Wound complication risk factors following open reduction and internal fixation of ankle fractures.

This study was designed to identify risk factors for wound complications including surgical site infection (SSI) and wound healing issues following open reduction and internal fixation (ORIF) of ankle fractures. A retrospective analysis of individuals with ankle fractures treated with ORIF was undertaken. Study subjects were divided into a wound complications (WC) group and a no wound complication (NWC) group. The WC group was further divided into an SSI group and wound healing issues group. Twenty-one potential risk factors associated with wound complications after ORIF were tracked. Uni- and multivariate binary logistical regression analyses were used to identify risk factors associated with wound complications, ISS and wound healing issues. In total, 613 individuals, who had undergone surgery for ankle fractures formed the study cohort. The incidence of postoperative wound complications was 10.3% (63 cases), including 5.2% of SSI (32 cases) and 5.1% of wound healing issues (31 cases). The independent risk factors for wound complications were age 65 years or older, preoperative serum albumin level below 35 g/L, peripheral neuropathy, open fracture, fewer than seven cases per year in surgical volume, and attending surgeon level. The independent risk factors for SSI were age 65 years or older, preoperative serum albumin level below 35 g/L, open fracture and fewer than seven cases per year in surgical volume. The independent risk factors for wound healing issues were preoperative serum albumin level below 35 g/L, peripheral neuropathy, open fracture and attending surgeon level. Herein we found both factors inherent to the injury and individual and those pertaining to the surgical team affected the frequency of wound complications after ORIF of ankle fractures. Specifically, advanced age and low surgical volume were associated with a greater risk of SSI. Peripheral neuropathy and the low expertise level on the part of the surgeon were associated with a greater risk of wound healing issues. Hypoproteinaemia and open fracture were both associated with a greater risk of both SSI and wound healing issues.

A Modified Approach to Measuring Femoro-Epiphyseal Acetabular Roof (FEAR) Index Has Better Intraobserver and Interobserver Reliability Compared With the Original FEAR Index.

PURPOSE: To propose a modified approach to measuring the femoro-epiphyseal acetabular roof (FEAR) index while still abiding by its definition and biomechanical basis, and to compare the intra- and interobserver reliabilities of the original and the modified FEAR index. To propose a classification for medial sourcil edges. METHODS: We retrospectively reviewed a consecutive series of patients treated with periacetabular osteotomy and/or hip arthroscopy at a single institute. Patients with unilateral or bilateral symptomatic borderline hip(s) were included. Hips with remarkable osteoarthritis, deformities, history of previous surgery, or without symptoms were excluded. A modified FEAR index was defined using a best-fit circle to determine the sourcil line and 2 ancillary lines connecting femoral head and sourcil edges to determine epiphyseal line. Lateral center-edge angle, Sharp angle, Tönnis angle on all hips, as well as FEAR index with original and modified approaches, were measured. Intra- and interobserver reliability were calculated as intraclass correlation coefficients (ICCs) for the FEAR index with both approaches and other alignments. A classification was proposed to categorize medial sourcil edges. ICCs for the 2 approaches across different sourcil groups also were calculated. RESULTS: After we reviewed 411 patients, 49 were finally included. Thirty-two patients (40 hips) were identified as having borderline dysplasia defined by a lateral center-edge angle of 18 to 25°. Intraobserver ICCs for the modified method were good to excellent for borderline hips; poor to excellent for developmental dysplasia of the hip; and moderate to excellent for normal hips. As for interobserver reliability, the modified approach outperformed original approach with moderate-to-good interobserver reliability (developmental dysplasia of the hip group, ICC = 0.650; borderline dysplasia group, ICC = 0.813; normal hip group, ICC = 0.709). The medial sourcil edge was classified to 3 groups upon its morphology. Type II (39.0%) and III (43.9%) sourcil were the dominant patterns. The sourcil classification had substantial intraobserver agreement (observer 4, kappa = 0.68; observer 1, kappa = 0.799) and moderate interobserver agreement (kappa = 0.465). The modified approach to FEAR index possessed greater interobserver reliability in all medial sourcil edge patterns. CONCLUSIONS: The modified FEAR index has better intra- and interobserver reliability compared with the original approach in all hip groups and sourcil groups. Type II and III sourcil types account for the majority, to which the modified approach is better. LEVEL OF EVIDENCE: Level II, development of diagnostic criteria (consecutive patients with consistently applied reference standard and blinding).

Characteristics of the patellofemoral joint of patients with DDH and the effects of Bernese periacetabular osteotomy on the patellofemoral joint.

BACKGROUND: Some patients with developmental dysplasia of the hip (DDH) complained of anterior knee pain (AKP) before and after Bernese periacetabular osteotomy (PAO) surgery. The purpose of this study was to (1) identify the characteristics of patellofemoral joint (PFJ) deformities in patients with DDH and (2) to determine the effects of PAO on the PFJ. METHODS: Seventy patients (86 hips) were included in the DDH group. Thirty-three patients (33 knees) without AKP and hip pain were included in the control group. All patients underwent simultaneous CT scans of the hip and knee joints before PAO and after hardware removal surgery. The distance from the anterior inferior iliac spine to the ilioischial line (DAI), was measured in DDH patients. Imaging parameters of knees, including the sulcus angle (SA), femoral trochlear depth (FTD), patellar width (PW), tibial tuberosity-trochlear groove (TT-TG), patellar tilt angle (PTA) and lateral shift of the patella (LSP) were measured in patients in both the DDH and control group. TT-TG, PTA, and LSP of DDH patients were measured before PAO and after hardware removal. The DAI, PTA, LSP and TT-TG of all DDH patients before and after Bernese PAO were compared using paired t-tests. The FTD, PW, and SA of the DDH patients and the control group were analyzed using independent t-tests. PTA, TT-TG, and LSP between the control group and preoperative DDH patients, between the control group and post PAO patients were compared using independent t-tests. RESULTS: The DAI changed from 4.04 ± 0.61 mm before PAO surgery to 5.44 ± 0.63 mm after PAO surgery. The SA of the DDH group (140.69 ± 11.30 degree) was greater than that of the control group (130.82 ± 6.43 degree). The FTD and the PW of the DDH group (5.45 ± 1.59 mm, 4.16 ± 0.36 mm) were smaller than that of the control group (7.39 ± 1.20 mm, 4.24 ± 0.38 mm). The changes in LSP, PTA, and TT-TG before and after surgery were not statistically significant. Both before and after PAO, there was no statistically significant difference in the parameters of LSP, PTA, and TT-TG compared with the control group. CONCLUSION: The knee joints of DDH patients presented a certain degree of femur trochlear groove dysplasia and patellofemoral instability. PAO surgery did not change PFJ stability, although the origination point of the rectus femoris muscle moved laterally during PAO surgery.

What is the agreement between intraoperative fluoroscopy and postoperative radiographs in Bernese periacetabular osteotomy?

BACKGROUND: It is important to reorient the acetabular fragment into an optimal position and version to ensure a good long-term outcome after Bernese periacetabular osteotomy (PAO). Unfortunately, the intraoperative balance between overcorrection and undercorrection remains challenging for the surgeon. The purpose of this study was to answer two questions: (1) Does the femoral head coverage measured on intraoperative fluoroscopy agree with that measured on postoperative radiography? (2) What is the reliability of intraoperative fluoroscopy in identifying hip center correction in PAO? METHODS: A total of 173 patients (173 hips) who underwent PAO for developmental dysplasia of the hip (DDH) at our center from July 01, 2020, to December 31, 2020, were retrospectively reviewed. Imaging data from 111 patients (female/male, 98/13; right/left, 72/39; mean age, 28.93 years) were included in this study. The analysis included measurement of the lateral center-edge angle (LCEA), acetabular index (AI), anterior wall index (AWI), posterior wall index (PWI), extrusion index (EI), and medial offset distance (MO). These measurements were acquired from intraoperative fluoroscopic images and postoperative radiographs and compared by paired t test using SPSS (version 24.0). Significance was determined at a p value of < 0.05. Bland-Altman analysis, conducted using GraphPad Software (version 9), was used to quantify the agreement between intraoperative fluoroscopic images and postoperative radiographs. RESULTS: The means (standard deviations, SDs) of the LCEA, AI, AWI, PWI, EI, and MO obtained on intraoperative fluoroscopy were 32.86° (5.73°), 0.66° (5.55), 0.29 (0.10), 0.75 (0.17), 11.15% (6.50%), and 8.49 mm (3.68 mm), respectively. On postoperative radiography, the corresponding values were 32.91° (6.31°), 1.63° (5.22°), 0.29 (0.15), 0.85 (0.14), 11.27% (7.36%), and 9.60 mm (3.79 mm). The differences in the LCEA, AWI, and EI acquired from intraoperative fluoroscopic images and postoperative radiographs were not significant (p = 0.90, 0.95, and 0.83, respectively), but those in the AI, PWI, and MO were significant (p < 0.05). The mean biases (95% limits of agreement) of the LCEA, AI, AWI, PWI, EI, and MO were - 0.04 (- 6.85), - 0.97 (- 7.78), 0 (- 0.30), - 0.11 (- 0.36), - 0.12 (- 11.92), and - 1.11 (- 5.51), respectively. CONCLUSION: The LCEA, EI, and AWI can be used to reliably predict postoperative femoral head coverage at the level of 2D graphics. Acetabular inclination can be cautiously assessed using AI on intraoperative fluoroscopy. In the absence of intraoperative 3D image evaluation, the AWI and PWI demonstrate acceptable agreement between fluoroscopy and radiography in assessing the acetabular version. Although the MO shows slight bias, it can be helpful in properly positioning the acetabulum during PAO.

Variations in lower limb alignments indicate pelvic tilt after total hip arthroplasty.

OBJECTIVE: We sought to correlate various spinopelvic and lower limb alignments, and to examine the current spinopelvic theories on a Chinese cohort. METHODS: We retrospectively reviewed 166 patients undergoing THA. Among them, 138 patients with unilateral THA met the inclusion criteria. Sagittal alignments and cup orientations were measured on standing and sitting lateral EOS images. Patients were categorized into two groups with a scoring system for lumbar spine degeneration. Patients' demographics including age, sex, lumbar spine degeneration and radiographic measurements were studied. RESULTS: PT, SS, LL and TK differed significantly between standing and sitting within each group except for TK in degenerative group (32.8 ± 13.9 vs. 32.9 ± 14.2, p = 0.905). Compared with degenerative spine group, non-degenerative spine patients have great pelvic mobility (ΔPT, -24.4 ± 12.5° vs. -17.6 ± 10.7, p = 0.0008), greater lumbar mobility (ΔLL, -34.8 ± 15.2 vs. -21.7 ± 12.2, p = < 0.0001) and compensatory cup orientation changes (ΔRA, -15.5 ± 11.1 vs. -12.0 ± 8.4, p = 0.00920; ΔRI, -10.8 ± 11.5 vs. -5.6 ± 7.5, p = 0.0055). Standing PT and ankle dorsiflexion angle correlated positively (R2 = 0.236, p = 0.005). CONCLUSION: THA patients in this cohort showed a spinopelvic motion paradigm similar to that from previous studies on Caucasians. Ankle dorsiflexion indicate greater posterior pelvic tilt on standing. Surgeons should beware of risks of instability in patients with lower limb compensations. ADVANCES IN KNOWLEDGE: This study provides new insights into the clinical relevance of lower limb alignments to spinopelvic motion after THA in a relatively young Chinese population.

Loss of TIMP3 expression induces inflammation, matrix degradation, and vascular ingrowth in nucleus pulposus: A new mechanism of intervertebral disc degeneration.

Low back pain (LBP) is one of the most common complains in orthopedic outpatient department and intervertebral disc degeneration (IDD) is one of the most important reasons of LBP. The mechanisms of IDD contain a complex biochemical cascade which includes inflammation, vascular ingrowth, and results in degradation of matrix. In our study, we used both in vitro and in vivo models to investigate the relation between tissue inhibitor of metalloproteinase-3 (TIMP3) expression and IDD. Loss of TIMP3 expression was found in degenerative intervertebral disc (IVD), this change of expression was closely related with the dephosphorylation of smad2/3. Overexpression of TIMP3 significantly inhibited the release of TNF-α and matrix degradation induced by Lipopolysaccharide. Vascular ingrowth was also suppressed by TIMP3 in the in vitro and in vivo models. Further, animal experiments confirmed that the degeneration of IVD was reduced after overexpression of TIMP3 in nucleus pulposus. Taken together, our results indicated TIMP-3 might play an important role in the pathogenesis of IDD and therefore be a potential therapeutic target in the future.

Isorhamnetin attenuates osteoarthritis by inhibiting osteoclastogenesis and protecting chondrocytes through modulating reactive oxygen species homeostasis.

Increasing evidence indicates that osteoarthritis (OA) is a musculoskeletal disease affecting the whole joint, including both cartilage and subchondral bone. Reactive oxygen species (ROS) have been demonstrated to be one of the important destructive factors during early-stage OA development. The objective of this study was to investigate isorhamnetin (Iso) treatment on osteoclast formation and chondrocyte protection to attenuate OA by modulating ROS. Receptor activator of nuclear factor-kappa B ligand (RANKL) was used to establish the osteoclast differentiation model in bone marrow macrophages (BMMs) in vivo. H2 O2 was used to induce ROS, which could further cause chondrocyte apoptosis. We demonstrated that Iso suppressed RANKL-induced ROS generation, which could mediate osteoclastogenesis. Moreover, we found that Iso inhibited osteoclast formation and function by suppressing the expression of osteoclastogenesis-related genes and proteins. We proved that Iso inhibited RANKL-induced activation of mitogen-activated protein kinase activation of mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB) and AKT signalling pathways in BMMs. In addition, Iso inhibited ROS-induced chondrocyte apoptosis by regulating apoptosis-related proteins. Moreover, Iso was administered to an anterior cruciate ligament transection (ACLT)-induced OA mouse model. The results indicated that Iso exerted beneficial effects on inhibiting excessive osteoclast activity and chondrocyte apoptosis, which further remedied cartilage damage. Overall, our data showed that Iso is an effective candidate for treating OA.

Author Correction: Synergistic suppression of human breast cancer cells by combination of plumbagin and zoledronic acid in vitro.

The authors regretted to find the mis-representative images in Fig. 3a, c and Fig. 4a, c when re-read our previously published article Synergistic suppression of human breast cancer cells by combination of plumbagin and zoledronic acid In vitro (DOI: 10.1038/aps.2015.42) in the journal of Acta Pharmacologica Sinica. This mistake occurred due to the careless compilation when the authors tried to show the synergistic effect against tumor apoptosis during figure presentation process. The right Fig. 3a, c and Fig. 4a, c were provided below. Despite that this correction does not affect the results and conclusions of the aforementioned paper, all the authors still consent on the correction of this negligence. We apologize to the Editor and the readership of the journal for any inconvenience caused. Your thoughtful understanding is highly appreciated.

The imbalance between TIMP3 and matrix-degrading enzymes plays an important role in intervertebral disc degeneration.

It is well-known that one of the most important features of intervertebral disc degeneration (IDD) is the extracellular matrix (ECM) degradation. Collagen and aggrecan are major components of ECM; the degradation of ECM in intervertebral discs (IVDs) is closely related to the activities of collagenase and aggrecanase. TIMP-3 is the most efficient inhibitor of aggrecanase in IVD. However, only few studies focus on the potential relationship between TIMP-3 and IDD. In our study, we found TIMP-3 gene expression was decreased after stimulating with LPS in rat nucleus pulposus (NP) cells. Then we used a lentivirus vector to reconstruct rat NP cells which high expressed TIMP-3 gene (LV-TIMP3). The upregulation of MMPs and ADAMTSs induced by LPS was significantly inhibited in LV-TIMP3 cells. After overexpression of TIMP-3, the aggrecan breakdown caused by LPS was also reduced in both monolayer culture and three-dimension culture model. To further study the relation between TIMP-3 and IDD, we collected human NP tissue samples of different degenerative degrees. Real-time PCR and immunohistochemical staining showed that the expression of TIMP-3 was negatively correlated with the degree of intervertebral disc degeneration, while MMP-1 and ADAMTS-4 were markedly increased in degenerative IVD. Taken together, our results suggest that the imbalance between aggrecanase and TIMP-3 may play an important role in the pathogenesis of IDD and therefore be a potential therapeutic target for treating IDD.

TIMP3 regulates osteosarcoma cell migration, invasion, and chemotherapeutic resistances.

Tissue inhibitors of metalloproteinases (TIMPs) inhibit matrix metalloproteinases (MMPs) to limit degradation of the extracellular matrix. Low levels of TIMP3 have been demonstrated in cancer tissues at advanced clinical stages, with positive distant metastasis and chemotherapeutic resistance. We examined the role of TIMP3 in osteosarcoma (OS) cell invasiveness and chemoresistance. TIMP3 was overexpressed or knocked down in the human OS cell lines Saos2 and MG63. Cell migration and invasion capacities were then evaluated using Transwell assays, and resistance to cisplatin was assessed by CCK-8 assay and flow cytometry. Real-time PCR and western blotting were used to investigate activation of signaling pathways downstream of TIMP3. Overexpression of TIMP3 inhibited the migration and invasion of Saos2 and MG63 cells, while knockdown of TIMP3 had the opposite effect. Cell survival after exposure to cisplatin was inhibited by TIMP3 overexpression in both Saos2 and MG63 cells. Consistently, downregulation of TIMP3 gene expression significantly decreased the sensitivity of OS cells to cisplatin treatment. MMP1, MMP2, Bcl-2, and Akt1 were all downregulated following TIMP3 overexpression, while Bax and cleaved caspase-3 were upregulated. TIMP3 knockdown had opposite effects on the regulation of these genes. Taken together, our findings suggest TIMP3 as a new target for inhibition of OS progression and chemotherapeutic resistance.

Virtual reality for improving balance in patients after stroke: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the effectiveness of virtual reality interventions for improving balance in people after stroke. DESIGN: Systematic review and meta-analysis of randomized controlled trials. METHODS: Studies were obtained by searching the following databases: MEDLINE, CINAHL, EMBASE, Web of Science and CENTRAL. Two reviewers assessed studies for inclusion, extracted data and assessed trial quality. RESULTS: Sixteen studies involving 428 participants were included. People who received virtual reality interventions showed marked improvements in Berg Balance Scale (mean difference: 1.46, 95% confidence interval: 0.09-2.83, P<0.05, I²=0%) and Timed Up and Go Test (mean difference: -1.62, 95% confidence interval: -3.07- -0.16, P<0.05, I²=24%) compared with controls. CONCLUSIONS: This meta-analysis of randomized controlled trials supports the use of virtual reality to improve balance after stroke.

Three dimensional printed macroporous polylactic acid/hydroxyapatite composite scaffolds for promoting bone formation in a critical-size rat calvarial defect model.

We have explored the applicability of printed scaffold by comparing osteogenic ability and biodegradation property of three resorbable biomaterials. A polylactic acid/hydroxyapatite (PLA/HA) composite with a pore size of 500 µm and 60% porosity was fabricated by three-dimensional printing. Three-dimensional printed PLA/HA, ß-tricalcium phosphate (ß-TCP) and partially demineralized bone matrix (DBM) seeded with bone marrow stromal cells (BMSCs) were evaluated by cell adhesion, proliferation, alkaline phosphatase activity and osteogenic gene expression of osteopontin (OPN) and collagen type I (COL-1). Moreover, the biocompatibility, bone repairing capacity and degradation in three different bone substitute materials were estimated using a critical-size rat calvarial defect model in vivo. The defects were evaluated by micro-computed tomography and histological analysis at four and eight weeks after surgery, respectively. The results showed that each of the studied scaffolds had its own specific merits and drawbacks. Three-dimensional printed PLA/HA scaffolds possessed good biocompatibility and stimulated BMSC cell proliferation and differentiation to osteogenic cells. The outcomes in vivo revealed that 3D printed PLA/HA scaffolds had good osteogenic capability and biodegradation activity with no difference in inflammation reaction. Therefore, 3D printed PLA/HA scaffolds have potential applications in bone tissue engineering and may be used as graft substitutes in reconstructive surgery.

Synergistic suppression of human breast cancer cells by combination of plumbagin and zoledronic acid In vitro.

AIM: Zoledronic acid (ZA), a bisphosphonate, is currently used in combination with chemotherapeutic agents to suppress breast cancer cell proliferation or breast cancer-induced osteolysis. The aim of this study was to investigate the effects of ZA combined with a natural anticancer compound plumbagin (PL) against human breast cancer cells in vitro. METHODS: Human breast cancer MDA-MB-231SArfp cells were treated with ZA, PL or a combination of ZA and PL. The cell growth, apoptosis and migration were evaluated using CCK-8 assay, flow cytometry and transwell assay, respectively. The expression of apoptosis-related proteins was measured using real-time PCR and Western blotting. Synergism was evaluated using Compusyn software, and the combination index (CI) and drug reduction index (DRI) values were determined. RESULTS: PL or ZA alone caused mild cytotoxicity (the IC50 value at 24 h was 12.18 and above 100 µmol/L, respectively). However, the combination of ZA and PL caused a synergistic cytotoxicity (CI=0.26). The DRI values also showed a synergistic effect between PL and ZA, with actual values of 5.52 and 3.59, respectively. Furthermore, PL and ZA synergistically induced apoptosis and inhibited migration of the breast cancer cells. Moreover, the combination of ZA and PL decreased the expression of Notch-1, cleaved PARP, Bcl-2 and Bcl-xl, and increased the expression of cleaved caspase-3, CDKN1A and ID1. When the breast cancer cells were transfected with specific siRNA against Notch-1, the combination of ZA and PL markedly increased the expression of Bcl-2. CONCLUSION: Combination of ZA and PL synergistically suppresses human breast cancer MDA-MB-231SArfp cells in vitro. PL can inhibit ZA-induced activation of the Notch-1 signaling pathway and subsequently reduce the expression of Bcl-2, thus potentiating cancer cell apoptosis.

Changes in the small noncoding RNA transcriptome in osteosarcoma cells.

BACKGROUND: Osteosarcoma has the highest incidence among bone malignant tumors and mainly occurs in adolescents and the elderly, but the pathological mechanism is still unclear, which makes early diagnosis and treatment very difficult. Bone marrow mesenchymal stem cells (BMSCs) are considered to be one of the sources of osteosarcoma cells. Therefore, a full understanding of the gene expression differences between BMSCs and osteosarcoma cells is very important to explore the pathogenesis of osteosarcoma and facilitate the early diagnosis and treatment of osteosarcoma. Small noncoding RNAs (sncRNAs) are a class of RNAs that do not encode proteins but directly play biological functions at the RNA level. SncRNAs mainly include Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), small nuclear RNAs (snRNAs), repeat RNAs and microRNAs (miRNAs). METHODS: In this study, we compared the expression of sncRNAs in BMSCs and osteosarcoma cells by high-throughput sequencing and qPCR and looked for differentially expressed sncRNAs. CCK-8, clone formation and transwell assay were used to detect the effect of sncRNA in MG63 cells. RESULTS: We found that 66 piRNAs were significantly upregulated and 70 piRNAs were significantly downregulated in MG63 cells. As for snoRNAs, 71 snoRNAs were significantly upregulated and 117 snoRNAs were significantly downregulated in MG63 cells. As for snRNAs, 35 snRNAs were significantly upregulated and 17 snRNAs were significantly downregulated in MG63 cells. As for repeat RNAs, 6 repeat RNAs were significantly upregulated and 7 repeat RNAs were significantly downregulated in MG63 cells. As for miRNAs, 326 miRNAs were significantly upregulated and 281 miRNAs were significantly downregulated in MG63 cells. Overexpression of piRNA DQ596225, snoRNA ENST00000364830.2, snRNA ENST00000410533.1 and miRNA hsa-miR-369-5p inhibited the proliferation and migration of MG63 cells. CONCLUSIONS: Our results provide a theoretical basis for the pathogenesis, early diagnosis and treatment of osteosarcoma.

A Bone-Targeting Enoxacin Delivery System to Eradicate Staphylococcus Aureus-Related Implantation Infections and Bone Loss.

Post-operative infections in orthopaedic implants are severe complications that require urgent solutions. Although conventional antibiotics limit bacterial biofilm formation, they ignore the bone loss caused by osteoclast formation during post-operative orthopaedic implant-related infections. Fortunately, enoxacin exerts both antibacterial and osteoclast inhibitory effects, playing a role in limiting infection and preventing bone loss. However, enoxacin lacks specificity in bone tissue and low bioavailability-related adverse effects, which hinders translational practice. Here, we developed a nanosystem (Eno@MSN-D) based on enoxacin (Eno)-loaded mesoporous silica nanoparticles (MSN), decorated with the eight repeating sequences of aspartate (D-Asp8), and coated with polyethylene glycol The release results suggested that Eno@MSN-D exhibits a high sensitivity to acidic environment. Moreover, this Eno@MSN-D delivery nanosystem exhibited both antibacterial and anti-osteoclast properties in vitro. The cytotoxicity assay revealed no cytotoxicity at the low concentration (20 µg/ml) and Eno@MSN-D inhibited RANKL-induced osteoclast differentiation. Importantly, Eno@MSN-D allowed the targeted release of enoxacin in infected bone tissue. Bone morphometric analysis and histopathology assays demonstrated that Eno@MSN-D has antibacterial and antiosteoclastic effects in vivo, thereby preventing implant-related infections and bone loss. Overall, our study highlights the significance of novel biomaterials that offer new alternatives to treat and prevent orthopaedic Staphylococcus aureus-related implantation infections and bone loss.

FOXP1 drives osteosarcoma development by repressing P21 and RB transcription downstream of P53.

Osteosarcoma has a poor prognosis, and the poor understanding of the genetic drivers of osteosarcoma hinders further improvement in therapeutic approaches. Transcription factor forkhead box P1 (FOXP1) is a crucial modulator in skeletal development and aging. Here, we determined the role and regulatory mechanisms of FOXP1 in osteosarcoma. Higher FOXP1 expression correlated with malignancy in both osteosarcoma cell lines and clinical biopsies. FOXP1 overexpression and knockdown in osteosarcoma cell lines revealed that FOXP1 promoted proliferation, tumor sphere formation, migration and invasion, and inhibited anoikis. Mechanistically, FOXP1 acted as a repressor of P21 and RB (retinoblastoma protein) transcription, and directly interacted with the tumor suppressor p53 to inhibit its activity. Extracellular signal-regulated kinase/c-Jun N-terminal kinase (ERK/JNK) signaling and c-JUN/c-FOS transcription factors were found to be upstream activators of FOXP1. Moreover, FOXP1 silencing via lentivirus or adeno-associated virus (AAV)-mediated delivery of shRNA suppressed osteosarcoma development and progression in cell-derived and patient-derived xenograft animal models. Taken together, we demonstrate that FOXP1, which is transactivated by ERK/JNK-c-JUN/c-FOS, drives osteosarcoma development by regulating the p53-P21/RB signaling cascade, suggesting that FOXP1 is a potential target for osteosarcoma therapy.

2D vanadium carbide MXenzyme to alleviate ROS-mediated inflammatory and neurodegenerative diseases.

Reactive oxygen species (ROS) are generated and consumed in living organism for normal metabolism. Paradoxically, the overproduction and/or mismanagement of ROS have been involved in pathogenesis and progression of various human diseases. Here, we reported a two-dimensional (2D) vanadium carbide (V2C) MXene nanoenzyme (MXenzyme) that can mimic up to six naturally-occurring enzymes, including superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), glutathione peroxidase (GPx), thiol peroxidase (TPx) and haloperoxidase (HPO). Based on these enzyme-mimicking properties, the constructed 2D V2C MXenzyme not only possesses high biocompatibility but also exhibits robust in vitro cytoprotection against oxidative stress. Importantly, 2D V2C MXenzyme rebuilds the redox homeostasis without perturbing the endogenous antioxidant status and relieves ROS-induced damage with benign in vivo therapeutic effects, as demonstrated in both inflammation and neurodegeneration animal models. These findings open an avenue to enable the use of MXenzyme as a remedial nanoplatform to treat ROS-mediated inflammatory and neurodegenerative diseases.

2-methylbenzoyl berbamine, a multi-targeted inhibitor, suppresses the growth of human osteosarcoma through disabling NF-κB, ERK and AKT signaling networks.

Osteosarcoma is the most common malignant bone tumor in children and young adults, and it has a survival rate of only 60% with current cytotoxic chemotherapy combined with aggressive surgery. The aim of this study was to evaluate the therapeutic efficacy of the berbamine derivative 2-methylbenzoyl berbamine (BBD24) for osteosarcoma in vitro and in vivo. We used human osteosarcoma cell lines, primary osteosarcoma cells and mouse models to evaluate the inhibitory effects of BBD24 on osteosarcoma and to determine the molecular mechanism. Our results showed that BBD24 inhibited the growth of the human osteosarcoma cell lines HOS and MG63 in a time- and dose-dependent manner. BBD24 also exhibited significant inhibitory effects on primary osteosarcoma cells. In contrast, BBD24 did not affect normal blood cells under the same conditions. Treatment with BBD24 induced apoptosis, necrosis and autophagy in osteosarcoma cells. Western blot analysis revealed that BBD24 activated the caspase-dependent pathway and downregulated the NF-kB, AKT, and ERK pathways. Finally, BBD24 treatment induced a significant inhibitory effect on the growth of osteosarcoma in nude mice. Our findings indicate that BBD24 is a multitarget inhibitor and may represent a new type of anticancer agent for osteosarcoma treatment.

Modified ZIF-8 Nanoparticles Attenuate Osteoarthritis by Reprogramming the Metabolic Pathway of Synovial Macrophages.

Accumulating evidence suggests that activation of proinflammatory M1-type macrophages in the synovium plays a vital role in the progression of osteoarthritis (OA). Redundant nitric oxide (NO) and hydrogen peroxide (H2O2) are key factors that drive macrophages to polarize to the M1 type. Herein, modified zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs) have been synthesized. By regulating intracellular gases and reprogramming the metabolism phenotype, modified NPs transformed macrophage polarization from proinflammatory M1 to anti-inflammatory M2 phenotype. Specifically, S-methylisothiourea hemisulfate salt was loaded into ZIF-8 NPs to inhibit inducible nitric oxide synthase, hence reducing NO production. Catalase was encapsulated to catalyze the production of oxygen (O2) from H2O2. Results demonstrated that modified NPs were capable of catalyzing H2O2 to produce O2 and eliminate NO, hence inhibiting hypoxia-inducible factor 1α, further rescuing mitochondrial function. Moreover, anti-CD16/32 antibody modification could prolong the retention time of NPs in knee joints of OA mice with anterior cruciate ligament transection. More significantly, modified NPs suppressed M1 macrophages and up-regulated M2 macrophage infiltration in the synovium, further inhibiting cartilage degeneration. This ZIF-8 NP-based gas regulation and metabolic reprogramming strategy may pave a new avenue for OA treatment.

Enzyme-Instructed Peptide Assemblies Selectively Inhibit Bone Tumors.

Alkaline phosphatases (ALP) contribute to immunosuppression in solid tumors, but they, unfortunately, are "undruggable". Here we report enzyme-instructed assembly of peptides for selectively inhibiting the tumors that overexpress ALP. We developed a precursor with two parts; an amphiphilic, self-assembling peptides joined to a hydrophilic block (i.e., tyrosine phosphate). ALP, overexpressed on and in osteosarcoma cancer cells (e.g., Saos-2), cleaves the phosphates from the tyrosine residue of the precursor and triggers the self-assembly of the resulting peptides. Being selectively formed on and inside the cancer cells, the peptide assemblies induce the cancer cell death and efficiently inhibit the tumor growth in an orthotopic osteosarcoma mice model without harming normal organs. Accordingly, the peptide assemblies significantly improve the survival ratio of metastatic tumor bearing mice. Without relying on inhibiting ALP, this approach integrates enzyme reaction and molecular self-assembly for generating peptide fibrils as potential anticancer therapeutics.