and Jagged1/Notch signaling exhibits an OA-stimulative role, and miR-140-5p plays an OA-protective effect, providing attractive targets for OA therapeutics.

Transcriptome-wide association study reveals candidate causal genes for lumbar spinal stenosis.

Aims: Lumbar spinal stenosis (LSS) is a common skeletal system disease that has been partly attributed to genetic variation. However, the correlation between genetic variation and pathological changes in LSS is insufficient, and it is difficult to provide a reference for the early diagnosis and treatment of the disease. Methods: We conducted a transcriptome-wide association study (TWAS) of spinal canal stenosis by integrating genome-wide association study summary statistics (including 661 cases and 178,065 controls) derived from Biobank Japan, and pre-computed gene expression weights of skeletal muscle and whole blood implemented in FUSION software. To verify the TWAS results, the candidate genes were furthered compared with messenger RNA (mRNA) expression profiles of LSS to screen for common genes. Finally, Metascape software was used to perform enrichment analysis of the candidate genes and common genes. Results: TWAS identified 295 genes with permutation p-values < 0.05 for skeletal muscle and 79 genes associated for the whole blood, such as RCHY1 (PTWAS = 0.001). Those genes were enriched in 112 gene ontology (GO) terms and five Kyoto Encyclopedia of Genes and Genomes pathways, such as 'chemical carcinogenesis - reactive oxygen species' (LogP value = -2.139). Further comparing the TWAS significant genes with the differentially expressed genes identified by mRNA expression profiles of LSS found 18 overlapped genes, such as interleukin 15 receptor subunit alpha (IL15RA) (PTWAS = 0.040, PmRNA = 0.010). Moreover, 71 common GO terms were detected for the enrichment results of TWAS and mRNA expression profiles, such as negative regulation of cell differentiation (LogP value = -2.811). Conclusion: This study revealed the genetic mechanism behind the pathological changes in LSS, and may provide novel insights for the early diagnosis and intervention of LSS.

Injectable sodium alginate hydrogel loaded with plant polyphenol-functionalized silver nanoparticles for bacteria-infected wound healing.

A novel injectable hydrogel dressing (GA@AgNPs-SA) with long-term antimicrobial effect is developed that can accelerate the closure of bacteria-infected wounds. The hydrogel dressing was prepared by cross-linking sodium alginate molecular chains and gallic acid functionalized silver nanoparticles (GA@AgNPs) via calcium ions to form a three-dimensional network. The hydrogel dressing demonstrates excellent biocompatibility and can achieve a sustainable release of silver ions, ensuring a long-term antibacterial activity and inhibiting biofilm formation. Moreover, an in vivo study demonstrates that the GA@AgNPs-SA hydrogel can effectively decrease the expression of IL-6 and TNF-α to alleviate the inflammatory response, and promote angiogenesis by upregulating CD31, α-SMA and VEGF expression, thus significantly accelerating the repair of infected wounds. Given these interesting properties, this antibacterial hydrogel has great potential for application in the clinical care of bacteria-infected wounds.

Influence of patellofemoral joint degeneration on clinical outcomes after medial unicompartmental knee arthroplasty.

BACKGROUND: Patellofemoral joint (PFJ) degeneration has traditionally been regarded as a contraindication to unicompartmental knee arthroplasty (UKA). More recently, some researchers have proposed that PFJ degeneration can be ignored in medial UKA, and others have proposed that this change should be reviewed in PFJ degenerative facets and severity. This study aimed to systematically evaluate the effect of PFJ degeneration on patient-reported outcome measures (PROMs) and revision rates after medial UKA. METHODS: Electronic databases (PubMed, Embase, Web of Science, etc.) were searched for studies assessing the influence of PFJ degeneration on medial UKA. A random-effects meta-analysis was conducted for the Oxford knee score (OKS), Knee society score (KSS), and revision rates and stratified by PFJ degenerative facets (medial/lateral/trochlear/unspecified), severe PFJ degeneration (bone exposed), and bearing type (mobile/fixed). Heterogeneity was assessed by the Cochran Q test statistic and chi-squared tests with the I-squared statistic. RESULTS: A total of 34 articles with 7007 knees (2267 with PFJ degeneration) were included (5762 mobile-bearing and 1145 fixed-bearing and 100 unspecified). Slight to moderate degenerative changes in the medial and trochlear facets did not decrease the OKS and KSS, and only lateral facets significantly decreased the OKS (mean difference [MD] = -2.18, P   <  0.01) and KSS (MD = -2.61, P   <  0.01). The severity degree of PFJ degeneration had no additional adverse effect on the OKS, KSS, or revision rates. For mobile-bearing UKA, only lateral PFJ degeneration significantly decreased the OKS (MD = -2.21, P  < 0.01) and KSS (MD = -2.44, P  < 0.01). For fixed-bearing UKA, no correlation was found between PROMs/revision rates and PFJ degeneration. CONCLUSION: For medial mobile-bearing UKA, slight to moderate degenerative changes in the PFJ, except lateral facet, did not compromise PROMs or revision rates. For medial fixed-bearing UKA, although it might not be conclusive enough, PROMs or revision rates were not adversely affected by PFJ degeneration (regardless of the facet).

Transcriptome-wide association study identifies new susceptibility genes for degenerative cervical spondylosis.

AIMS: Degenerative cervical spondylosis (DCS) is a common musculoskeletal disease that encompasses a wide range of progressive degenerative changes and affects all components of the cervical spine. DCS imposes very large social and economic burdens. However, its genetic basis remains elusive. METHODS: Predicted whole-blood and skeletal muscle gene expression and genome-wide association study (GWAS) data from a DCS database were integrated, and functional summary-based imputation (FUSION) software was used on the integrated data. A transcriptome-wide association study (TWAS) was conducted using FUSION software to assess the association between predicted gene expression and DCS risk. The TWAS-identified genes were verified via comparison with differentially expressed genes (DEGs) in DCS RNA expression profiles in the Gene Expression Omnibus (GEO) (Accession Number: GSE153761). The Functional Mapping and Annotation (FUMA) tool for genome-wide association studies and Meta tools were used for gene functional enrichment and annotation analysis. RESULTS: The TWAS detected 420 DCS genes with p < 0.05 in skeletal muscle, such as ribosomal protein S15A (RPS15A) (PTWAS = 0.001), and 110 genes in whole blood, such as selectin L (SELL) (PTWAS = 0.001). Comparison with the DCS RNA expression profile identified 12 common genes, including Apelin Receptor (APLNR) (PTWAS = 0.001, PDEG = 0.025). In total, 148 DCS-enriched Gene Ontology (GO) terms were identified, such as mast cell degranulation (GO:0043303); 15 DCS-enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were identified, such as the sphingolipid signalling pathway (ko04071). Nine terms, such as degradation of the extracellular matrix (R-HSA-1474228), were common to the TWAS enrichment results and the RNA expression profile. CONCLUSION: Our results identify putative susceptibility genes; these findings provide new ideas for exploration of the genetic mechanism of DCS development and new targets for preclinical intervention and clinical treatment.Cite this article: Bone Joint Res 2023;12(1):80-90.

Transcriptome-wide association study identifies novel genes associated with bone mineral density and lean body mass in children.

OBJECTIVE: To identify novel candidate genes whose expression is associated with bone mineral density (BMD) and body lean mass (LM) in children. METHODS: A tissue-specific transcriptome-wide association study (TWAS) was conducted utilizing a large-scale genome-wide association study (GWAS) dataset associated with BMD and LM and involving 10,414 participants. The measurement of BMD and LM phenotypes was made based on total-body dual-energy X-ray absorptiometry (TB-DXA) scans. TWAS was conducted by using FUSION software. Reference panels for muscle skeleton (MS), peripheral blood (NBL) and whole blood (YBL) were used for TWAS analysis. Functional enrichment and protein-protein interaction (PPI) analyses of the genes identified by TWAS were performed by using the online tool Metascape ( http://metascape.org ). RESULTS: For BMD, we identified 174 genes with P < 0.05, such as IKZF1 (P = 1.46 × 10-9) and CHKB (P = 8.31 × 10-7). For LM, we identified 208 genes with P < 0.05, such as COPS5 (P = 3.03 × 10-12) and MRPS33 (P = 5.45 × 10-10). Gene ontology (GO) enrichment analysis of the BMD-associated genes revealed 200 GO terms, such as protein catabolic process (Log P = -5.09) and steroid hormone-mediated signaling pathway (Log P = -3.13). GO enrichment analysis of the LM-associated genes detected 287 GO terms, such as the apoptotic signaling pathway (Log P = -8.08) and lipid storage (Log P = -3.55). CONCLUSION: This study identified several candidate genes for BMD and LM in children, providing novel clues to the genetic mechanisms underlying the development of childhood BMD and LM.

miR-140-5p protects cartilage progenitor/stem cells from fate changes in knee osteoarthritis.

Cartilage progenitor/stem cells (CPCs) are promising seed cells for cartilage regeneration, but their fate changes and regulatory mechanisms in osteoarthritis (OA) pathogenesis remain unclear. This study aimed to investigate the role and potential mechanism of the microRNA-140-5p (miR-140-5p), whose protective role in knee OA has been confirmed by our previous studies, in OA CPCs fate reprogramming. Firstly, the normal and OA CPCs were isolated, and the fate indicators, miR-140-5p, Jagged1, and Notch signals were detected and analyzed. Then, the effect of miR-140-5p and the Notch pathway on CPCs fate reprogramming and miR-140-5p on Jagged1/Notch signaling was investigated in IL-1ß-induced chondrocytes in vitro. Finally, the effect of miR-140-5p on OA CPCs fate reprogramming and the potential mechanisms were validated in OA rats. As a result, CPCs percentage was increased in the mild OA cartilage-derived total chondrocytes while decreased in the advanced OA group. Significant fate changes (including reduced cell viability, migration, chondrogenesis, and increased apoptosis), increased Jagged1 and Notch signals, and reduced miR-140-5p were observed in OA CPCs and associated with OA progression. IL-1ß induced OA-like changes in CPCs fate, which could be exacerbated by miR-140-5p inhibitor while alleviated by DAPT (a specific Notch inhibitor) and miR-140-5p mimic. Finally, the in vitro phenomenal and mechanistic findings were validated in OA rats. Overall, miR-140-5p protects CPCs from fate changes via inhibiting Jagged1/Notch signaling in knee OA, providing attractive targets for OA therapeutics.

Combination of Intravenous and Intra-Articular Application of Tranexamic Acid and Epsilon-Aminocaproic Acid in Primary Total Knee Arthroplasty: A Prospective Randomized Controlled Trial.

OBJECTIVE: There were limited randomized controlled trials (RCTs) of epsilon-aminocaproic acid (EACA) versus tranexamic acid (TXA) in total knee arthroplasty (TKA). The aim of the study was to compare the efficacy and safety of TXA and EACA in the combination of intravenous (IV) and intra-articular (IA) administration on reducing blood loss in patients following primary TKA. METHODS: From January 2020 to January 2021, a total of 181 patients undergoing a primary unilateral TKA were enrolled in this prospective randomized controlled trial. Patients in the TXA group (n = 90) received 20 mg/kg of intravenous TXA preoperatively, 1 g of intra-articular TXA intraoperatively, and three doses of 20 mg/kg intravenous TXA at 0, 3, 6 h postoperatively. Patients in the EACA group (n = 91) received 120 mg/kg of intravenous EACA preoperatively, 2 g of intra-articular EACA intraoperatively, and three doses of 40 mg/kg intravenous EACA at 0, 3, 6 h postoperatively. The primary outcomes were total blood loss (TBL), transfusion rates and drop of hemoglobin (HB) level. The secondary outcomes included postoperative hospital stays and postoperative complications. The chi-square tests and Fisher's exact tests were utilized to compare categorical variables, while the independent-samples t-tests and Mann-Whitney tests were used to compare continuous variables. RESULTS: The patients who received TXA averaged less TBL than the patients who received EACA (831.83 ml vs 1065.49 ml, P = 0.015), and HB drop in TXA group was generally less than that of EACA group on postoperative day 1 and 3 (20.84 ± 9.48 g/L vs 24.99 ± 9.40 g/L, P = 0.004; 31.28 ± 11.19 vs 35.46 ± 12.26 g/L, P = 0.047). The length of postoperative stays in EACA group was 3.66 ± 0.81 day, which is longer than 2.62 ± 0.68 day in TXA group (P < 0.001). No transfusions were required in either group. The risk of nausea and vomiting in TXA group was significantly higher than that in EACA group (11/90 vs 0/91, P < 0.01). CONCLUSION: Although the TBL and HB drop were slightly greater in EACA group, these results were not clinically important, given that no transfusions were required. EACA could be an alternative to TXA, especially for patients with severe nausea and vomiting after using TXA postoperatively. Further studies are needed to adjust dosage of EACA to make better comparison of the two drugs.

No genetic causal association between iron status and osteoporosis: A two-sample Mendelian randomization.

Objective: To explore the genetic causal association between osteoporosis (OP) and iron status through Mendelian randomization (MR). Methods: Publicly available genome-wide association study (GWAS) summary data were used for MR analysis with four iron status-related indicators (ferritin, iron, total iron binding capacity, and transferrin saturation) as exposures and three different types of OP (OP, OP with pathological fracture, and postmenopausal OP with pathological fracture) as outcomes. The inverse-variance weighted (IVW) method was used to analyze the genetic causal association between the four indicators of iron status and OP. The heterogeneity of MR results was determined using IVW and MR-Egger methods. The pleiotropy of MR results was determined using MR-Egger regression. A leave-one-SNP-out test was performed to determine whether the MR results were affected by a single nucleotide polymorphism (SNP). The weighted median method was conducted to further validate our results. Results: Based on IVW, MR-Egger and weighted median models, we found no causal association between iron status (ferritin, iron, total iron binding capacity, or transferrin saturation) and OP (Pbeta > 0.05 in all models). IVW and MR-Egger analysis of OP with pathological fracture and iron status indicators showed no potential genetic causal association (Pbeta> 0.05 in the two analyses). The results of the weighted median were consistent with those of IVW (Pbeta> 0.05 in all analyses). There was no potential genetic causal association between iron status and postmenopausal OP with pathological fracture based on serum iron (Pbeta>0.05 in all models). No heterogeneity or horizontal pleiotropy was found in any of the analyses. None of the leave-one-out tests in the analyses found any SNP that could affect the results of MR. Conclusion: Our results demonstrate that there is no genetic causal association between OP and iron status, but the effects of other factors were not excluded.

The therapeutic effect and mechanism of melatonin on osteoarthritis: From the perspective of non-coding RNAs.

Osteoarthritis (OA) is a slowly progressing and irreversible joint disease. The existing non-surgical treatment can only delay its progress, making the early treatment of OA a research hotspot in recent years. Melatonin, a neurohormone mainly secreted by the pineal gland, has a variety of regulatory functions in different organs, and numerous studies have confirmed its therapeutic effect on OA. Non-coding RNAs (ncRNAs) constitute the majority of the human transcribed genome. Various ncRNAs show significant differentially expressed between healthy people and OA patients. ncRNAs play diverse roles in many cellular processes and have been implicated in many pathological conditions, especially OA. Interestingly, the latest research found a close interaction between ncRNAs and melatonin in regulating the pathogenesis of OA. This review discusses the current understanding of the melatonin-mediated modulation of ncRNAs in the early stage of OA. We also delineate the potential link between rhythm genes and ncRNAs in chondrocytes. This review will serve as a solid foundation to formulate ideas for future mechanistic studies on the therapeutic potential of melatonin and ncRNAs in OA and better explore the emerging functions of the ncRNAs.

The Role Played by Ferroptosis in Osteoarthritis: Evidence Based on Iron Dyshomeostasis and Lipid Peroxidation.

Ferroptosis, a recently discovered regulated cell death modality, is characterised by iron-dependent accumulation of lipid hydroperoxides, which can reach lethal levels but can be specifically reversed by ferroptosis inhibitors. Osteoarthritis (OA), the most common degenerative joint disease, is characterised by a complex pathogenesis involving mechanical overload, increased inflammatory mediator levels, metabolic alterations, and cell senescence and death. Since iron accumulation and oxidative stress are the universal pathological features of OA, the role played by ferroptosis in OA has been extensively explored. Increasing evidence has shown that iron dyshomeostasis and lipid peroxidation are closely associated with OA pathogenesis. Therefore, in this review, we summarize recent evidence by focusing on ferroptotic mechanisms and the role played by ferroptosis in OA pathogenesis from the perspectives of clinical findings, animal models, and cell research. By summarizing recent research advances that characterize the relationship between ferroptosis and OA, we highlight avenues for further research and potential therapeutic targets.

Genetic Causal Association between Iron Status and Osteoarthritis: A Two-Sample Mendelian Randomization.

Objective: Observational studies have shown the association between iron status and osteoarthritis (OA). However, due to difficulties of determining sequential temporality, their causal association is still elusive. Based on the summary data of genome-wide association studies (GWASs) of a large-scale population, this study explored the genetic causal association between iron status and OA. Methods: First, we took a series of quality control steps to select eligible instrumental SNPs which were strongly associated with exposure. The genetic causal association between iron status and OA was analyzed using the two-sample Mendelian randomization (MR). Inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods were used for analysis. The results were mainly based on IVW (random effects), followed by sensitivity analysis. IVW and MR-Egger were used for heterogeneity testing. MR-Egger was also used for pleiotropy testing. Leave-one-SNP-out analysis was used to identify single nucleotide polymorphisms (SNPs) with potential impact. Maximum likelihood, penalized weighted median, and IVW (fixed effects) were performed to further validate the reliability of results. Results: IVW results showed that transferrin saturation had a positive causal association with knee osteoarthritis (KOA), hip osteoarthritis (HOA) and KOA or HOA (p < 0.05, OR > 1), and there was a negative causal association between transferrin and HOA and KOA or HOA (p < 0.05, OR < 1). The results of heterogeneity test showed that our IVW analysis results were basically free of heterogeneity (p > 0.05). The results of the pleiotropy test showed that there was no pleiotropy in our IVW analysis (p > 0.05). The analysis results of maximum likelihood, penalized weighted median and IVW (fixed effects) were consistent with our IVW results. No genetic causal association was found between serum iron and ferritin and OA. Conclusions: This study provides evidence of the causal association between iron status and OA, which provides novel insights to the genetic research of OA.

A Cross-Tissue Transcriptome-Wide Association Study Identifies Novel Susceptibility Genes for Juvenile Idiopathic Arthritis in Asia and Europe.

Background: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children, and its pathogenesis is still unclear. Genome-wide association studies (GWASs) of JIA have identified hundreds of risk factors, but few of them implicated specific biological mechanisms. Methods: A cross-tissue transcriptome-wide association study (TWAS) was performed with the functional summary-based imputation software (FUSION) tool based on GWAS summary datasets (898 JIA patients and 346,102 controls from BioBank Japan (BBJ)/FinnGen). The gene expression reference weights of skeletal muscle and the whole blood were obtained from the Genotype-Tissue Expression (GTExv8) project. JIA-related genes identified by TWAS findings genes were further compared with the differentially expressed genes (DEGs) identified by the mRNA expression profile of JIA from the Gene Expression Omnibus (GEO) database (accession number: GSE1402). Last, candidate genes were analyzed using functional enrichment and annotation analysis by Metascape to examine JIA-related gene sets. Results: The TWAS identified 535 significant genes with P < 0.05 and contains 350 for Asian and 195 for European (including 10 genes both expressed in Asian and European), such as CDC16 (P = 1.72E-03) and PSMD5-AS1 (P = 3.65E-02). Eight overlapping genes were identified based on TWAS results and DEGs of JIA patients, such as SIRPB1 (PTWAS = 4.21E-03, PDEG = 1.50E-04) and FRAT2 (PTWAS = 2.82E-02, PDEG = 1.43E-02). Pathway enrichment analysis of TWAS identified 183 pathways such as cytokine signaling in the immune system and cell adhesion molecules. By integrating the results of DEGs pathway and process enrichment analyses, 19 terms were identified such as positive regulation of T-cell activation. Conclusion: By conducting two populations TWAS, we identified a group of JIA-associated genes and pathways, which may provide novel clues to uncover the pathogenesis of JIA.