Intra-Articular Injection of PLGA/Polydopamine Core-Shell Nanoparticle Attenuates Osteoarthritis Progression.

Osteoarthritis (OA) is a common joint disease characterized by progressive cartilage degeneration. Unfortunately, currently available clinical drugs are mainly analgesics and cannot alleviate the development of OA. Kartogenin (KGN) has been found to promote the differentiation of bone marrow mesenchymal stem cells (BMSCs) into chondrocytes for the treatment of cartilage damage in early OA. However, KGN, as a small hydrophobic molecule, is rapidly cleared from the synovial fluid after intra-articular injection. This study synthesized a KGN-loaded nanocarrier based on PLGA/polydopamine core/shell structure to treat OA. The fluorescence signal of KGN@PLGA/PDA-PEG-E7 nanoparticles lasted for 4 weeks, ensuring long-term sustained release of KGN from a single intra-articular injection. In addition, the polyphenolic structure of PDA enables it to effectively scavenge reactive oxygen species, and the BMSC-targeting peptide E7 (EPLQLKM) endows KGN@PLGA/PDA-PEG-E7 NPs with an effective affinity for BMSCs. As a result, the KGN@PLGA/PDA-PEG-E7 nanoparticles could effectively induce cartilage in vitro and protect the cartilage and subchondral bone in a rat ACLT model. This therapeutic strategy could also be extended to the delivery of other drugs, targeting other tissues to treat joint diseases.

ADAM8 silencing suppresses the migration and invasion of fibroblast-like synoviocytes via FSCN1/MAPK cascade in osteoarthritis.

OBJECTIVE: Osteoarthritis (OA) is a degenerative joint disease that affects elderly populations worldwide, causing pain and disability. Alteration of the fibroblast-like synoviocytes (FLSs) phenotype leads to an imbalance in the synovial inflammatory microenvironment, which accelerates the progression of OA. Despite this knowledge, the specific molecular mechanisms of the synovium that affect OA are still unclear. METHODS: Both in vitro and in vivo experiments were undertaken to explore the role of ADAM8 playing in the synovial inflammatory of OA. A small interfering RNA (siRNA) was targeting ADAM8 to intervene. High-throughput sequencing was also used. RESULTS: Our sequencing analysis revealed significant upregulation of the MAPK signaling cascade and ADAM8 gene expression in IL-1ß-induced FLSs. The in vitro results demonstrated that ADAM8 blockade inhibited the invasion and migration of IL-1ß-induced FLSs, while also suppressing the expression of related matrix metallomatrix proteinases (MMPs). Furthermore, our study revealed that inhibiting ADAM8 weakened the inflammatory protein secretion and MAPK signaling networks in FLSs. Mechanically, it revealed that inhibiting ADAM8 had a significant effect on the expression of migration-related signaling proteins, specifically FSCN1. When siADAM8 was combined with BDP-13176, a FSCN1 inhibitor, the migration and invasion of FLSs was further inhibited. These results suggest that FSCN1 is a crucial downstream factor of ADAM8 in regulating the biological phenotypes of FLSs. The in vivo experiments demonstrated that ADAM8 inhibition effectively reduced synoviocytes inflammation and alleviated the progression of OA in rats. CONCLUSIONS: ADAM8 could be a promising therapeutic target for treating OA by targeting synovial inflammation.

Tumor microenvironment phenotypes and prognostic evaluation tools for osteosarcoma characterized by different prognostic outcomes and immunotherapy responses.

BACKGROUND: The physiological and immunological characteristics of the tumor microenvironment (TME) have a profound impact on the effectiveness of immunotherapy. The present study aimed to define the TME subtype of osteosarcoma according to the signatures representing the global TME of the tumor, as well as create a new prognostic assessment tool to monitor the prognosis, TME activity and immunotherapy response of patients with osteosarcoma. METHODS: The enrichment scores of 29 functional gene expression signatures in osteosarcoma samples were calculated by single sample gene set enrichment analysis (ssGSEA). TME classification of osteosarcoma was performed and a prognostic assessment tool was created based on 29 ssGSEA scores to comprehensively correlate them with TME components, immunotherapy efficacy and prognosis of osteosarcoma. RESULTS: Three TME subtypes were generated that differed in survival, TME activity and immunotherapeutic response. Four differentially expressed genes between TME subtypes were involved in the development of prognostic assessment tools. The established prognosis assessment tool had strong performance in both training and verification cohorts, could be effectively applied to the survival prediction of samples of different ages, genders and transfer states, and could well distinguish the TME status of different samples. CONCLUSIONS: The present study describes three different TME phenotypes in osteosarcoma, provides a risk stratification tool for osteosarcoma prognosis and TME status assessment, and provides additional information for clinical decision-making of immunotherapy.

What do osteoporosis and osteoarthritis have in common? An integrated study of overlapping differentially expressed genes in bone mesenchymal stem cells of osteoporosis and osteoarthritis.

OBJECTIVE: For identification of aberrantly expressed genes in mesenchymal stem cells of osteoporosis (OP) and osteoarthritis (OA), Gene Expression Omnibus (GEO) datasets were integrated to investigate the intersection point. METHODS: GSE35958 (osteoporosis) and GSE19664 (osteoarthritis) datasets were obtained from GEO database. The abnormally expressed genes were analyzed by GEO2R. Functional enrichment was explored by Metascape database and R software. The String database and Cytoscape software were used to build the protein-protein interaction network and identify hub genes. GSE35957 and GSE116925 were used as verification datasets. Single-cell analysis and pseudotime analysis were undertaken. CTDbase, Network Analyst, HPA database, HERB database and MIRW database were used to research the information, tissue and cell distribution, regulation, interaction and ingredients targeting the hub genes. Additionally, in vitro experiments such as RT-PCR, ALP staining and immunofluorescence were undertaken as verification tests. RESULTS: Ten hub genes were identified in this study. All these genes play an important role in bone or cartilage generation. They have diagnostic values and therapeutic potential for OA and OP. Single-cell analysis visualized the cell distribution and pseudotime distribution of these genes. Some potential therapeutic ingredients of these genes were identified, such as curcumin, wogonin and glycerin. In vitro experiments, RT-PCR results showed that COL9A3 and MMP3 were downregulated and PTH1R was upregulated during osteogenic induction of BMSC. Immunohistochemical results showed the expression trend of MMP3 and COL2A1. CONCLUSION: Ten abnormal hub genes of osteoporosis and osteoarthritis were identified successfully by this study. They were important regulatory genes for healthy bone and cartilage. These genes could be the common connections between osteoporosis and osteoarthritis as well as treatment targets. Further study of the regulatory mechanism and treatment effects of these genes would be valuable. The results of this study could contribute to further research.

Patellar resurfacing versus nonresurfacing in total knee arthroplasty: an updated meta-analysis of randomized controlled trials.

BACKGROUND: Whether resurface the patella or not in total knee arthroplasty (TKA) was controversial. In 2013, we conducted a meta-analysis of randomized controlled trials (RTCs). After that, plenty of studies have been carried out, but there still existed a great deal of controversy. In order to update our previous study, we conducted this update meta-analysis to evaluate the efficacy of patellar resurfacing in TKA. METHODS: Databases were searched for RCTs comparing the outcomes of patellar resurfacing and nonresurfacing in TKA. Outcomes of knee relevant indicators were analysed. To see the short- and long-term effects, we calculated the data in total and divided the patients who were followed up for ≤ 3 years and ≥ 5 years into two subgroups as well. RESULTS: Thirty-two trials assessing 6887 knees were eligible. There was a significant difference in terms of reoperation (in total and ≥ 5 years), Knee Society Score (KSS), function score (in total and ≥ 5 years) and noise. While no significant difference was found in the following items: reoperation (≤ 3 years), anterior knee pain (AKP), function score (≤ 3 years), range of motion (ROM), Oxford score, the Knee Injury and Osteoarthritis Outcome Score (KOOS), visual analogue score (VAS), Feller score, patellar tilt and the patients' satisfaction. CONCLUSIONS: We found that patellar resurfacing could reduce the occurrence of reoperation and noise after surgery, as well as increase the KSS and function score, while it might not influence the outcomes such as AKP, ROM, Oxford score, KOOS, VAS, Feller score, patellar tilt and the patients' satisfaction. The results are different from our previous finding in the meta-analysis. In conclusion, we prefer patellar resurfacing in TKA.

An analysis of perioperative hidden blood loss in femoral intertrochanteric fractures: bone density is an important influencing factor.

BACKGROUND: To explore the influencing factors of perioperative hidden blood loss in intertrochanteric fractures. METHOD: We undertook a retrospective analysis from January 2016 to October 2019. Clinical data of 118 patients with intertrochanteric fractures were included. Hidden blood loss was calculated from the haematocrit changes before and after surgery using the Gross equation based on height, weight, and haematocrit (HCT) changes before and after surgery. Patients' gender, age, presence of underlying diseases, fracture types, anaesthesia methods, time from injury to surgery, administration of antiplatelet drugs within 6 months before surgery, use of anticoagulant drugs after surgery, and bone density were statistically analysed. Factors having an effect on hidden blood loss were screened out. Then, hidden blood loss was used as the dependent variable, and each influencing factor was used in turn as the independent variable. Multivariate linear regression analysis was employed to analyse the related risk factors that affect hidden blood loss during the perioperative period of patients with intertrochanteric fractures. RESULT: The apparent blood loss during the operation was 203.81 ±105. 51 ml, and the hidden blood loss was 517.55±191.47 ml. There were significant differences in the hidden blood loss of patients with different fracture types (stable vs unstable), anaesthesia methods (general anaesthesia vs intraspinal anaesthesia), antiplatelet or postoperative anticoagulant drugs, and bone densities (P< 0.05). 05). Multiple linear regression analysis showed that internal fixation, age, fracture type, anaesthesia method, anticoagulant application, and bone density were related risk factors that affected hidden blood loss during the surgical treatment of intertrochanteric fractures. CONCLUSION: Hidden blood loss is the main cause of perioperative blood loss in intertrochanteric fractures, and the risk factors for hidden blood loss include internal fixation, fracture type (e.g., unstable), anaesthesia (e.g., intraspinal), and use of anticoagulant drugs. Specifically, we found that low bone density was a risk factor for hidden blood loss. It is not reliable to use apparent blood loss as the basis for fluid replacement and transfusion. We must fully consider the existence of hidden blood loss and intervene as soon as possible to prevent complications. LEVEL OF EVIDENCE: III.

No Evidence of Increased Risk of Stroke with Consumption of Refined Grains: A Meta-analysis of Prospective Cohort Studies.

OBJECTIVES: Results of the relationships between dietary consumption of refined grains and the risk of stroke are mixed. This study was based on a meta-analysis of prospective cohort studies. METHODS: We systematically searched the MEDLINE (from January 1, 1966) and EMBASE (from January 1, 1974) databases up to November 30, 2014. Random-effects models were used to calculate summary relative risks (SRRs) and 95% confidence intervals (CIs). Between-study heterogeneity was assessed using Cochran's Q and I(2) statistics. RESULTS: Eight prospective studies (7 publications) with a total of 410,821 subjects and 8284 stroke events were included in the meta-analysis. Overall, a diet containing greater amounts of refined grains was not associated with risk of stroke, with no evidence of heterogeneity among studies (SRR = 1.02; 95% CI, .93-1.10; P(heterogeneity) = .970; I(2) = 0). In addition, no significant associations between consumption of refined grains and risk of stroke were found for both women and men, for both hemorrhagic and ischemic strokes, and for both incident and fatal strokes. These null results are consistent with those of linear dose-response meta-analyses (SRR = .98; 95% CI, .73-1.03 for per 3 servings/day). Consumption of white rice was not associated with risk of stroke (SRR = 1.01; 95% CI, .93-1.11; P(heterogeneity) = .966; I(2) = 0). CONCLUSIONS: The current meta-analysis provides some evidence for the hypothesis that consumption of refined grains was not associated with risk of stroke and its subtypes.

Development and linear growth in diabetic children receiving insulin pigment.

OBJECTIVE: The aim of this study was to ascertain if there are differences in the development and linear growth between a group of diabetic children who had been receiving insulin pigment and healthy children. METHODS: A total of 57 Chinese children with type 1 diabetes diagnosed at the age from 6 to 10 years old (26 boys and 31 girls) were included in the study. Their height and weight and development conditions were recorded until they reached their 18th birthday. RESULTS: Diabetic children were taller than healthy children at the onset of diabetes, even though there was no significant difference between them [male height standard deviation score (SDS): 0.34 +/- 0.93, female height SDS: 0.38 +/- 0.50]. When they reached their final height, they were slightly shorter than the healthy group. However, there were still no significant differences between these two groups (male height SDS: -0.42 +/- 0.95, female height SDS: -0.60 +/- 0.98). The median age at onset of puberty, 12.62 years in boys and 11.13 years in girls, was significantly delayed in diabetic boys compared to 10.55 years in healthy boys and 9.2 years in healthy girls. The median age at menarche in diabetic girls (14.15 years) was also delayed compared with 12.27 years in healthy girls. The majority of these diabetic children were thinner than the healthy children when they were diagnosed [male body mass index (BMI): 14.45 +/- 1.35 kg/m2 vs. 16.08 +/- 0.59 kg/m2, t = -0.63, p < 0.05; female BMI: 13.50 +/- 1.87 kg/m2 vs. 15.46 +/- 0.45 kg/m2, t = -6.67, p < 0.05]; however, as they reached their final height, they became fatter, especially the girls (male BMI: 21.43 +/- 1.62 kg/m2 vs. 20.8 +/- 0.00 kg/m2, t = 1.97, p > 0.05; female BMI: 23.95 +/- 2.37 kg/m2 vs. 20.3 +/- 0.00 kg/m2, t = 8.60, p < 0.05). CONCLUSION: Even with well-controlled glucose levels, the development of children with diabetes who had been receiving insulin pigment were still adversely affected. However, linear growth had only been slightly affected. All patients, especially girls, became fatter when they reached their final height.