Efficacy and safety of flurbiprofen cataplasms versus loxoprofen sodium cataplasms in knee osteoarthritis: a randomized controlled trial.

BACKGROUND: Clinical trial evidence is limited to identify better topical non-steroidal anti-inflammatory drugs (NSAIDs) for treating knee osteoarthritis (OA). We aimed to compare the clinical efficacy and safety of flurbiprofen cataplasms (FPC) with loxoprofen sodium cataplasms (LSC) in treating patients with knee OA. METHODS: This is an open-label, non-inferiority randomized controlled trial conducted at Peking University Shougang Hospital. Overall, 250 patients with knee OA admitted from October 2021 to April 2022 were randomly assigned to FPC and LSC treatment groups in a 1:1 ratio. Both medications were administered to patients for 28 days. The primary outcome was the change of pain measured by visual analog scale (VAS) score from baseline to day 28 (range, 0-10 points; higher score indicates worse pain; non-inferiority margin: 1 point; superiority margin: 0 point). There were four secondary outcomes, including the extent of pain relief, the change trends of VAS scores, joint function scores measured by the Western Ontario and McMaster University Osteoarthritis Index (WOMAC), and adverse events. RESULTS: Among 250 randomized patients (One patient without complete baseline record in the flurbiprofen cataplasms was excluded; age, 62.8 ± 10.5 years; 61.4% [153/249] women), 234 (93.6%) finally completed the trial. In the intention-to-treat analysis, the decline of the VAS score for the 24-h most intense pain in the FPC group was non-inferior, and also superior to that in the LSC group (differences and 95% confidence interval, 0.414 (0.147-0.681); P <0.001 for non-inferiority; P = 0.001 for superiority). Similar results were observed of the VAS scores for the current pain and pain during exercise. WOMAC scores were also lower in the FPC group at week 4 (12.50 [8.00-22.50] vs . 16.00 [11.00-27.00], P = 0.010), mainly driven by the dimension of daily activity difficulty. In addition, the FPC group experienced a significantly lower incidence of adverse events (5.6% [7/124] vs . 33.6% [42/125], P <0.001), including irritation, rash and pain of the skin, and sticky hair uncovering pain. CONCLUSIONS: This study suggested that FPC is superior to LSC for treating patients with knee OA in pain relief, joint function improvement, and safety profile.

Comparison of doublet and triplet therapies for metastatic hormone-sensitive prostate cancer: A systematic review and network meta-analysis.

Background: The best choice of first-line treatment for metastatic hormone-sensitive prostate cancer (mHSPC) is unclear. We aimed to compare the effectiveness and safety determined in randomized clinical trials of doublet and triplet treatments for mHSPC. Methods: Medline, Embase, Cochrane Central and ClinicalTrials.gov were searched from inception through July 01, 2022. Eligible studies were phase III randomized clinical trials evaluating androgen deprivation treatment (ADT) alone, doublet therapies [ADT combined with docetaxel (DOC), novel hormonal agents (NHAs), or radiotherapy (RT)], or triplet therapies (NHA+DOC+ADT) as first-line treatments for mHSPC. Outcomes of interest included overall survival (OS), progression-free survival (PFS) and grades 3-5 adverse events (AEs). Subgroup analyses were performed based on tumor burden. The effects of competing treatments were assessed by Bayesian network meta-analysis using R software. Results: Ten trials with 12,298 patients comparing nine treatments were included. Darolutamide (DARO) +DOC+ADT ranked best in terms of OS benefits (OR 0·52 [95% CI 0·39-0·70]), but its advantages were all statistically insignificant compared with other therapy options except for DOC+ADT (OR 0·68 [95% CI 0·53-0·88]) and RT+ADT (OR 0·57 [95% CI 0·40-0·80]). In terms of PFS, enzalutamide(ENZA)+DOC+ADT (OR 0·32 [95% CI 0·24-0·44]) and abiraterone and prednisone (AAP) +DOC+ADT (OR 0·33 [95% CI 0·25-0·45]) ranked best. For patients with high volume disease (HVD), low volume disease (LVD), and visceral metastases, the optimal therapies were AAP+DOC+ADT (OR 0·52 [95% CI 0·33-0·83]), apalutamide+ADT (OR 0·52 [95% CI 0·26-1·05]) and DARO+DOC+ADT (OR 0·42 [95% CI 0·13-1·34]), respectively. For safety, AAP+DOC+ADT (OR 3·56 [95% CI 1·51-8·43]) ranked worst with the highest risk of grade 3-5 AEs. Conclusions: Triple therapies may further improve OS and PFS but may be associated with a decrease in safety. Triplet therapies could be suggested for HVD patients, while doublet combinations should still be preferred for LVD patients. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPEROFILES/303117_STRATEGY_20220202.pdf, identifier CRD4202303117.

Vaspin promotes chondrogenic differentiation of BMSCs via Akt activation in osteoarthritis.

BACKGROUND: The aim of this study was to investigate the role of Vaspin on the chondrogenic differentiation of bone mesenchymal stem cells (BMSCs), and its effect on chondrocyte survival and ECM secretion. We also assessed whether the Akt activation participates in these processes. METHODS: In vivo, immunohistochemistry was used to examine the positive rate of the protein expressions of Akt in Wistar rat articular cartilage and subchondral bone after Vaspin intraperitoneal injection for 14 days. In vitro, we isolated and expanded BMSCs from Wistar rats, and further cultured BMSCs as pellets in a chondrogenic-differentiation medium supplemented with different concentrations of Vaspin. After 21 days, the pellets were processed for cell counting kit assay. The mRNA level of Akt, SOX9 and COL2A1 in the pellets were investigated using quantitative Real-Time polymerase chain reaction, and the protein level of COMP was detected using western blot. RESULTS: During the chondrogenic differentiation of BMSCs, Vaspin promoted the chondrogenic differentiation of BMSCs and chondrocyte survival by activating the Akt pathway. These effects were significantly reduced by treatment with an Akt inhibitor. Moreover, Vaspin promoted chondrogenic differentiation of BMSCs by increasing the expression of markers in cartilage formation and extracellular matrix secretion. Furthermore, our study also found that Vaspin could increase Akt expression in cartilage cavities and subchondral bone in vivo. CONCLUSION: These findings demonstrate that Vaspin can promote the chondrogenic differentiation of BMSCs and chondrocyte survival via Akt activation. Our study provides new insights into the potential ability of Vaspin to ameliorate the chondrogenic differentiation of BMSCs and chondrocyte survival in OA.

COVID-19 Control in Community Hospitals: Experience From Four Community Hospitals in Beijing, China.

By September 20, 2021, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been pandemic in 237 countries and regions, resulting in 228,506,698 confirmed cases and 4,692,361 deaths. At the same time, a total of 1123 cases of COVID-19 had been confirmed in Beijing, China. Peking University Shougang Hospital has 4 community hospitals with 174 staff members, covering 230,000 residents in Shijingshan district, Beijing. The community hospitals were the basic units of China's healthcare system for public health services, as the main battlefield for screening and controlling of COVID-19. We reported our experience about the prevention of SARS-CoV-2. We suggest that community hospitals should change their process for admitting patients. While the screening of suspected cases of COVID-19 is vital, patients with suspected infections should be isolated immediately.

Corresponding Changes of Autophagy-Related Genes and Proteins in Different Stages of Knee Osteoarthritis: An Animal Model Study.

OBJECTIVE: To investigate the effect of autophagy expression levels of different weight-bearing states and different stages of osteoarthritis in animal models, as well as the corresponding mechanisms. METHODS: We used the male Sprague-Dawley (SD) rats (12-week-old, SPF) to establish the OA animal models by modified Hulth method, and grouped animal models according to the length of time after surgery and different weight-bearing areas. RT-qPCR was carried out for detection of autophagy-related genes such as Atg7, Atg12, P62, etc. Western blot analysis was used to detect the expression levels of corresponding autophagy-related proteins such as LC3B, P62, etc. T test was performed for statistical analysis to compare different groups, while the differences were deemed statistically significant with P < 0.05. Transmission electron microscopy was used to observe the autophagosome to demonstrate the level of autophagy expression and the status of the chondrocytes. RESULTS: The results of the RT-qPCR testing showed that when the weight-bearing cartilage of the 4-week group (relatively mild) was compared with that of the 10-week group (relatively severe), there were statistically significant differences in all the genes tested, in detail: Atg3 (P < 0.01), Atg7 (P < 0.01), Atg12 (P < 0.01), P62 (P < 0.0001). The expression of autophagy-related mRNA in the 4-week group is increased compared with that of the 10-week group. As for the expression of proteins, Western blotting showed that in the comparison between the 4- and the 10-week groups, statistically significant results include Atg12 (P < 0.01) in the non-weight-bearing area, with decreased autophagy in the 10-week group compared with that of the 4-week group, while expression of LC3B (P < 0.05) protein was significantly higher in the 4-week group than in the control in the non-weight-bearing area. The expression of LC3B (P < 0.0001) and P62 (P < 0.05) in the 10-week group were higher than that of the control. Transmission electron microscope showed that autophagy in the weight-bearing area is stronger than that in the non-weight-bearing area, and autophagy in the 4-week group is stronger than in the 10-week group for the weight-bearing area. CONCLUSIONS: The expression of autophagy varies during different stages of osteoarthritis, in which the autophagy is stronger in the early stage of osteoarthritis, and gradually decreases with the progression of the disease. Autophagy in different weight-bearing areas may also be different.

A review on current research status of the surface modification of Zn-based biodegradable metals.

Recently, zinc and its alloys have been proposed as promising candidates for biodegradable metals (BMs), owning to their preferable corrosion behavior and acceptable biocompatibility in cardiovascular, bone and gastrointestinal environments, together with Mg-based and Fe-based BMs. However, there is the desire for surface treatment for Zn-based BMs to better control their biodegradation behavior. Firstly, the implantation of some Zn-based BMs in cardiovascular environment exhibited intimal activation with mild inflammation. Secondly, for orthopedic applications, the biodegradation rates of Zn-based BMs are relatively slow, resulting in a long-term retention after fulfilling their mission. Meanwhile, excessive Zn2+ release during degradation will cause in vitro cytotoxicity and in vivo delayed osseointegration. In this review, we firstly summarized the current surface modification methods of Zn-based alloys for the industrial applications. Then we comprehensively summarized the recent progress of biomedical bulk Zn-based BMs as well as the corresponding surface modification strategies. Last but not least, the future perspectives towards the design of surface bio-functionalized coatings on Zn-based BMs for orthopedic and cardiovascular applications were also briefly proposed.

BI-1 ameliorates myocardial injury by activating the mitochondrial unfolded protein response and FUNDC1-related mitophagy in cardiorenal syndrome type 3.

It has been suggested that mitochondrial dysfunction underlies the myocardial injury seen following cardiorenal syndrome type 3 (CRS-3). Both mitophagy and the mitochondrial unfolded protein response (UPRmt) are protective programs that preserve mitochondrial homeostasis. Here, we explored whether Bax inhibitor-1 (BI-1) overexpression attenuates CRS-3-related myocardial injury through activation of mitophagy and the UPRmt in cardiomyocytes. Following CRS-3 induction via renal ischemia-reperfusion injury, BI-1 transgenic (BI1TG) mice showed greater preservation of myocardial integrity and relaxation function and less cardiomyocyte apoptosis than wild-type (WT) mice. Moreover, BI-1 overexpression attenuated CRS-3-mediated myocardial inflammation, as indicated by decreased MCP-1 and IL-6 expression and normalized ATP production in cardiomyocytes. After CRS-3 induction, mitophagy was inhibited in cardiomyocytes from WT mice, as indicated by both decreased Fundc1 transcription and mt-Keima fluorescence, and modest activation of the UPRmt, denoted by a slight increase in Atf6 mRNA levels. By contrast, activation of mitophagy and marked UPRmt upregulation were observed in cardiac tissue from BI1TG mice. shRNA-mediated silencing of Fundc1 or Atf6 greatly impaired mitochondrial metabolism and survival in cultured cardiomyocytes overexpressing BI-1. Thus, upregulation of BI-1 expression aimed at activating mitophagy and the UPRmt may represent a useful therapeutic approach for the treatment of CRS-3.

Peritumoral Microgel Reservoir for Long-Term Light-Controlled Triple-Synergistic Treatment of Osteosarcoma with Single Ultra-Low Dose.

Local minimally invasive injection of anticancer therapies is a compelling approach to maximize the utilization of drugs and reduce the systemic adverse drug effects. However, the clinical translation is still hampered by many challenges such as short residence time of therapeutic agents and the difficulty in achieving multi-modulation combination therapy. Herein, mesoporous silica-coated gold nanorods (AuNR@SiO2 ) core-shell nanoparticles are fabricated to facilitate drug loading while rendering them photothermally responsive. Subsequently, AuNR@SiO2 is anchored into a monodisperse photocrosslinkable gelatin (GelMA) microgel through one-step microfluidic technology. Chemotherapeutic drug doxorubicin (DOX) is loaded into AuNR@SiO2 and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is loaded in the microgel layer. The osteosarcoma targeting ligand alendronate is conjugated to AuNR@SiO2 to improve the tumor targeting. The microgel greatly improves the injectability since they can be dispersed in buffer and the injectability and degradability are adjustable by microfluidics during the fabrication. The drug release can, in turn, be modulated by multi-round light-trigger. Importantly, a single super low drug dose (1 mg kg-1 DOX with 5 mg kg-1 DMXAA) with peritumoral injection generates long-term therapeutic effect and significantly inhibited tumor growth in osteosarcoma bearing mice. Therefore, this nanocomposite@microgel system can act as a peritumoral reservoir for long-term effective osteosarcoma treatment.

Pharmaceutical electrospinning and 3D printing scaffold design for bone regeneration.

Bone regenerative engineering provides a great platform for bone tissue regeneration covering cells, growth factors and other dynamic forces for fabricating scaffolds. Diversified biomaterials and their fabrication methods have emerged for fabricating patient specific bioactive scaffolds with controlled microstructures for bridging complex bone defects. The goal of this review is to summarize the points of scaffold design as well as applications for bone regeneration based on both electrospinning and 3D bioprinting. It first briefly introduces biological characteristics of bone regeneration and summarizes the applications of different types of material and the considerations for bone regeneration including polymers, ceramics, metals and composites. We then discuss electrospinning nanofibrous scaffold applied for the bone regenerative engineering with various properties, components and structures. Meanwhile, diverse design in the 3D bioprinting scaffolds for osteogenesis especially in the role of drug and bioactive factors delivery are assembled. Finally, we discuss challenges and future prospects in the development of electrospinning and 3D bioprinting for osteogenesis and prominent strategies and directions in future.

Destination Joint Spacers: A Similar Infection-Relief Rate But Higher Complication Rate Compared with Two-Stage Revision.

OBJECTIVE: To evaluated the clinical outcomes of periprosthetic joint infection (PJI) patients with destination joint spacer compared with that of two-stage revision. METHODS: From January 2006 to December 2017, data of PJI patients who underwent implantation with antibiotic-impregnated cement spacers in our center due to chronic PJI were collected retrospectively. The diagnosis of PJI was based on the American Society for Musculoskeletal Infection (MSIS) criteria for PJI. One of the following must be met for diagnosis of PJI: a sinus tract communicating with the prosthesis; a pathogenis isolated by culture from two separate tissue or fluid samples obtained from the affected prosthetic joint; four of the following six criteria exist: (i) elevated ESR and CRP; (ii) elevate dsynovial fluid white blood cell (WBC) count; (iii) elevated synovial fluid neutrophil percentage (PMN%); (iv) presence of purulence in the affected joint; (v) isolation of a microorganism in one periprosthetic tissue or fluid culture; (vi) more than five neutrophilsper high-power fields in five high-power fields observed from histological analysis of periprosthetic tissue at ×400 magnification. Age, sex, body mass index (BMI), and laboratory test results were recorded. All patients were followed up regularly after surgery, the infection-relief rates were recorded, Harris hip score (HHS) and knee society score (KSS) were used for functional evaluation, a Doppler ultrasonography of the lower limb veins was performed for complication evaluation. The infection-relief rates and complications were compared between destination joint spacer group and two-stage revision group. RESULTS: A total of 62 patients who were diagnosed with chronic PJI were enrolled, with an age of 65.13 ± 9.94 (39-88) years. There were 21 cases in the destination joint spacer group and 41 cases in the temporary spacer group, namely, two-stage revision group (reimplantation of prosthesis after infection relief). The Charlson comorbidity index (CCI) in the destination joint spacer group was higher than that in the temporary spacer group, and this might be the primary reason for joint spacer retainment. As for infection-relief rate, there were three cases of recurrent infection (14.29%) in the destination joint spacer group and four cases of recurrent infection (9.76%) in the two-stage revision group, there were no significant differences with regard to infection-relief rate. Moreover, there two patients who suffered from spacer fractures, three cases of dislocation, one case of a periarticular fracture, and three cases of deep venous thrombosis in destination joint spacer group, while there was only one case of periprosthetic hip joint fracture, one case of dislocation, and one patient suffered from deep venous thrombosis of the lower extremity in two-stage revision. The incidence of complications in the destination joint spacer group was higher than that of two-stage revision. CONCLUSIONS: In summary, the present work showed that a destination joint spacer might be provided as a last resort for certain PJI patients due to similar infection-relief rate compared with two-stage revision.

Microbial yield from infectious tissues pretreated by various methods: an invitro study.

BACKGROUND: This study aimed to evaluate the effects of different pretreatment methods on the microbial yield from infectious tissues. METHODS: Strains of Staphylococcus aureus (SA), Escherichia coli (EC) and Candida albicans (CA) were used to construct single-surface, full-surface, and internal infection models in sterile pork tissue. Manual milling (MM), mechanical homogenization (MH), sonificated (SF), dithiothreitol (DTT), and direct culture (DC) were used to pretreat these tissues, the microbial yield from different pretreatment methods were recorded and compared. Moreover, periprosthetic tissues collected intraoperatively from periprosthetic joint infection (PJI) patients were used as a verification. RESULTS: The study showed that the microbial yield from MH pretreatment was significantly higher than that of MM (P < 0.01) and SF pretreatment method (P < 0.01). Furthermore, in the internal infection model, the microbial yield from MH group was also significantly higher than that of SF (P < 0.01), DTT (P < 0.01), and DC group (P < 0.01). Moreover, the number of bacterial colonies obtained from periprosthetic tissues pretreated by MH was significantly higher than pretreated by other pretreatment methods (P = 0.004). CONCLUSIONS: The effects of MH and DTT in microbial yield were significantly higher than that of DC, SF and MM, and these methods can be used to process multiple tissue samples at the same time, which might further improve the diagnostic sensitivity of infectious disease.

Histological characteristics of bone in-growth of proximal humeral implants with different spatial structures.

This study compares the longitudinal histological characteristics of proximal humeral implants with different spatial structures in rabbits. Thirty skeletally-mature male rabbits were divided into a trabecular structure group and regular hexahedron structure group according to the different spatial structures of a biological titanium alloy screw inserted into the greater tuberosity of the proximal humerus. Samples were collected 3, 6, and 12 weeks after the implantation surgery. Histological results showed that the amount of bone in-growth in the porous cavity of the screw implant increased over time. Quantitative analysis showed there was significantly more bone in-growth in the trabecular structure group than the classic structure group 3 weeks (25.4% ± 6.9% vs 19.6% ± 3.7%, P < 0.05) and 6 weeks (31.2% ± 1.7% vs 26.9% ± 5.3, P < 0.05) after the implantation surgery. No significant difference was detected between the two groups 12 weeks after the surgery (41.7% ± 2.5% vs 39% ± 4.1%, P > 0.05). Our data found that bone in-growth significantly differed among the three time points (P < 0.05) in both groups, but not between the implants with different spatial structures 12 weeks after the surgery.

Vaspin deficiency failed to promote the proliferation of BMSCs in osteoarthritis.

OBJECTIVE: The aim of this study was to estimate the possible role of vaspin in the proliferation of bone mesenchymal stem cells (BMSCs) and its molecular mechanisms in the bone marrow microenvironment of osteoarthritis (OA). METHODS: This study included 15 non-obese elderly patients with severe knee OA and 15 non-obese controls with femoral neck fracture. Patients all underwent hip or knee arthroplasty surgery to restore joint shape and function. Bone marrow samples were taken during surgery to estimate vaspin and transforming growth factor (TGF)-ß1 levels by enzyme-linked immunosorbent assay and to observe the effect of vaspin on BMSCs proliferation by Cell Counting Kit-8. Real-time polymerase chain reaction and western blot were performed to evaluate the effect of vaspin on the genes and proteins of Akt involved in the PI3K/AKT signaling pathway. RESULTS: Bone marrow vaspin levels were significantly lower in OA patients compared to controls (P = .03). Furthermore, we found a significant correlation between vaspin and TGF-ß1 concentrations in bone marrow (r = .60, P < .01). In addition, the in vitro studies indicated the proliferation of BMSCs was significantly promoted when the vaspin treatment concentration was 150 ng/mL (P < .01). Meanwhile, we found that the Akt messenger RNA and pAkt protein levels in BMSCs were increased after vaspin treatment (P < .05). CONCLUSION: The findings of this study suggest there was abnormal expression of vaspin in OA bone marrow microenvironment, and vaspin likely had a mediator role in the proliferation of BMSCs, which may work by promoting the activation of the PI3K/AKT signaling pathway.

Development of an innovative measurement method for patellar tracking disorder.

In this study, we investigated whether the measurement of patellar tracking can be used as a diagnostic parameter of patellofemoral joint disease. Patellar tracking is defined as the movement of the patella in relation to the femorotibial joint within the full range of flexion and extension of the knee joint. The PubMed, EMBASE, Medline, PsychINFO, and AMED databases were used to find relevant articles. Analyzed were the patellar tracking coordinate system and the measurement objects, precision, methods used in those studies, as well as the results obtained. Origin points for coordinate systems varied across the studies. The research object and methods of patellar tracking varied in the studies. Most studies focused on a static description of the internal and external displacement and the internal and external inclination. The in vivo, noninvasive, and six degrees of freedom evaluation of patellar tracking reflect patellar motion more comprehensively, though each of these methods does so in different ways. Dynamic and quantitative evaluation of patellar tracking is still lacking in clinical work. Accurate and quantitative patellar tracking measurement could provide clinicians with a comprehensive evaluation of the stability of the knee joint.

Detecting the presence of bacteria in low-volume preoperative aspirated synovial fluid by metagenomic next-generation sequencing.

OBJECTIVES: Preoperative diagnosis is important for patients who need revision surgery due to PJI. Microbial culture plays an important role in PJI diagnosis, but the sensitivity of cultures is low when the sample amount is limited or when a patient is treated with antibiotics before sample collection. In this study, metagenomic next-generation sequencing (mNGS) was used to detect bacteria in preoperative puncture synovial fluid samples from patients with suspected PJI, and the preoperative and intraoperative culture results were compared to estimate its diagnostic efficiency. METHODS: From July 2016 to December 2018, patients with suspected PJI who underwent prosthetic joint revision surgery were included, and the results of those who had been tested by preoperative synovial fluid culture and mNGS were obtained. The demographic characteristics, medical history, laboratory test results, culture results, and mNGS results of each patient were recorded. Then, the efficiency of preoperative synovial fluid mNGS was compared to that of synovial fluid culture for diagnosing PJI. RESULTS: A total of 37 patients were included, and 24 patients (25 joints) were diagnosed with PJI. The sensitivity, specificity, and accuracy of preoperative synovial fluid mNGS were 92%, 91.7%, and 83.7%, respectively. The sensitivity, specificity, and accuracy of preoperative synovial fluid culture were 52%, 91.7%, and 43.7%, respectively. CONCLUSIONS: With a low volume of synovia (1 ml), mNGS can be performed with higher sensitivity and specificity compared to synovial culture. Thus, mNGS can be a useful supplemental method to improve diagnostic efficiency during the preoperative period.

Plant homeodomain finger protein 23 inhibits autophagy and promotes apoptosis of chondrocytes in osteoarthritis.

BACKGROUND: Plant homeodomain finger protein 23 (PHF23) is a novel autophagy inhibitor gene that has been few studied with respect to orthopedics. This study was to investigate the expression of PHF23 in articular cartilage and synovial tissue, and analyze the relationship between PHF23 and chondrocyte autophagy in osteoarthritis (OA). METHODS: Immunohistochemical staining and western blot were applied to show the expression of PHF23 in cartilage of different outbridge grades and synovial tissue of patient with OA and healthy control. The normal human chondrocyte pre-treated with rapamycin or 3-methyladenine, treated with interleukin-1ß (IL-1ß). IL-1ß induced expression level of PHF23 and autophagy-related proteins light chain 3B-I (LC3B-I), LC3B-II, and P62, were examined by Western blot. A PHF23 gene knock-down model was constructed with small interfering RNA. Western blot was performed to detect the efficiency of PHF23 and the impact of PHF23 knockout on IL-1ß-induced expression of autophagy-related and apoptotic-related proteins in chondrocyte. RESULTS: The expression of PHF23 was significantly increased in the high-grade cartilage and synovial tissue of patients with OA. The IL-1ß-induced expression of PHF23 was gradually enhanced with time. The level of LC3B-II, P62 changed with time. After knockdown of PHF23, the level of autophagy-related proteins increased and apoptotic-related proteins decreased in IL-1ß-induced OA-like chondrocytes. CONCLUSIONS: The expression of PHF23 increased in human OA cartilage and synovium, and was induced by IL-1ß through inflammatory stress. PHF23 can suppress autophagy of chondrocytes, and accelerate apoptosis.

Circ_0136474 and MMP-13 suppressed cell proliferation by competitive binding to miR-127-5p in osteoarthritis.

Osteoarthritis (OA) is a prevalent degenerative joint disease whose pathogenesis remains unclear. The research aims to investigate the roles of Circ_0136474/miR-127-5p/MMP-13 axis in OA. Differentially expressed circRNAs and miRNAs in OA cartilage tissue were screened out and visualized by R project based on RNA-seq data and microarray data respectively. qRT-PCR was carried out for detection of relative expression levels of Circ_0136474, miR-127-5p, MMP-13 and other inflammatory factors and Western blot analysis was conducted to detect the protein expression level of MMP-13. CCK-8 assay and flow cytometry were conducted to determine cell proliferation and cell apoptotic ability respectively. RNA-fluorescence in situ hybridization (RNA-FISH) experiments were conducted to confirm the immune-localization of the Circ_0136474 and MMP-13 in human tissues. Targeted relationships were predicted by bioinformatic analysis and verified by dual-luciferase reporter assay. Our findings revealed that the expression levels of both Circ_0136474 and MMP-13 in OA cartilage tissue were significantly higher than that in normal cartilage tissue. Circ_0136474 could suppress cell proliferation by facilitating MMP-13 expression and suppressing miR-127-5p expression in OA. Overexpression of miR-127-5p negatively regulated MMP-13 expression to enhance cell proliferation. Our study demonstrated that Circ_0136474 and MMP-13 suppressed cell proliferation, while enhanced cell apoptosis by competitive binding to miR-127-5p in OA, which may well provide us with a new therapeutic strategy for osteoarthritis.

Effects of Tumor Necrosis Factor Alpha on the Expression of Programmed Cell Death Factor 5 in Arthritis.

OBJECTIVE: To investigate the effect of tumor necrosis factor alpha (TNF-α) on the proliferation of fibroblast-like synoviocytes (FLS) and the expression of programmed cell death factor 5 (PDCD5) in an inflammatory microenvironment, for the further understanding of the mechanism of action of TNF-α in promoting the proliferation of synovial cells and the apoptosis of the chondrocytes. METHODS: Articular carriage specimens were obtained from 21 cases with osteoarthritis and 12 cases with femoral neck fractures as healthy controls during arthroplasties. The expression of PDCD5 was evaluated by immunofluorescence analyzed by mean option density (MOD) detected using the software ImagePro Plus. Real-time PCR was performed to evaluate the transcriptions of PDCD5 and TNF-α in synovium. FLS cells derived from rheumatoid arthritis patients were cultured in vitro and incubated with different concentrations of TNF-α. The effects of TNF-α at different concentrations on the proliferation of FLS cells were detected by Cell Counting Kit-8 (CCK-8) assay to evaluate the cell proliferation rate. After incubation with the absence or presence of recombinant human TNF-α at different concentrations, the FLS cells were isolated for detection of PDCD5 protein and PDCD5 gene. The expression of PDCD5 protein was detected by western-blot and the transcription of PDCD5 gene from the cells was detected by real-time quantitative PCR. RESULTS: The MOD of PDCD5 as well as TNF-α of osteoarthritis cartilage sections were significantly increased compared with those of the controls, and in synovium there was a positive correlation between transcriptions of their mRNA. When the concentration of TNF-α was 1 ng/mL, the cell proliferation rate was not significantly different from that of the control group (P = 0.592), while the proliferation of FLS cells was significantly promoted when the concentration of TNF-α was 5, 10, 15, or 20 ng/mL, and the proliferation-promoting rates were 35.64% ± 6.96%, 48.72% ± 7.69%, 45.60% ± 8.85%, and 39.32% ± 6.18%, respectively (P < 0.01). The transcription of PDCD5 gene was significantly downregulated, which was 80.44% ± 4.07% and 84.30% ± 5.48%, respectively (P < 0.05), in the FLS cells incubated with TNF-α at the concentration of 10 and 15 ng/mL for 24 h. When the concentration of TNF-α was 1, 5, or 20 ng/mL, the transcription of PDCD5 mRNA in FLS cells was not significantly different from that in the control group (P > 0.05). The expression of PDCD5 protein was only significantly downregulated when the concentration of TNF-α was 10 ng/mL (P < 0.01), while the expression of PDCD5 protein in FLS cells was not significantly different from that in the control group (P > 0.05). CONCLUSION: The expression of PDCD5 as well as TNF-α in osteoarthritis cartilage and synovium was significantly higher than in healthy tissues, and TNF-α can promote the proliferation of FLS cells in patients with rheumatoid arthritis, and inhibit the expression of PDCD5. PDCD5 may be involved in the abnormal proliferation of synoviocytes and the degeneration of chondrocytes stimulated by TNF-α.

Osteogenic and pH stimuli-responsive self-healing coating on biomedical Mg-1Ca alloy.

Various coatings have been used to slow down the corrosion rate of biomedical magnesium alloys. However, these coatings usually act only as passive barriers. It is much more desirable to endow such coatings with active, biocorrosion-responsive self-repairing capacity. In the present work, a self-healing coating system (denoted as "silk-PA") was constructed in the form of a sandwich architecture of fluoride precoating (bottom), silk-phytic acid (PA) coating (middle), and silk fibroin coating (top). Here, PA was loaded in the middle coating as a corrosion inhibitor by harnessing its strong chelating ability toward dissolving Mg2+ and Ca2+ ions. The self-healing property was evaluated by scratch and SVET tests, and the corrosion resistance was evaluated by in vitro immersion and electrochemical measurements. The results showed that the silk-PA manifested intriguing self-healing capacity with pH responsiveness, hence profiting the corrosion resistance of the Mg-1Ca alloy. The biocompatibility and osteogenic activity of the coating system were further evaluated using MC3T3-E1 cells, and it demonstrated favorable responses in multiple cellular behaviors, i.e., adherence, spreading, proliferation, and differentiation. These findings open new opportunities in the study of self-healing coatings for protection against corrosion in biomedical Mg alloys. STATEMENT OF SIGNIFICANCE: In the present study, a self-healing coating system with pH stimuli-responsiveness and osteogenic activity was fabricated on Mg-1Ca alloy by integrating a silk fibroin barrier coating, a silk fibrin/phytic acid composite coating, and a fluoride precoating. This coating system demonstrated interesting self-healing ability as compared to traditional surface modification layers. Furthermore, the self-healing ability enhanced the corrosion resistance of biomedical magnesium alloys, while effective compositions of the coating system endowed the substrate with osteogenic activity. This work provides some new insights into smart surface modification for biomedical Mg alloys.