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Introduction: Decrease in allogenic red blood cell (RBC) transfusion rates following total hip arthroplasty (THA) has been reported in the United States, but whether other countries share the same trend remains unclear. Additionally, the relation of allogenic RBC transfusion to the risk of complications in THA remains controversial. Using the Chinese national inpatient database, the current study aimed to examine trends, complications, charges, and readmission patterns of allogeneic RBC transfusion in THA. Materials and methods: Patients undergoing primary THA between 2013 and 2019 were included, and then stratified into the transfusion and the non-transfusion group based on the database transfusion records. A generalized estimating equation model was used to investigate trends in transfusion rates. After propensity-score matching, a logistic regression model was used to compare the complications, rates and causes of 30-day readmission between two groups. Results: A total of 10,270 patients with transfusion and 123,476 patients without transfusion were included. Transfusion rates decreased from 19.11% in 2013 to 9.94% in 2019 (P for trend < 0.001). After matching, no significant differences in the risk of of in-hospital death (odds ratio [OR], 4.00; 95% confidence interval [CI] 0.85–18.83), wound infection (OR 0.72; 95%CI 0.45–1.17), myocardial infarction (OR 1.17; 95%CI 0.62–2.19), deep vein thrombosis (OR 1.25; 95%CI 0.88–1.78), pulmonary embolism (OR 2.25; 95%CI 0.98–5.17), readmission rates (OR 1.07; 95%CI 0.88–1.30) and readmission causes were observed between two groups. However, the transfusion group had higher hospitalization charges than the non-transfusion group (72,239.89 vs 65,649.57 Chinese yuan [CNY], P < 0.001). Conclusions: This study found that allogeneic RBC transfusion in THA was not associated with the increased risk of complications and any-cause readmission. However, the currently restrictive transfusion policy should be continued because excessive blood transfusion may increase the socioeconomic burden. [ABSTRACT FROM AUTHOR]

Hand osteoarthritis is a common heterogeneous joint disorder with unclear molecular mechanisms and no disease-modifying drugs. In this study, we performed single-cell RNA sequencing analysis to compare the cellular composition and subpopulation-specific gene expression between cartilage with macroscopically confirmed osteoarthritis (n = 5) and cartilage without osteoarthritis (n = 5) from the interphalangeal joints of five donors. Of 105 142 cells, we identified 13 subpopulations, including a novel subpopulation with inflammation-modulating potential annotated as inflammatory chondrocytes. Fibrocartilage chondrocytes exhibited extensive alteration of gene expression patterns in osteoarthritic cartilage compared with nonosteoarthritic cartilage. Both inflammatory chondrocytes and fibrocartilage chondrocytes showed a trend toward increased numbers in osteoarthritic cartilage. In these two subpopulations from osteoarthritic cartilage, the ferroptosis pathway was enriched, and expression of iron overload-related genes, e.g., FTH1, was elevated. To verify these findings, we conducted a Mendelian randomization study using UK Biobank and a population-based cross-sectional study using data collected from Xiangya Osteoarthritis Study. Genetic predisposition toward higher expression of FTH1 mRNA significantly increased the risk of hand osteoarthritis (odds ratio = 1.07, 95% confidence interval: 1.02–1.11) among participants (n = 332 668) in UK Biobank. High levels of serum ferritin (encoded by FTH1), a biomarker of body iron overload, were significantly associated with a high prevalence of hand osteoarthritis among participants (n = 1 241) of Xiangya Osteoarthritis Study (P-for-trend = 0.037). In conclusion, our findings indicate that inflammatory and fibrocartilage chondrocytes are key subpopulations and that ferroptosis may be a key pathway in hand osteoarthritis, providing new insights into the pathophysiology and potential therapeutic targets of hand osteoarthritis. [ABSTRACT FROM AUTHOR]

Complicated relationships exist in both occurrence and progression of surgical complications, which are difficult to account for using a separate quantitative method such as prediction or grading. Data of 51,030 surgical inpatients were collected from four academic/teaching hospitals in a prospective cohort study in China. The relationship between preoperative factors, 22 common complications, and death was analyzed. With input from 54 senior clinicians and following a Bayesian network approach, a complication grading, cluster-visualization, and prediction (GCP) system was designed to model pathways between grades of complication and preoperative risk factor clusters. In the GCP system, there were 11 nodes representing six grades of complication and five preoperative risk factor clusters, and 32 arcs representing a direct association. Several critical targets were pinpointed on the pathway. Malnourished status was a fundamental cause widely associated (7/32 arcs) with other risk factor clusters and complications. American Society of Anesthesiologists (ASA) score ⩾3 was directly dependent on all other risk factor clusters and influenced all severe complications. Grade III complications (mainly pneumonia) were directly dependent on 4/5 risk factor clusters and affected all other grades of complication. Irrespective of grade, complication occurrence was more likely to increase the risk of other grades of complication than risk factor clusters. [ABSTRACT FROM AUTHOR]

Purpose: Previous studies highlighted an increased risk of venous thromboembolism (VTE) among patients with anterior cruciate ligament reconstruction (ACLR); however, the risk for those with ACL tear but without undergoing ACLR has not been reported yet. The aim of this study was to evaluate the risk of VTE among ACL tear individuals with or without ACLR derived from the general population. Methods: A cohort study was conducted using data from the IQVIA Medical Research Database of the United Kingdom. Up to five non-ACL tear individuals (n = 22,235) were matched to each case of ACL tear (n = 4474) by age, sex, body mass index and entry-time. The relation of ACL tear to VTE [pulmonary embolism (PE) and deep vein thrombosis (DVT)] was examined using a multivariable Cox proportional hazard model. A sub-cohort analysis, in which the ACL tear individuals were stratified into those with ACLR and those without ACLR, was also conducted. Results: VTE developed in 13 individuals with ACL tear and nine individuals without ACL tear (incidence rates: 3.1 vs. 0.4/1000 person-years), with multivariable-adjusted hazard ratio (HR) being 6.59 (95% CI 2.28–19.08) in 1-year follow-up. For ACL tear individuals with ACLR, the HR was 11.44 (95% CI 2.71–48.28), and for those without ACLR, the HR was 6.02 (95% CI 1.44–24.25), compared with individuals without ACL tear. Conclusion: This large-sample population-based cohort study provides the first evidence on an increased risk of VTE in ACL tear individuals regardless of subsequent ACLR, which supports the necessity for monitoring venous-thromboembolic complications in the target population, including those without ACLR. Level of evidence: III. [ABSTRACT FROM AUTHOR]

Introduction: Attentions have been paid to the optimal anesthesia for knee arthroplasty (KA). We sought to investigate whether neuraxial anesthesia (NA) is superior to general anesthesia (GA) in terms of perioperative outcomes and resource utilization following KA. Methods: Patients undergoing primary KA registered in the Hospital Quality Monitoring System (HQMS) in China during 2013–2019 were identified. By utilizing a time-stratified propensity score matching, every patient receiving NA was matched by propensity score to a patient receiving GA. Then, we conducted Poisson, logistic, and linear regression to compare NA with GA in terms of perioperative outcomes and resource utilization. Results: Of 109,132 included participants, 75,945 (69.59%) underwent KA with GA and 33,187 (30.41%) with NA. After propensity score matching (26,425 participants per group), NA was associated with lower incidence of blood transfusion (OR: 0.82, 95% CI 0.77–0.87; p < 0.0001), 30-day readmission (OR: 0.76, 95% CI 0.68–0.84; p < 0.0001), and 90-day readmission (OR: 0.83, 95% CI 0.77–0.90; p < 0.0001). No statistically significant difference in in-hospital mortality, incidence of pulmonary embolism, deep vein thrombosis, and surgical site infection was found. In addition, NA was associated with a 1% decrease in length of stay (95% CI 0–2%; p = 0.0070) and a 3% lower total hospital charge (95% CI 2–4%; p < 0.0001) when compared with GA. Conclusion: Compared with GA, NA was associated with decreased incidence of blood transfusion, readmission, reduced length of stay, and total hospital charge following KA, suggesting the favorable role of NA for perioperative outcomes and resource utilization in KA. [ABSTRACT FROM AUTHOR]

In the synovial joint, mechanical force creates an important signal that influences chondrocyte behavior. The conversion of mechanical signals into biochemical cues relies on different elements in mechanotransduction pathways and culminates in changes in chondrocyte phenotype and extracellular matrix composition/structure. Recently, several mechanosensors, the first responders to mechanical force, have been discovered. However, we still have limited knowledge about the downstream molecules that enact alterations in the gene expression profile during mechanotransduction signaling. Recently, estrogen receptor α (ERα) has been shown to modulate the chondrocyte response to mechanical loading through a ligand-independent mechanism, in line with previous research showing that ERα exerts important mechanotransduction effects on other cell types, such as osteoblasts. In consideration of these recent discoveries, the goal of this review is to position ERα into the mechanotransduction pathways known to date. Specifically, we first summarize our most recent understanding of the mechanotransduction pathways in chondrocytes on the basis of three categories of actors, namely mechanosensors, mechanotransducers, and mechanoimpactors. Then, the specific roles played by ERα in mediating the chondrocyte response to mechanical loading are discussed, and the potential interactions of ERα with other molecules in mechanotransduction pathways are explored. Finally, we propose several future research directions that may advance our understanding of the roles played by ERα in mediating biomechanical cues under physiological and pathological conditions. [ABSTRACT FROM AUTHOR]

Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis (OA). In this study, we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modifying OA drugs (DMOADs). Specifically, human bone marrow-derived mesenchymal stromal cells (MSCs) were expanded in vitro up to passage 10 (P10-MSCs). Following their senescent phenotype formation, P10-MSCs were subjected to pellet culture in chondrogenic medium. Results from qRT-PCR, histology, and immunostaining indicated that cartilage generated from P10-MSCs displayed both senescent and OA-like phenotypes without using other OA-inducing agents, when compared to that from normal passage 4 (P4)-MSCs. Interestingly, the same gene expression differences observed between P4-MSCs and P10-MSC-derived cartilage tissues were also observed between the preserved and damaged OA cartilage regions taken from human samples, as demonstrated by RNA Sequencing data and other analysis methods. Lastly, the utility of this senescence-initiated OA-like cartilage model in drug development was assessed by testing several potential DMOADs and senolytics. The results suggest that pre-existing cellular senescence can induce the generation of OA-like changes in cartilage. The P4- and P10-MSCs derived cartilage models also represent a novel platform for predicting the efficacy and toxicity of potential DMOADs on both preserved and damaged cartilage in humans. [ABSTRACT FROM AUTHOR]

Insufficient apoptosis of inflammatory macrophages and osteoclasts (OCs) in rheumatoid arthritis (RA) joints contributes toward the persistent progression of joint inflammation and destruction. Here, we deliver celastrol (CEL) to selectively induce apoptosis of OCs and macrophages in arthritic joints, with enzyme-responsive nanoparticles (termed PRNPs) composed of RGD modified nanoparticles (termed RNPs) covered with cleavable PEG chains. CEL-loaded PRNPs (CEL-PRNPs) dually target OCs and inflammatory macrophages derived from patients with RA via an RGD-αvβ3 integrin interaction after PEG cleavage by matrix metalloprotease 9, leading to increased apoptosis of these cells. In an adjuvant-induced arthritis rat model, PRNPs have an arthritic joint-specific distribution and CEL-PRNPs efficiently reduce the number of OCs and inflammatory macrophages within these joints. Additionally, rats with advanced arthritis go into inflammatory remission with bone erosion repair and negligible side effects after CEL-PRNPs treatment. These findings indicate potential for targeting chemotherapy-induced apoptosis in the treatment of advanced inflammatory arthritis. Celastrol might be useful in treating rheumatoid arthritis in part by inhibiting apoptosis of macrophages; however, systemic toxicity is a concern. Here the authors design celastrol-loaded nanoparticles that release a payload in response to MMP9 cleavage and show these NPs are effective at inducing apoptosis of human macrophages in vitro and a therapeutic effect with an adjuvant-induced arthritis model in rats. [ABSTRACT FROM AUTHOR]

Objective: This study aimed at examining the association between symptomatic knee osteoarthritis and all-cause mortality based on four population-based longitudinal surveys. Method: Data were retrieved from the English Longitudinal Study of Aging (ELSA), the Survey of Health, Aging and Retirement in Europe (SHARE), the Korean Longitudinal Study of Aging (KLoSA), and the Indonesian Family Life Survey (IFLS). The association between symptomatic knee osteoarthritis and all-cause mortality over the 8- to 12-year follow-up period was assessed using Cox-proportional hazard models. Results: In the entire sample of 59,522 participants (4823 with symptomatic knee osteoarthritis; 54,699 without symptomatic knee osteoarthritis [control group]; mean age: 61.8 years; female percentage: 55.3%), 8375 died (937 in the symptomatic knee osteoarthritis group, 7438 in the control group) during the follow-up period. Patients with symptomatic knee osteoarthritis had a higher risk of all-cause mortality than control group without adjusting for potential confounders in each survey, and the unadjusted hazard ratios (HRs) of all-cause mortality were 1.32 (95% confidence interval [CI] 1.18 to 1.47) in ELSA, 1.40 (95%CI 1.24 to 1.56) in SHARE, 1.25 (95%CI 1.06 to 1.47) in KLoSA, and 1.65 (95%CI 1.31 to 2.07) in IFLS. However, with adjustment of potential confounders, the corresponding HRs dropped to 1.07 (95%CI 0.94 to 1.20) in ELSA, 1.08 (95%CI 0.97 to 1.22) in SHARE, 0.91 (95%CI 0.77 to 1.08) in KLoSA, and 0.89 (95%CI 0.66 to 1.21) in IFLS, respectively. Conclusions: In these four population-based longitudinal studies, no association between symptomatic knee osteoarthritis and increased risk of all-cause mortality was observed after adjusting for potential confounders. Key Points • This study evaluated the association between symptomatic knee OA and the risk of all-cause mortality among the participants retrieved from four large population-based longitudinal studies across the world. • No association between symptomatic knee osteoarthritis and increased risk of all-cause mortality was observed after considering potential confounders, and our findings were consistent with the results derived from four independent longitudinal studies. • The present study included four international population-based longitudinal studies, comprising both developed and developing areas, which allowed the findings to be interpreted under larger circumstance. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a common form of arthritis in humans. It has long been regarded as a non-inflammatory disease, but a degree of inflammation is now recognized as being a vital inducer of subpopulation of OA. Besides inflammation, the establishment and development of OA are associated with alterations in metabolism and profiles of amino acids (AA), including glutamate- and arginine-family AA as well as their related metabolites (e.g., creatinine, hydroxyproline, γ-aminobutyrate, dimethylarginines and homoarginine). Functional AA (e.g., glutamine, arginine, glutamate, glycine, proline, and tryptophan) have various benefits (i.e., anti-inflammation and anti-oxidation) in treatment of inflammation-associated diseases, including OA. Thus, these AA have potential as immunomodulatory nutrients for patients with inflammation-induced OA. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint swelling, joint tenderness, and destruction of synovial joints, leading to severe disability and premature mortality. RA is a multifactorial disease with genetic, environmental, and stochastic components related to its susceptibility. It has been demonstrated that the expression of osteopontin (OPN) is upregulated in the RA patients. Numerous studies have indicated that the full-length OPN or even OPN fragments, such as thrombin-cleaved OPN and its receptors, play the key roles in RA pathogenesis. Therapeutic application of siRNA to target OPN or neutralizing antibodies related to OPN epitopes in RA animal models are in progress, and some results are encouraging. However, there is a long way to go along with the clinical trials. This review focuses on the recent development in research associated with the OPN role in the pathogenesis of RA and provides insights concerning the OPN targeting as therapeutic approaches for patients with RA. [ABSTRACT FROM AUTHOR]

The joint disease osteoarthritis (OA) is the most common form of arthritis, which mainly affects the older people. OA is becoming one of the major non-fatal health burdens of the world. The etiology of OA is mostly unclear, and it cannot be cured totally. Osteopontin (OPN) is a multifunctional phosphoprotein, of which overexpression and high level of presence in synovial fluid and articular cartilage were found to be associated with OA progression. Usually, in OA progression, OPN plays important role as an intrinsic regulator. Recent studies have taken attempt to use this protein as a diagnostic marker of OA and use OPN as a target for the drug development against OA. This review summarizes the role of OPN in OA, with focusing on the mechanism of action, and also discussing the diagnostic and therapeutic aspects of OA related to OPN. [ABSTRACT FROM AUTHOR]

The Wnt signaling pathway regulates some of the crucial aspects of cellular processes. The beta-catenin dependent Wnt signaling (Wnt/β-catenin) pathway controls the expression of key developmental genes, and acts as an intracellular signal transducer. The association of Wnt/β-catenin pathway is often reported with different cancers. In this study, we have reviewed the association of Wnt/β-catenin pathway with bone cancers, focusing on carcinogenesis and therapeutic aspects. Wnt/β-catenin pathway is a highly complex and unique signaling pathway, which has ability to regulate gene expression, cell invasion, migration, proliferation, and differentiation for the initiation and progression of bone cancers, especially osteosarcoma. Association of Wnt/β-catenin pathway with chondrosarcoma, Ewing's sarcoma and chondroma is also documented. Recently, targeting Wnt/β-catenin pathway has gained significant interests as a potential therapeutic application for the treatment of bone cancers. Small RNA technology to knockdown aberrant Wnt/β-catenin or inhibition of β-catenin expression by natural component has shown promising effects against bone cancers. Advances in understanding the mechanisms of Wnt signaling and new technologies have facilitated the discovery of agents that can target and regulate Wnt/β-catenin signaling pathway, and these may provide a basement for the innovative therapeutic approaches in the treatment of bone cancers. [ABSTRACT FROM AUTHOR]

The type X collagen gene, COL10A1, is specifically expressed by hypertrophic chondrocytes during endochondral ossification. Endochondral ossification is a well-coordinated process that involves a cartilage intermediate and leads to formation of most of the skeleton in vertebrates during skeletogenesis. Chondrocyte hypertrophy is a critical stage of endochondral ossification linking both bone and cartilage development. Given its specific association with chondrocyte hypertrophy, type X collagen plays essential roles in endochondral ossification. It was previously shown that transgenic mice with mutant type X collagen develop variable skeleton-hematopoietic abnormalities indicating defective endochondral ossification, while mutations and abnormal expression of human COL10A1 cause abnormal chondrocyte hypertrophy that has been seen in many skeletal disorders, including skeletal chondrodysplasia and osteoarthritis. In this review, we summarized the skeletal chondrodysplasia with COL10A1 gene mutation that shows growth plate defect. We also reviewed recent studies that correlate the type X collagen gene expression and chondrocyte hypertrophy with osteoarthritis. Due to its significant clinical relevance, the type X collagen gene regulation has been extensively studied over the past two decades. Here, we focus on recent progress characterizing the cis-enhancer elements and their binding factors that together confer hypertrophic chondrocyte-specific murine type X collagen gene ( Col10a1) expression. Based on literature review and our own studies, we surmise that there are multiple factors that contribute to hypertrophic chondrocyte-specific Col10a1 expression. These factors include both transactivators (such as Runx2, MEF2C etc.) and repressors (such as AP1, NFATc1, Sox9 etc.), while other co-factors or epigenetic control of Col10a1 expression may not be excluded. [ABSTRACT FROM AUTHOR]

The purpose of this study is to observe the differences of osteopontin (OPN) phosphorylation in osteoarthritis (OA) cartilage and normal cartilage, and evaluate the possible correlations between the OPN phosphorylation and MMP-13 expression. Degenerative cartilage ( n = 29) and normal cartilage ( n = 10) were identified by hematoxylin-eosin, safranin-O staining and modified Mankin score. The phosphorylation level of OPN in OA cartilage and normal cartilage was detected by immunoprecipitation. Chondrocytes were treated with phospho-OPN, OPN or buffer. Quantitative reverse transcription polymerase chain reaction (qPCR) and ELISA were used to assess the expression of MMP-13 in different treatments. The OD values of phosphorylation of OPN in normal cartilage and OA cartilage were 137.89 ± 10.59 and 153.52 ± 8.80, respectively, ( P = 0.000). Chondrocytes treated with OPN showed a higher MMP-13 expression at gene and protein level compared with control group. Chondrocytes treated with phospho-OPN showed the highest MMP-13 expression in gene and protein. In conclusion, our results revealed a higher phosphorylation level of OPN in OA cartilage than in normal cartilage. We found OPN leads to elevated expression of MMP-13 (both at gene level and protein level), and phospho-OPN had a more obvious upregulation effect on MMP-13 expression than nonphospho-OPN. Further studies are needed to reveal the mechanism of OPN phosphorylation on cartilage degeneration. [ABSTRACT FROM AUTHOR]