Changes in serum inflammatory factors after hip arthroplasty and analysis of risk factors for prosthesis loosening.

OBJECTIVE: To explore the relationship of serum levels of IL-1ß, IL-6, and TNF-α with prosthesis loosening after hip arthroplasty, and to establish a predictive model for prosthesis loosening. METHODS: We retrospectively analyzed the data of 501 patients who underwent hip arthroplasty in Xi'an International Medical Center Hospital from January 2020 to August 2022. Based on radiological diagnosis, the patients were divided into a prosthesis loosening group and a non-loosening group. Clinical data including postoperative serum levels of inflammatory cytokines were collected. Univariant analysis, Lasso regression, decision tree, and random forest models were used to screen feature variables. Based on the screening results, a nomogram model for predicting the risk of prosthesis loosening was established and then validated using ROC curve, and calibration curve, and other methods. RESULTS: There were 50 cases in the loosening group and 451 cases in the non-loosening group. Postoperative levels of IL-1ß, IL-6, and TNF-α were found to be significantly higher in the loosening group (P<0.0001). Univariant analysis showed that osteoporosis and postoperative infection were risk factors for prosthesis loosening (P<0.001). The machine learning algorithm identified osteoporosis, postoperative infection, IL-1ß, IL-6, and TNF-α as 5 relevant variables. The predictive model based on these 5 variables exhibited an area under the ROC curve of 0.763. The calibration curve and DCA curve verified the accuracy and practicality of the model. CONCLUSION: Serum levels of IL-1ß, IL-6, and TNF-α were significantly elevated in patients with postoperative prosthesis loosening. Osteoporosis, postoperative infection, and inflammatory cytokines are independent risk factors for prosthesis loosening. The predictive model we established through machine learning can effectively determine the risk of prosthesis loosening. Monitoring inflammatory cytokines and postoperative infections, combined with prevention of osteoporosis, can help reduce the risk of prosthesis loosening.

The impact of population agglomeration on ecological resilience: Evidence from China.

Due to climate change and human activities, ecological and environmental issues have become increasingly prominent and it is crucial to deeply study the coordinated development between human activities and the ecological environment. Combining panel data from 31 provinces in China spanning from 2011 to 2020, we employed a fixed-effects model, a threshold regression model, and a spatial Durbin model to empirically examine the intricate impacts of population agglomeration on ecological resilience. Our findings indicate that population agglomeration can have an impact on ecological resilience and this impact depends on the combined effects of agglomeration and crowding effects. Also, the impact of population agglomeration on ecological resilience exhibits typical dual-threshold traits due to differences in population size. Furthermore, population agglomeration not only directly impacts the ecological resilience of the local area, but also indirectly affects the ecological resilience of surrounding areas. In conclusion, we have found that population agglomeration does not absolutely impede the development of ecological resilience. On the contrary, to a certain extent, reasonable population agglomeration can even facilitate the progress of ecological resilience.

Effects of temperature on microstructures of MSA-type electroplating solution: a coarse-grained molecular dynamics simulation.

In this study, we employ coarse-grained molecular dynamics simulations to explore the microstructure of MSA (methanesulfonic acid)-type electroplating solution, containing Sn(MSA)2 as the primary salt, MSA as the stabilizer, amphiphilic alkylphenol ethoxylate (APEO) as surfactants and cinnamaldehyde (CA) as the brightener agents, as well as water as the solvent. Our simulation indicates that temperature variations can significantly affect the structural properties of the electroplating solution and the adsorption behavior of its key components onto the substrate. Specifically, at low temperatures, the primary salt ions aggregate into ionic clusters, and the amphiphilic APEO surfactants and CA molecules form micelles composed of hydrophobic cores and hydrophilic shells, which reduces the uniformity of the solution and hinders the adsorption of ions, CA and surfactants onto the substrate. Appropriately increasing the temperature can weaken the aggregation of these components in bulk solution due to the accelerated molecular movements and arouse their adsorption. However, on further increasing the temperature, the elevated kinetic energy of the components thoroughly overwhelms the adsorption interactions, and therefore, the ions, surfactants, and CA desorb from the substrate and redissolve into the solution. We systematically analyze the complex interactions between these components at different temperatures and clarify the mechanism of the non-monotonic dependence of adsorption strength on the temperature at the molecular level. Our simulations demonstrate that there is low-temperature scope for reprocessing/recycling and intermediate-temperature scope for substrate-adsorptions of the key components. This study confers insights into a fundamental understanding of the microscopic mechanism for electroplating and can provide guidance for the development of precise electroplatings.

A Multiplier Bootstrap Approach to Designing Robust Algorithms for Contextual Bandits.

Upper confidence bound (UCB)-based contextual bandit algorithms require one to know the tail property of the reward distribution. Unfortunately, such tail property is usually unknown or difficult to specify in real-world applications. Using a tail property heavier than the ground truth leads to a slow learning speed of the contextual bandit algorithm, while using a lighter one may cause the algorithm to diverge. To address this fundamental problem, we develop an estimator (evaluated from historical rewards) for the contextual bandit UCB based on the multiplier bootstrap technique. Our proposed estimator mitigates the problem of specifying a heavier tail property by adaptively converging to the ground truth contextual bandit UCB (i.e., eliminating the impact of the specified heavier tail property) with theoretical guarantees on the convergence. The design and convergence analysis of the proposed estimator is technically nontrivial. The proposed estimator is generic and it can be applied to improve a variety of UCB-based contextual bandit algorithms. To demonstrate the versatility of the proposed estimator, we apply it to improve the linear reward contextual bandit UCB (LinUCB) algorithm resulting in our bootstrapping LinUCB (BootLinUCB) algorithm. We prove that the BootLinUCB has a sublinear regret. We conduct extensive experiments on both synthetic dataset and real-world dataset from Yahoo! to validate the benefits of our proposed estimator in reducing regret and the superior performance of BootLinUCB over the latest baseline.

Simultaneous Determination of Fifteen Polyphenols in Fruit Juice Using Ultrahigh-Performance Liquid Chromatography-Tandem Mass Spectrometry Combining Dispersive Liquid-Liquid Microextraction.

Polyphenols are secondary metabolites of plants and used as effective antioxidants in dietary supplements, whose main sources are fruits, vegetables, and grains. To clarify the content and distribution of polyphenols in different fruit species samples accurately, a rapid and sensitive ultrahigh-pressure liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) method combining dispersive liquid-liquid microextraction (DLLME) was developed for quantitative determination of fifteen polyphenol compounds in fruit juice. In this method, the targets were first extracted from 1 g of fruit juice sample using 10 mL of 80% ethanol solution by ultrasonic-assisted extraction (UAE). Then, 1.0 mL of UAE extracted solution, 60 µL of n-octanol and 2.0 mL of H2O were performed in the following DLLME procedure. A C18 reversed-phase column, ZORBAX SB (100 × 4.6 mm, 3.5 µm), was proposed under gradient elution with 0.1% formic acid aqueous solution and methanol mobile phases for the determination of 15 polyphenols, allowing us to obtain polyphenolic profiles in less than 23.0 min. Under the optimum conditions, the enrichment factors ranged from 162 to 194. The results showed that the 15 polyphenols had linear correlation coefficients (R 2) more than 0.99. The limits of detection (LODs) were between 18.3 and 103.5 ng/g, and the average recoveries were between 96.9 and 116.3% with interday relative standard deviations (RSDs) ranging from 4.4 to 8.2% in all cases. The method was successfully applied to the analysis of real fruit juice samples and presented itself as a simple, rapid, practical, and environment-friendly technique.

LINC01534/miR-135b-5p/PTPRT axis regulates inflammatory response in loosening total hip replacement via modulating NF-κB signaling pathway.

Aseptic loosening after total hip replacement brings adverse health outcomes and increased risk for complications. The resorptive activity of inflammatory cells activated by the presence of wear-generated debris plays a critical role in debris-induced osteolysis. Previous studies indicate that the abnormally expressed LINC01534 plays a critical role in inflammatory responses. In this study, we aimed to elucidate the functional role and underlying mechanism of LINC01534 in debris-induced osteolysis. We first confirmed that LINC01534 was highly expressed in hip cartilage tissues from aseptic loosening patients. By using an IL-1ß-induced inflammation model mimicking debris-induced osteolysis, we demonstrated that LINC01534 promoted IL-1ß-induced inflammatory response in hip chondrocytes. Knockdown of LINC01534 inhibited the expression of inflammatory IL-6, IL-8, and TNF-α in hip chondrocytes. Our results showed that LINC01534 functioned as a competing endogenous RNA (ceRNA) by sponging miR-135b-5p in hip chondrocytes. Moreover, bioinformatics analysis and luciferase reporter assay demonstrated that CCHC-Type Zinc Finger Nucleic Acid Binding Protein (PTPRT) is a downstream target of miR-135b-5p. Knockdown of PTPRT attenuated the IL-1ß-induced inflammatory responses in hip chondrocytes. In addition, we revealed that inhibition of miR-135b-5p or overexpression of PTPRT could antagonize the effects of LINC01534 knockdown on inflammation attenuation in hip chondrocytes. Mechanistically, we demonstrated that LINC01534/miR-135b-5p/PTPRT axis regulated the NF-κB signaling pathway in hip chondrocytes. Taken together, our findings suggest that LINC01534/miR-135b-5p/PTPRT axis might be a valuable therapeutic target for the treatment of debris-induced osteolysis.

Microbiology of Periprosthetic Hip and Knee Infections in Surgically Revised Cases from 34 Centers in Mainland China.

BACKGROUND AND AIM: Periprosthetic joint infection (PJI) is one of the most devastating complications after total joint arthroplasty (TJA). However, the antibiotic resistance of infecting pathogens can significantly vary in different parts of the country. In the current study, we analyzed the demographic and microbiological profiles of knee and hip PJI over three years and compared the microbiological differences between them. METHODS: A multicenter retrospective study of PJI patients in 34 referral medical centers in mainland China from January 2015 to November 2017 was performed. RESULTS: A total of 925 PJI patients were recruited, 452 were identified as knee PJIs, and 473 were hip PJIs. The most common causative pathogens were Staphylococcus aureus (26.5%) and coagulase-negative staphylococci (14.3%). Methicillin-resistant staphylococci were involved in 25.6% (237/925) of all PJI cases. Mycobacterium and fungus only accounted for 6.5% (61) of all cases. Enteric gram-negative bacilli, anaerobes, and polymicrobial pathogens were more common in hip joint prostheses than in knee PJI (P = 0.014; P = 0.006; P = 0.002, respectively). CONCLUSION: While the majority of causative pathogens in PJI cases are staphylococcal species, the prevalence of atypical organisms and resistant pathogens should also be given attention and warrant the need for empiric antibiotic treatment.

Association between the inclination angle of the proximal tibiofibular joint surface and medial compartment knee osteoarthritis.

BACKGROUND: Fibular support for the lateral tibial plateau through the proximal tibiofibular joint (PTFJ) results in nonuniform settlement of the tibial plateau in middle-aged and elderly persons and may lead to medial compartment knee osteoarthritis. However, the inclination angle of the PTFJ surface varies widely and may affect nonuniform settlement. The purpose of this case-control study was to assess the association between the inclination angle of the PTFJ surface and medial compartment knee osteoarthritis. METHODS: The fibular inclination angle (FIA) and tibial inclination angle (TIA) of the PTFJ surface were measured using radiographs. Differences of FIA and TIA among groups were assessed with t tests and the odds ratios (ORs) for risk factors of medial compartment knee osteoarthritis were calculated with binary logistic regression analysis. RESULTS: Forty patients and 40 control participants were included in this case-control study. Patients had both a lower FIA (P=0.005) and TIA (P=0.000) than the controls, and logistic regression analysis showed that FIA (OR =7.000) and TIA (OR =17.000) were risk factors for medial compartment knee osteoarthritis. CONCLUSIONS: A lower inclination angle of the PTFJ surface is associated with a risk of medial compartment knee osteoarthritis. Clinically, early prevention of medial compartment knee osteoarthritis should be considered for middle-aged and elderly persons with low PTFJ inclination angles.

Medium-Term Clinical Results of High-Flexion Knee Prostheses in Patients with Rheumatoid Arthritis.

OBJECTIVE: This study was performed to evaluate the function and satisfaction outcome of patients with rheumatoid arthritis (RA) who underwent total knee arthroplasty (TKA) with high-flexion prostheses. MATERIALS AND METHODS: Twenty-two patients (35 knees) using high-flexion prostheses (Zimmer, Warsaw, IN) were followed up for a period of 7-11 years from February 2007 to December 2009. Clinical and radiographic follow-up was performed using Hospital for Special Surgery (HSS), Short-Form 36 scores (SF-36), American Knee Society score (KSS), and Knee Society Total Knee Arthroplasty Roentgenographic Evaluation and Scoring System. Patient satisfaction assessments took place at the final follow-up sessions using the Marsh Satisfaction Questionnaire. RESULTS: The average ROM improved from preoperative 68.43° ± 33.78° to 95.54° ± 7.03° at the final follow-up. The HSS score and KSS score for pain improved from (46.49 ± 12.73) points to (85.46 ± 3.90) points and from 20.57 ± 5.91 points to 47.43 ± 3.51 points at the follow-up evaluation, respectively. Physical Component Summary(PCS) and Physical Component Summary (MCS) scores were 45.38 and 52.56, respectively by the end of follow-up. Deep venous thrombosis developed in one patient and one patient required surgical revision due to infection. There were no instances of prosthetic loosening. The satisfaction rate of patients was 95.5%. CONCLUSION: Although this particular model of TKA did not yield high-flexion angles (ie, 140°) required for kneeling, squatting, or rising from the floor, significant clinical and radiographic gains were evident in these patients with RA.

QKI deficiency leads to osteoporosis by promoting RANKL-induced osteoclastogenesis and disrupting bone metabolism.

Quaking (QKI), an RNA-binding protein, has been reported to exhibit numerous biological functions, such as mRNA regulation, cancer suppression, and anti-inflammation. However, little known about the effects of QKI on bone metabolism. In this study, we used a monocyte/macrophage-specific QKI knockout transgenic mouse model to investigate the effects of QKI deficiency on receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis. The loss of QKI promoted the formation of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts (OCs) from bone marrow macrophages, and upregulated the expression of OC-specific markers, including TRAP (Acp5) and cathepsin K (Ctsk). The pro-osteoclastogenesis effect of QKI deficiency was achieved by amplifying the signaling cascades of the NF-κB and mitogen-activated protein kinase (MAPK) pathways; then, signaling upregulated the activation of nuclear factor of activated T cells c1 (NFATc1), which is considered to be the core transcription factor that regulates OC differentiation. In addition, QKI deficiency could inhibit osteoblast (OB) formation through the inflammatory microenvironment. Taken together, our data suggest that QKI deficiency promoted OC differentiation and disrupted bone metabolic balance, and eventually led to osteopenia under physiological conditions and aggravated the degree of osteoporosis under pathological conditions.

Proximal femoral nail anti-rotation versus cementless bipolar hemiarthroplasty for unstable femoral intertrochanteric fracture in the elderly: a retrospective study.

BACKGROUND: The treatment for unstable intertrochanteric fractures in the elderly has always been a controversial issue. The aim in this study was to compare the curative effects of proximal femoral nail anti-rotation (PFNA) and cementless bipolar hemiarthroplasty (CPH) on femoral intertrochanteric fracture in the elderly. METHODS: From March 2008 to December 2012, 108 elderly patients with femoral intertrochanteric fractures were treated by PFNA or CPH. There were 63 males and 45 females, aged 75.3-99.1 years [(83.7 ± 5.6) years]. The patients' bone mineral density was routinely measured, and the fractures were classified according to Evans-Jensen. The patients were divided into CPH group and PFNA group. The differences in operation time, intraoperative bleeding, immobilization duration, hospitalization time, Harris scores and postoperative complications including deep venous thrombosis, lung and urinary infection were analyzed. RESULTS: All patients were followed for 12.5-36.2 months [(28.0 ± 6.3) months)]. The operation time was (53.7 ± 15.2) min and (77.5 ± 16.8) min in PFNA group and CPH group, respectively (P < 0.05); intraoperative bleeding was (132.5 ± 33.2) mL and (286.3 ± 43.2) mL, respectively (P < 0.05); immobilization duration was (28.2 ± 3.7) days and (3.1 ± 1.2) days, respectively (P < 0.05); hospitalization time was (7.6 ± 1.8) days and (6.9 ± 2.2) days, respectively (P > 0.05); and the Harris scores after 1 year were (87.7 ± 7.9) points and (88.3 ± 9.2) points, respectively (P > 0.05). There was no significant difference in postoperative complications between the two groups (P > 0.05). CONCLUSION: Both PFNA and CPH are safe and effective treatments for femoral intertrochanteric fracture in elderly patients. Nonetheless, CPH allows faster mobilization and recovery. TRIAL REGISTRATION: Registration Number: ChiCTR1900022846 . Reg Date:2019-04-26 00:27:33 Retrospective registration.

MiRNA-199a-5p positively regulated RANKL-induced osteoclast differentiation by target Mafb protein.

MicroRNAs are involved in osteoclast differentiation. Although miR-199a-5p plays an important role in many different systems and diseases, its function during osteoclastogenesis remains unclear. In this study, we investigated the function and the target gene of miR-199a-5p in osteoclast differentiation. The in vitro data showed that miR-199a-5p was significantly upregulated after the stimulation by receptor activator of nuclear factor kappa-B ligand in macrophages and RAW 264.7 cells. After transfection of miR-199a-5p mimic, the messenger RNA expression level of nuclear factor of activated T-cells cytoplasmic 1, tartrate-resistant acid phosphatase (TRAP), and receptor activator of nuclear factor kappa-B was significantly increased in RAW 264.7 cells and the number of TRAP-positive cells was also increased. MiR-199a-5p inhibitor showed the complete opposite outcome which brought additional proof to our finding. Overexpression of miR-199a-5p led to downregulation of Mafb protein. The luciferase activity was obviously repressed when WT-pGL3-Mafb and miR-199a-5p mimics were cotransfected into 293 T cells and the inhibitors cotransfected demonstrated reverse result. MiR-199a-5p overexpressed during osteoclast differentiation and positively regulated osteoclast formation in vitro by target Mafb.

A Novel Cluster Validity Index Based on Local Cores.

It is critical to evaluate the quality of clusters for most cluster analysis. A number of cluster validity indexes have been proposed, such as the Silhouette and Davies-Bouldin indexes. However, these validity indexes cannot be used to process clusters with arbitrary shapes. Some researchers employ graph-based distance to cluster nonspherical data sets, but the computation of graph-based distances between all pairs of points in a data set is time-consuming. A potential solution is to select some representative points. Inspired by this idea, we propose a novel Local Cores-based Cluster Validity (LCCV) index to improve the performance of Silhouette index. Local cores, with local maximum density, are selected as representative points. Since graph-based distance is used to evaluate the dissimilarity between local cores, the LCCV index is effective for obtaining the optimal cluster number for data sets containing clusters with arbitrary shapes. Moreover, a hierarchical clustering algorithm based on the LCCV index is proposed. The experimental results on synthetic and real data sets indicate that the new index outperforms existing ones.

Metformin protects bone mass in ultra-high-molecular-weight polyethylene particle-induced osteolysis by regulating osteocyte secretion.

Metformin, an anti-hyperglycemic agent used for type 2 diabetes, has recently been found to have more effects apart from glucose regulation. We found that, in ultra-high-molecular-weight polyethylene particle-induced osteolysis mouse models, metformin had bone protect property and reduced the negative regulator of bone formation sclerostin (SOST) and Dickkopf-related protein 1 (DKK1), and increased osteoprotegerin (OPG) secretion and the ratio of OPG/Receptor Activator for Nuclear Factor-κB Ligand (RANKL). In vitro, we established a 3D co-culture system in which metformin affects osteoblasts and osteoclasts through mature osteocytes secretion. Metformin (50 µM) significantly decreased SOST and DKK1 mRNA expression, stimulating alkaline phosphatase activity and proliferation of osteoblast, and increased OPG secretion and the ratio of OPG/RANKL, inhibiting osteoclastogenesis. Moreover, the effect on OPG was reversed by adenosine 5'-monophosphate-activated protein kinase inhibitor, Compound C. Our finding suggests that metformin induces differentiation and mineralization of osteoblasts, while inhibits osteoclastogenesis via mature osteocytes secretion. Therefore, the drug might be beneficial for not only diabetes but also in other bone disorders by acting on mature osteocytes.

Metformin suppresses UHMWPE particle-induced osteolysis in the mouse calvaria by promoting polarization of macrophages to an anti-inflammatory phenotype.

BACKGROUND: Implant failure remains a major obstacle to successful treatment via TJA. Periprosthetic osteolysis and aseptic loosening are considered as proof of wear debris-induced disruption of local regulatory mechanisms related to excessive bone resorption associated with osteolysis and the damage at the bone-prosthesis interface. Therefore, there is an immediate need to explore strategies for limiting and curing periprosthetic osteolysis and aseptic loosening. METHODS: We analyzed the in vitro cytokine production by primary mouse bone marrow macrophages (BMMs) that were exposed to ultra-high molecular weight polyethylene (UHMWPE) particles and treated with metformin at different concentrations with or without 5-aminoimidazole-4-carboxamide ribonucleoside to activate or inhibit AMPK. A mouse calvarial model was used to examine the in vivo effects of metformin on UHMWPE particle-induced osteolysis. RESULTS: With particles, primary mouse BMMs secreted more pro-inflammatory cytokines tumor necrosis factor-α and interleukin (IL)-6. Treatment with metformin inhibited these variations and promoted the release of cytokine IL-10 with anti-inflammatory capability. In vivo, metformin reduced the production of pro-inflammatory cytokines, osteoclastogenesis, and osteolysis, increasing IL-10 production. Metformin also promoted the polarization of macrophages to an anti-inflammatory phenotype in vivo via AMPK activation. DISCUSSION: A crucial point in limiting and correcting the periprosthetic osteolysis and aseptic loosening is the inhibition of inflammatory factor production and osteoclast activation induced by activated macrophages. The ability of metformin to attenuate osteolysis induced in mouse calvaria by the particles was related to a reduction in osteoclast number and polarization of macrophages to an anti-inflammatory functional phenotype. CONCLUSIONS: Metformin could limit the osteolysis induced by implant debris. Therefore, we hypothesized that metformin could be a potential drug for osteolysis induced by implant debris.

Bottom-Up Electrodeposition of Large-Scale Nanotwinned Copper within 3D Through Silicon Via.

This paper is the first to report a large-scale directcurrent electrodeposition of columnar nanotwinned copper within through silicon via (TSV) with a high aspect ratio (~4). With this newly developed technique, void-free nanotwinned copper array could be fabricated in low current density (30 mA/cm²) and convection conditions (300 rpm), which are the preconditions for copper deposition with a uniform deep-hole microstructure. The microstructure of a whole cross-section of deposited copper array was made up of (111) orientated columnar grains with parallel nanoscale twins that had thicknesses of about 22 nm. The hardness was also uniform along the growth direction, with 2.34 and 2.68 GPa for the top and bottom of the TSV, respectively. The gelatin additive is also first reported hereas a key factor in forming nanoscale twins by adsorbing on the cathode surface, in order to enhance the overpotential for cathodic reaction during the copper deposition process.

Incorporation of Efficient Second-Order Solvers Into Latent Factor Models for Accurate Prediction of Missing QoS Data.

Generating highly accurate predictions for missing quality-of-service (QoS) data is an important issue. Latent factor (LF)-based QoS-predictors have proven to be effective in dealing with it. However, they are based on first-order solvers that cannot well address their target problem that is inherently bilinear and nonconvex, thereby leaving a significant opportunity for accuracy improvement. This paper proposes to incorporate an efficient second-order solver into them to raise their accuracy. To do so, we adopt the principle of Hessian-free optimization and successfully avoid the direct manipulation of a Hessian matrix, by employing the efficiently obtainable product between its Gauss-Newton approximation and an arbitrary vector. Thus, the second-order information is innovatively integrated into them. Experimental results on two industrial QoS datasets indicate that compared with the state-of-the-art predictors, the newly proposed one achieves significantly higher prediction accuracy at the expense of affordable computational burden. Hence, it is especially suitable for industrial applications requiring high prediction accuracy of unknown QoS data.

Treatment Effects of the Second-Generation Tyrosine Kinase Inhibitor Dasatinib on Autoimmune Arthritis.

Rheumatoid arthritis (RA) is a multifactorial autoimmune disease that primarily manifests as persistent synovitis and progressive joint destruction. Imatinib exhibited a therapeutic effect in murine collagen-induced arthritis (CIA) via selective inhibition tyrosine kinases. The second-generation tyrosine kinase inhibitor dasatinib exhibits more durable hematological and cytogenetic effects and more potency compared to imatinib. However, the effect of dasatinib on CIA is poorly understood. The present study investigated the treatment effect of dasatinib on autoimmune arthritis. We demonstrated that dasatinib alleviated arthritis symptoms and histopathological destruction in CIA mice. Dasatinib treatment inhibited the production of proinflammatory cytokines including IL-1ß, TNF-α, and IL-6, and promoted the production of the anti-inflammatory cytokine IL-10. Dasatinib treatment also suppressed the expression of anti-mouse CII antibodies including total IgG, IgG1, IgG2, and IgG2b, in CIA mice. We further demonstrated that dasatinib inhibited the migration and proliferation of fibroblast-like synoviocytes (FLS) from RA patients and promoted FLS apoptosis. The mRNA expression of MMP13, VEGF, FGF, and DKK1 was down-regulated in FLS treated with dasatinib. Our findings suggest that dasatinib exhibited treatment effects on CIA mice and that FLS are an important target cell of dasatinib treatment in autoimmune arthritis.

CD11b promotes the differentiation of osteoclasts induced by RANKL through the spleen tyrosine kinase signalling pathway.

Macrophage surface antigen-1 (Mac-1, CD11b/CD18) has been implicated in the regulation of osteoclastogenesis. In the synovial tissues of patients with aseptic loosening after total hip replacement, CD11b was up-regulated, which indicated that CD11b is closely involved in osteolysis around the prosthesis. We found that CD11b, but not CD18, promoted osteoclast (OC) maturation. Here, we show CD11b up-regulated the levels of spleen tyrosine kinase (Syk), c-Fos and nuclear factor of activated T cells, cytoplasmic-1 (NFATc1), as well as the activity of extracellular-regulated kinase (Erk), and as a result, osteoclast precursors (OCPs) differentiated and became tartrate-resistant acid phosphatase (TRAP)-positive. In addition, increased tumour necrosis factor-α (TNF-α) induced by ultra-high molecular weight polyethylene (UHMWPE) particles up-regulated the level of CD11b. Taken together, these findings suggest that CD11b is a positive regulator of osteoclastogenesis and that it functions by activating the Syk signalling pathway, while CD18 does not have the same effect.