The BRD4-SRPK2-SRSF2 signal modulates the splicing efficiency of ACSL3 pre-mRNA and influences erastin-induced ferroptosis in osteosarcoma cells.

Lipid metabolism is the key to ferroptosis susceptibility. However, little is known about the underlying mechanisms in osteosarcoma cells. Functional restriction of bromodomain-containing protein 4 (BRD4) reduced the susceptibility to erastin-induced ferroptosis of osteosarcoma cells both in vitro and in vivo. Mechanically, BRD4 controls the splicing efficiency of the RNA precursor (pre-mACSL3) of ACSL3 (ACSL3) by recruiting serinerich/threonine protein kinase 2 (SRPK2) to assemble the splicing catalytic platform. Moreover, the AMP-binding domain of ACSL3 significantly influences arachidonic acid synthesis and thus determines the susceptibility to erastin-induced ferroptosis. Overall, we found a BRD4-mediated pre-mACSL3 splicing influences erastin-induced ferroptosis by affecting arachidonic acid synthesis in osteosarcoma cells. Data in this study fills some of the gap in understanding the post-transcriptional regulatory mechanisms of ACSL3 and provides new insights into the mechanisms of lipid metabolism regulation and its effect on susceptibility to ferroptosis in osteosarcoma cells.

Epidemiological updates of post-traumatic related limb osteomyelitis in china: a 10 years multicentre cohort study.

BACKGROUND: Post-traumatic related limb osteomyelitis (PTRLO) is a complex bone infection. Currently, there are no available microbial data on a national scale that can guide appropriate antibiotic selection, and explore the dynamic changes in dominant pathogens over time. This study aimed to conduct a comprehensive epidemiological analysis of PTRLO in China. METHODS: The study was approved by the Institutional Research Board (IRB), and 3526 PTRLO patients were identified from 212 394 traumatic limb fracture patients at 21 hospitals between 1 January 2008 and 31 December 2017. A retrospective analysis was conducted to investigate the epidemiology of PTRLO, including changes in infection rate (IR), pathogens, infection risk factors and antibiotic resistance and sensitivity. RESULTS: The IR of PTRLO increased gradually from 0.93 to 2.16% (Z=14.392, P <0.001). Monomicrobial infection (82.6%) was significantly higher than polymicrobial infection (17.4%) ( P <0.001). The IR of Gram-positive (GP) and Gram-negative (GN) pathogens showed a significant increase from the lowest 0.41% to the highest 1.15% (GP) or 1.62% (GN), respectively. However, the longitudinal trend of GP vs. GN's composition did not show any significance (Z=±1.1918, P >0.05). The most prevalent GP strains were Methicillin-sensitive Staphylococcus aureus (MSSA) (17.03%), Methicillin-resistant Staphylococcus aureus (MRSA) (10.46%), E. faecalis (5.19%) and S. epidermidis (4.87%). In contrast, the dominant strains GN strains were Pseudomonas Aeruginosa (10.92%), E. cloacae (10.34%), E. coli (9.47%), Acinetobacter Baumannii (7.92%) and Klebsiella Pneumoniae (3.33%). In general, the high-risk factors for polymicrobial infection include opened-fracture (odds ratio, 2.223), hypoproteinemia (odds ratio, 2.328), and multiple fractures (odds ratio, 1.465). It is important to note that the antibiotics resistance and sensitivity analysis of the pathogens may be influenced by complications or comorbidities. CONCLUSIONS: This study provides the latest data of PTRLO in China and offers trustworthy guidelines for clinical practice. (China Clinical Trials.gov number, ChiCTR1800017597).

Efficacy and safety of platelet-rich plasma combined with hyaluronic acid versus platelet-rich plasma alone for knee osteoarthritis: a systematic review and meta-analysis.

PURPOSE: To systematically evaluate the curative efficacy and safety of platelet-rich plasma (PRP) combined with hyaluronic acid (HA) in the treatment of knee osteoarthritis (KOA), comparing with platelet-rich plasma alone. METHODS: Cochrane Library, PubMed, China National Knowledge Infrastructure (CNKI) and Embase were searched for randomized controlled trials (RCTs) and cohort studies regarding the efficacy and safety of platelet-rich plasma (PRP) combined with hyaluronic acid (HA) in the treatment of knee osteoarthritis (KOA) comparing with platelet-rich plasma alone before January 15, 2022. The methodological quality of the ultimately included studies was assessed comprehensively, and meta-analysis was implemented using RevMan 5.3 software. RESULTS: Thirteen articles (9 RCTs, 4 cohort studies), including 1118 patients, were covered. There was no significant difference between the PRP + HA therapy and PRP-alone therapy in VAS scores at 3 months, 6 months and 12 months, WOMAC total scores at 3 months and KOOS at 1 month and 6 months. Compared with PRP-alone therapy, PRP + HA therapy was associated with significantly better improvement in VAS scores at 1 month, WOMAC total scores at 6 months, KOOS at 3 months, IKDC scores at 6 months and Lequesne index scores at 3 and 6 months. However, the smallest treatment effect of VAS scores, WOMAC total scores, KOOS and IKDC scores did not exceed the minimum clinically important difference (MCID). However, PRP + HA therapy got a greater reduction in the rate of adverse events, compared with PRP-alone therapy. CONCLUSION: The results of this meta-analysis indicated that PRP + HA therapy was not found to be superior to PRP-alone therapy in pain relief and function improvement for patients with KOA. However, combined PRP with HA injections was generally safer than PRP injections alone, by assessing the incidence of adverse events.

Single Modified Posterior Approach through the Space of the Proximal Radioulnar Joint for Terrible Triad Injury: A Comparative Study.

OBJECTIVE: In order to reduce surgical scars and the risk of neurovascular injury for the treatment of terrible triad injuries of the elbow (TTI), minimally invasive and better therapeutic effect approaches are being explored to replace the conventional combined lateral and medial approach (CLMA). This study was performed to compare the clinical effect and security of the modified posterior approach (MPA) through the space of the proximal radioulnar joint vs the CLMA for treatment of TTI. METHODS: This study retrospectively analyzed 76 patients treated for TTI from January 2009 to December 2020 (MPA: n = 44; CLMA: n = 32). Treatment involved plate and screw fixation or Steinmann pin fixation for the radial head and ulnar coronoid process fractures. Surgeons only sutured the lateral ligament because the medial collateral ligament was usually integrated in the TTI. The continuous variables were compared by the independent Student t-test and the categorical variables by the χ2 -test or Fisher's exact test. RESULTS: Both groups of patients attained a satisfactory MEPS after the operation. The MEPS (MPA: 96.82 ± 6.04 vs CLMA: 96.56 ± 5.51) was not significantly different between the two groups (p > 0.05). However, the MPA resulted in better elbow flexion and extension (MPA: 123.98 ± 10.09 vs CLMA: 117.66 ± 8.29), better forearm rotation function (MPA: 173.41 ± 6.81 vs CLMA: 120.00 ± 12.18), and less intraoperative hemoglobin (MPA: 9.34 ± 5.64 vs CLMA: 16.5 ± 8.75) and red cell volume loss (MPA: 3.09 ± 2.20 vs CLMA: 6.70 ± 2.97) (All p < 0.05). Although the CLMA had a shorter surgery time (MPA: 171.73 ± 80.68 vs CLMA: 130.16 ± 71.50) (p < 0.05), it had a higher risk of neurologic damage (MPA: 0 vs CLMA: 4) (p < 0.05). Four patients developed forearm or hand numbness after the CLMA, but no patients developed numbness after the MPA. All 76 patients were followed up for 15 months postoperatively. CONCLUSION: The MPA through the space of the proximal radioulnar joint has more prominent advantages than the CLMA for TTI, including single scar, clear exposure, good fixation, lower risk of neurovascular injury, and better elbow joint motion. It is a safe and effective surgical approach that is worthy of clinical promotion.

Distally Based Peroneal Artery Perforator-Plus Fasciocutaneous Flap to Reconstruct Soft Tissue Defect Combined With Chronic Osteomyelitis in the Lateral Malleolus.

Distally based peroneal artery perforator-plus fasciocutaneous (DPAPF) flaps are widely used to reconstruct soft tissue defects of the lower extremity. Treatment for soft tissue defect combined with chronic osteomyelitis in the lateral malleolus has rarely been reported. The aim of this study was to elaborate the superiority of the DPAPF flap and provide referential experience for using the DPAPF flap in this situation. Between June 2010 and December 2017, soft tissue defects in the setting of chronic osteomyelitis in the lateral malleolus were reconstructed with DPAPF flaps in 17 patients. After thorough debridement, the defect was repaired with the DPAPF flap, and patients subsequently followed an antibiotic regimen for 6 weeks. Follow-up periods for all patients were at least 24 months. The reconstruction outcomes and the satisfaction of the 17 patients were evaluated. Of the 17 flaps, 16 survived uneventfully, except one occurrence of partial necrosis. No infection occurred in the follow-up period. In the study, 17 patients except one were satisfied with flap appearance. All the patients were satisfied with the reconstruction outcomes. In a one-stage procedure, the use of DPAPF flaps is ideal for reconstructing soft tissue defects in the setting of chronic osteomyelitis in the lateral malleolus.

Old unreduced obturator dislocation of the hip: A case report.

BACKGROUND: Obturator dislocation is a rare type of hip dislocation, accounting for about 2%-5% of all hip dislocations. The occurrence of old unreduced obturator dislocation is even more infrequent, with only 17 cases reported in nine studies, most of which were from the 1950s to 1980s in developing countries. CASE SUMMARY: A 38-year-old woman from Hunan Province, China presented with stiffness of the left hip in abduction, flexion, and external rotation after falling from a 2-meter-tall tree onto her left knee 1.5 mo prior. Pelvic radiograph and computed tomography revealed obturator dislocation of the left hip accompanied by impaction fracture at the superolateral aspect of the left femoral head without associated acetabulum fracture. Open reduction was performed, resulting in restoration of the concentric alignment of the left hip. After surgery, 6-wk skin traction was applied and the patient was kept in bed for an additional 2 wk. At 3 mo after surgery, the patient reported experiencing some pain, which did not affect the function of the affected limb, and some movement restriction but no abduction deformity or claudication was present. An X-ray showed that the left hip was homocentric, and there was no sign of posttraumatic arthritis or avascular necrosis. CONCLUSION: Open reduction may be an effective treatment strategy for the rare condition of old unreduced obturator dislocation with short neglect time.

miR-19b enhances osteogenic differentiation of mesenchymal stem cells and promotes fracture healing through the WWP1/Smurf2-mediated KLF5/ß-catenin signaling pathway.

Bone marrow mesenchymal stem cell (BMSC)-derived exosomes have been found to enhance fracture healing. In addition, microRNAs contributing to the healing of various bone fractures have attracted widespread attention in recent years, but knowledge of the mechanisms by which they act is still very limited. In this study, we clarified the function of altered microRNA-19b (miR-19b) expression in BMSCs in fracture healing. We modulated miR-19b expression via mimics/inhibitors in BMSCs and via agomirs in mice to explore the effects of these changes on osteogenic factors, bone cell mineralization and the healing status of modeled fractures. Through gain- and loss-of function assays, the binding affinity between miR-19b and WWP1/Smurf2 was identified and characterized to explain the underlying mechanism involving the KLF5/ß-catenin signaling pathway. miR-19b promoted the differentiation of human BMSCs into osteoblasts by targeting WWP1 and Smurf2. Overexpression of WWP1 or Smurf2 degraded the target protein KLF5 in BMSCs through ubiquitination to inhibit fracture healing. KLF5 knockdown delayed fracture healing by modulating the Wnt/ß-catenin signaling pathway. Furthermore, miR-19b enhanced fracture healing via the KLF5/ß-catenin signaling pathway by targeting WWP1 or Smurf2. Moreover, miR-19b was found to be enriched in BMSC-derived exosomes, and treatment with exosomes promoted fracture healing in vivo. Collectively, these results indicate that mesenchymal stem cell-derived exosomal miR-19b represses the expression of WWP1 or Smurf2 and elevates KLF5 expression through the Wnt/ß-catenin signaling pathway, thereby facilitating fracture healing.

Use of a Double Reverse Traction Repositor versus a Traction Table for the Treatment of Intertrochanteric Femur Fractures: A Comparative Study.

OBJECTIVE: The aim of the present study was to compare the clinical results for unstable femoral intertrochanteric fractures treated with a double reverse traction repositor (DRTR) and those treated using a traction table with the Asia proximal femoral nail antirotation (PFNA-II). METHODS: A retrospective study was performed including 95 patients with AO/OTA type 31-A2 and 31-A3 unstable femoral intertrochanteric fractures who underwent DRTR or traction table-facilitated PFNA-II nailing from April 2015 to December 2018 in our traumatic center. Demographics, duration of operation, blood loss, part loading time after surgery, fracture healing time, and early and late complications were assessed. Clinical and radiological outcomes were collected to compare the differences between the two groups. RESULTS: A total of 95 unstable intertrochanteric fracture patients treated with the PFNA-II were analyzed. Of these cases, 56 patients were treated with a DRTR and the other 39 patients were treated using a traction table to achieve fracture reduction. No patients died during surgery and hospitalization. There were no significant differences in respect to demographics and fracture characteristics of cases enrolled. The total operative time was significantly longer in the traction table group than in the DRTR group (72.5 ± 6.1 min for the traction table and 63.0 ± 4.1 min for the DRTR group, P < 0.001). No significant differences were observed in intraoperative blood loss and duration of hospitalization. The periods of follow up ranged from 12 to 31 months among all patients. At the last follow up, the Harris hip score (HHS) in the DRTR group was excellent in 10 patients (17.9%), good in 36 (64.3%), fair in 8 (14.3%), and poor in 2 (3.6%). These scores were comparable to those in the traction table group, which were: excellent in 8 patients (20.5%), good in 24 (61.5%), fair in 6 (15.4%), and poor in 1 (2.6%). Regarding the radiological evaluation, excellent rates of reduction rate were achieved in 39 cases (69.6%) in the DRTR group, which was comparable to 19 cases (48.7%) in the traction table group. In addition, the mean fracture healing time after surgery was 20.6 ± 2.3 weeks in the DRTR group and 21.4 ± 3.4 weeks in the traction table group, which did not reach a significant difference (P = 0.18). During the follow up, 6 cases of thigh pain, 4 cases of deep vein thrombosis, and 1 case of fracture of the anterior superior iliac spine were reported in the DRTR group. In the traction table group, there were 2 cases of deep vein thrombosis and 3 cases of thigh pain. CONCLUSION: When using the PFNA-II for unstable intertrochanteric fractures, the DRTR was superior to the traction table in respect to operative time and duration of patient position, despite an additional ipsilateral anterior superior iliac spine (ASIS) incision and drilling of the ASIS and the femur condyle.

Long non-coding RNA CIR inhibits chondrogenic differentiation of mesenchymal stem cells by epigenetically suppressing ATOH8 via methyltransferase EZH2.

BACKGROUND: Osteoarthritis (OA) is the most common articular disorder, leading to joint malfunction and disability. Although the incidence of OA is increasing globally, the treatment of OA is very limited. LncRNA CIR has been implicated in OA through unclear mechanisms. Here, we investigated the role of lncRNA CIR in chondrogenic differentiation. METHODS: Human umbilical-cord-derived mesenchymal stem cells (hUC-MSCs) were obtained from human umbilical cords. Flow cytometry was used to analyze the surface markers of hUC-MSCs. Various culture conditions and corresponding staining assays were employed to assess the differentiation abilities of hUC-MSC. qRT-PCR, western blot, and immunostaining were used to measure expression levels of related genes and proteins such as lncRNA CIR, ATOH8, EZH2, and H3K27me3. RNA immunoprecipitation assay, biotin pull-down, and chromatin immunoprecipitaion assay were performed to analyze the interactions of lncRNA CIR, EZH2, H3K27me3 and ATOH8 promoter. RESULTS: hUC-MSCs exhibited MSCs features and could differentiate into chondrocytes under specific conditions. LncRNA CIR was downregulated while ATOH8 was upregulated during the chondrogenic differentiation of hUC-MSCs. Knockdown lncRNA CIR or overexpression of ATOH8 promoted chondrogenic differentiation. Further, lncRNA CIR bound to EZH2 and repressed ATOH8 expression via EZH2-mediated H3K27me3, which promotes the methylation of ATOH8. Inhibition of ATOH8 reversed the effects of knockdown lncRNA CIR on chondrogenic differentiation. CONCLUSION: LncRNA CIR suppresses chondrogenic differentiation of hUC-MSCs. Mechanistically, lncRNA CIR could inhibit ATOH8 expression that functions to promote chondrogenic differentiation through EZH2-mediated epigenetic modifications.

Strontium-doped gelatin scaffolds promote M2 macrophage switch and angiogenesis through modulating the polarization of neutrophils.

The immune system mediates inflammation, vascularization and the first response to injuries or implanted biomaterials. Although the function of neutrophils in tissue repair has been extensively studied, its complete role in the tissue regeneration of biomaterials, specifically the resolution of inflammation and promotion of angiogenesis, is unclear. Here, we fabricate nanofibrous gelatin scaffolds containing 10% (w/w) strontium-hydroxyapatite (SrHA) via phase-separation methods to investigate Sr-mediated regulation of neutrophil polarization and, subsequently, the effects on angiogenesis and macrophage polarization. Compared with neutrophils cultured on pure gelatin or HA-incorporated gelatin scaffolds, neutrophils on SrHA-incorporated gelatin scaffolds show more N2 polarization in vitro and in vivo and significantly greater production of immunomodulatory and angiogenic factors. The Sr-induced immunomodulatory and proangiogenic functions of neutrophils are mediated through NF-κB pathway downregulation and increased STAT3 phosphorylation. Thus, neutrophils play a vital role in tissue engineering, and Sr-incorporated scaffolds efficiently promote neutrophil polarization to the N2 phenotype, enhancing resolution of inflammation and ultimately promoting angiogenesis and tissue regeneration. Thus, incorporation of neutrophils in analyses of the immune characteristics of scaffolds and the development of immunomodulatory biomaterials that can regulate neutrophils are novel and promising strategies in tissue engineering.

Utilisation of distally based sural fasciocutaneous flaps in lower extremity reconstruction: a single-centre experience with 88 paediatric patients.

BACKGROUND: No large series have analysed distally based sural fasciocutaneous (DBSF) flaps in paediatric patients. The aims of this study were to assess the reliability and analyse the potential risk factors for these flaps and to describe complications in the donor site and the functional follow-up results. METHODS: Between June 2002 and November 2017, 88 DBSF flaps were used to reconstruct soft tissue defects in paediatric patients. Potential risk factors, reconstruction outcomes, and complications in the donor site of the flaps were analysed. RESULTS: Among the 88 flaps, partial necrosis developed in 8 flaps (9.1%). The partial necrosis rate was significantly higher in flaps with the top edge located in the 9th zone (26.1%), with a length-width ratio (LWR) ≥ 5:1 (28.6%), and with a dimension of the skin island ≥ 100 cm2 (22.7%). Partial necrosis did not occur in flaps with a dimension of the skin island < 80.0 cm2 or with a skin-island width < 7.0 cm. The reconstruction outcomes in most paediatric patients were evaluated as "excellent" or "good". The incidence of obvious scarring was higher in the donor site. CONCLUSIONS: Partial necrosis of DBSF flaps will significantly increase when the top edge of the flap is located in the 9th zone, when the LWR of the flap is ≥ 5:1, or when the dimension of the skin island is ≥ 100.0 cm2. Flaps with a skin-island width < 7.0 cm or with a dimension of the skin island < 80 cm2 are relatively safe and reliable.

Distally based peroneal artery perforator-plus fasciocutaneous flap in the reconstruction of soft tissue defects over the distal forefoot: a retrospectively analyzed clinical trial.

BACKGROUND: Distally based peroneal artery perforator-plus fasciocutaneous (DPAPF) flaps are widely used for reconstructing soft-tissue defects of the lower extremity. However, reports on the reconstruction of the defects over the distal forefoot using the DPAPF flaps are scarce. Herein, we describe our experience on the reconstruction of these defects using DPAPF flaps in a considerable sample size. METHODS: Between February 2005 and August 2019, a total of 56 DPAPF flaps in 56 patients were used to reconstruct soft-tissue defects in the forefoot. In order to reduce the length of fascial pedicle and the total length of the DPAPF flaps, the ankles were fixed in dorsiflexion using a Kirschner wire before designing the flaps. The flaps were elevated by the anterograde-retrograde approach. Patient factors and flap factors were compared between the "survival" and "partial necrosis" groups. RESULTS: Overall, 47 flaps had survived completely in one stage. Partial necrosis developed in nine flaps, with only one remnant defect covered using a local flap. By fixing the ankles in dorsiflexion, the length of the fascial pedicle was reduced approximately 2.35 ± 0.58 cm, the total length of the flap was simultaneously shortened by the same amount as the length of the fascial pedicle. The width of the fascia pedicle varied from 3.0 cm to 6.0 cm. The fascial pedicle width > 4 cm was found in 21 flaps. The partial necrosis rate of the DPAPF flaps with the top edge located in the 8th zone was significantly lower than that in the 9th zone (p < 0.05). CONCLUSIONS: The DPAPF flaps can be effectively used to reconstruct the defects over the distal forefoot because of convenient harvest and reliability. By fixing the ankle in dorsiflexion with Kirschner wire and widening the fascial pedicle appropriately, the top edge and LWR of the flaps will be decreased, and thus the procedures are helpful for the flaps survival.

LncRNA TDRG1 Promotes Proliferation, Invasion and Epithelial-Mesenchymal Transformation of Osteosarcoma Through PI3K/AKT Signal Pathway.

OBJECTIVE: This study aimed to investigate the effect of long non-coding TDRG1 on proliferation and migration of osteosarcoma cells through PI3K/AKT signaling pathway. MATERIALS AND METHODS: Altogether 87 cases of osteosarcoma tissues and adjacent tissues were collected, and osteosarcoma cells and osteoblasts were purchased. The expression of LncRNA TDRG1 in tissues and cells was detected by RT-PCR. Si-NC, si-TDRG1, and Sh-TDRG1 were transfected into osteosarcoma cells. L740Y-P (activator of PI3K/AKT pathway) and LY294002 (inhibitor of PI3k/AKT pathway) were used to interfere with PI3k/Akt signaling pathway in osteosarcoma cells. qRT-PCR was used to detect the expression of TDRG1 in osteosarcoma tissues and cells. WB was used to detect the expression of p-PI3K, p-AKT, N-cadherin, E-Cadherin, vimentin, Bax, Caspase-3, and Bcl-2 in cells. CCK-8, Transwell and cell scratch tests were used to detect cell proliferation, invasion and migration, and flow cytometry was used to detect cell apoptosis. RESULTS: TDRG1 was highly expressed in osteosarcoma, and the levels of p-PI3K and p-AKT were also up-regulated. Cell experiments showed that inhibiting the expression of TDRG1 could inhibit the proliferation, invasion, migration and EMT of osteosarcoma cells, promote the apoptosis of cells, and up-regulating the expression of TDRG1 could promote the proliferation, invasion, migration and EMT of osteosarcoma cells and inhibit the apoptosis of cells. The 740Y-P intervention could reverse the inhibition of Si-TDRG1 on osteosarcoma cell proliferation, invasion, migration and EMT and the promotion of cell apoptosis. LY294002 intervention could reverse the promotion of Sh-TDRG1 on osteosarcoma cell proliferation, invasion, migration and EMT and the inhibition of cell apoptosis. CONCLUSION: TDRG1 is highly expressed in osteosarcoma tissue. Silencing the expression of osteosarcoma can inhibit the proliferation, invasion, migration and EMT of osteosarcoma cells by inhibiting PI3K/AKT signaling pathway, which may be a new target for diagnosis and treatment of osteosarcoma.

The Sp1/FOXC1/HOTTIP/LATS2/YAP/ß-catenin cascade promotes malignant and metastatic progression of osteosarcoma.

The prognosis for osteosarcoma (OS) is dismal due to the aggressive tumor growth and high incidence of metastasis. The long noncoding RNA human homeobox A transcript at the distal tip (HOTTIP) and the transcription factor forkhead box C1 (FOXC1) present oncogenic activities in OS. Here, we aimed at gaining insights into the underlying mechanisms and their crosstalk. The expression of FOXC1 and HOTTIP in OS tissues or cell lines was examined by real-time PCR (RT-PCR) and western blot. The in vitro effects of FOXC1 or HOTTIP on cell viability, proliferation, migration, invasion, and expression of target genes were examined using MTT, colony-forming assay, wound-healing, Transwell invasion, and western blot, respectively; the in vivo effects were examined using xenograft and experimental metastasis models. Molecular control of HOTTIP on large tumor suppressor 2 (LATS2) or transactivation of FOXC1 or Sp1 on HOTTIP was assessed by combining RNA immunoprecipitation, qRT-PCR, western blot, ChIP, and luciferase assay. Both FOXC1 and HOTTIP were potently up-regulated in OS tissues and cell lines. FOXC1 and HOTTIP essentially maintained viability, proliferation, migration, and invasion of OS cells in vitro and contributed to xenograft growth or lung metastasis in vivo. Mechanistically, HOTTIP recruited enhancer of zeste homolog 2 (EZH2) and lysine-specific demethylase 1 (LSD1) to silence LATS2 and thus activated YAP/ß-catenin signaling. Upstream, Sp1 activated FOXC1 and they both directly transactivated HOTTIP. In summary, we showed that the Sp1/FOXC1/HOTTIP/LATS2/YAP/ß-catenin cascade presented oncogenic activities in OS cells. Targeting FOXC1 or HOTTIP may therefore prove beneficial for OS treatment.

Unusual presentation of congenital radioulnar synostosis with osteoporosis, fragility fracture and nonunion: A case report and review of literature.

BACKGROUND: Congenital radioulnar synostosis (CRUS) is a rare deformity of the upper extremity. It is characterized by loss of rotation of the involved forearm and functional limitations in daily activities. No studies on CRUS with osteoporosis have been reported to date, and osteoporosis is usually recognized as an important dimension of genetic disorder in children. We discuss the possible relationship among this disorder, osteoporosis and fracture nonunion, investigate the strict surgical indications and recommended treatments. CASE SUMMARY: A 14-year-old male patient with bilateral CRUS with osteoporosis, fragility fracture and nonunion of fractures in ulna and radius presented our institution for further treatment, complaining of limitation in rotation. The bone mineral density of the hip and lumbar spine was 0.687 g/cm2 and 0.705 g/cm2, respectively, and the Z-score for both was -2.1, which revealed osteoporosis and a high risk of fracture. Tow serum bone turnover markers indicated an imbalance of bone metabolism. Reoperation for ulna fracture with autogenous bone grafting and a postoperative physiotherapy program were adopted rather than the separation of pathological synostosis. Radiological examination, observational posture assessment and limb function scale were evaluated before and 1 year after surgery. At 1 year, the fracture nonunion had almost recovered, forearm movement function on the fracture side was restored, and function on the healthy side was significantly improved compared with that before rehabilitation. CONCLUSION: Surgical indications for CRUS vary from person to person. Surgery should not be the first choice of treatment, and physiotherapy is not inferior to surgical treatment.

The regulatory effect of has-circ-0001146/miR-26a-5p/MNAT1 network on the proliferation and invasion of osteosarcoma.

Osteosarcoma is a malignant bone tumour with the lowest survival rates out of all paediatric cancers and is primarily diagnosed in children and adolescents. MNAT1 is a subunit in the cyclin-dependent kinase-activating kinase complex. Abnormal up-regulation of MNAT1 has been associated with the poor prognosis of multiple cancers. Bioinformatics analysis showed that has-circ-0001146 and miR-26a-5p were involved in the regulation of MNAT1 in osteosarcoma. The present study investigated the regulatory effects of has-circ-0001146 and miR-26a-5p on MNAT1 expression using luciferase reporter and RNA-pull down assays. The effects of the has-circ-0001146/miR26a-5p/Mnat1 network on the proliferation and invasion of osteosarcoma were evaluated by cell viability, apoptosis, migration, and invasion assays. Osteosarcoma tissues showed higher MNAT1 and has-circ-0001146 expression than adjacent normal tissues, although the expression of MNAT1 was not significantly up-regulated in sarcomas according to TCGA databases. As indicated by luciferase reporter and RNA-pull down assays, miR-26a-5p was able to bind to both has-circ-0001146 and MNAT1 mRNA. The depletion of has-circ-0001146 as well as the increase of miR-26a-5p decreased MNAT1 expression in osteosarcoma cells, while the reduction of miR-26a-5p was associated with increased MNAT1 expression. These data suggested that has-circ-0001146 promoted MNAT1 expression by competitively binding to miR-26a-5p with MNAT1 mRNA. The depletion of has-circ-0001146 or MNAT1 or the increase of miR-26a-5p inhibited osteosarcoma cell viability and invasion, and increased apoptosis. Reduction of miR-26a-5p conversely promoted osteosarcoma cell viability and invasion. The present study confirmed that has-circ-0001146 blocked miR-26a-5p targeting MNAT1 in osteosarcoma cells, thereby promoting the malignant behaviours of osteosarcoma cells.

Is hip fracture surgery safe for patients on antiplatelet drugs and is it necessary to delay surgery? A systematic review and meta-analysis.

BACKGROUND: Hip fractures are common and account for a large proportion of orthopedic surgical admissions in elderly patients. However, determining the timing for surgery has been controversial for patients who develop hip fractures while on antiplatelet treatment. METHODS: Computerized databases for studies published from the inception date to January 2020, including the Cochrane Library, PubMed (Medline), EMBASE, Web of ScienceTM, ClinicalTrials, ClinicalKey, and Google Scholar, were searched using the keywords "Hip AND Fracture", "Antiplatelet", "Antithrombocyte", "Platelet aggregation inhibitors", "Aspirin", "Plavix", and "Clopidogrel". RESULTS: In total, 2328 initial articles were identified. Twenty-four studies with 5423 participants were ultimately included in our analysis. Early surgery was associated with an increased transfusion rate in the antiplatelet group compared to the non-antiplatelet group (OR = 1.21; 95% CI, 1.01 to 1.44; p = 0.03). Early surgery for hip fracture patients on antiplatelet therapy was associated with a greater decrease in hemoglobin compared to delayed surgery (WMD = 0.75; 95% CI, 0.50 to 1.00; p < 0.001). However, early surgery appeared to decrease the length of hospitalization (WMD = - 6.05; 95% CI, - 7.06 to - 5.04; p < 0.001) and mortality (OR = 0.43; 95% CI, 0.23 to 0.79; p = 0.006). CONCLUSION: It is unnecessary to delay surgery to restore platelet function when patients with hip fractures receive antiplatelet therapy. Furthermore, early surgery can significantly reduce mortality and hospital stay, which is conducive to patient recovery. Future randomized trials should determine whether the results are sustained over time.

Comparison between distally based peroneal and posterior tibial artery perforator-plus fasciocutaneous flap for reconstruction of the lower extremity.

BACKGROUND: Distally based peroneal artery perforator-plus fasciocutaneous (DPAPF) flaps and distally based posterior tibial artery perforator-plus fasciocutaneous (DPTAPF) flaps are widely used to reconstruct soft-tissue defects of the distal lower leg, ankle, and foot. However, a comparative study of both flaps in a considerable sample size is lacking. This retrospective study aimed to compare the efficacy of the flaps and provide referential evidence for selection of flaps. METHODS: Between April 2001 and October 2016, 227 patients underwent reconstruction with DPAPF flaps (peroneal group; n = 150) or DPTAPF flaps (posterior tibial group; n = 82). The distal lower leg, ankle, and foot were divided into Zones I and II. Flap viability-related complications and their risk factors, reconstruction outcomes, and donor-site morbidities were compared. RESULTS: In Zone I, the partial necrosis rate was lower in the peroneal group than in the posterior tibial group (p > 0.05). In Zone II, the partial necrosis rate was significantly lower in the peroneal group (p < 0.05). Significantly lower incidences of donor-site morbidities in terms of hypertrophic scarring, itching, and pigmentation were observed in the peroneal group (p < 0.05). CONCLUSIONS: The DPAPF flap was superior to the DPTAPF flap with respect to reliability and decreased donor-site morbidities. The former is the recommended preferential choice between the two.

Proanthocyanidins attenuate breast cancer-induced bone metastasis by inhibiting Irf-3/c-jun activation.

We have previously demonstrated the pivotal role of Jnk-mediated Irf-3/c-Jun in regulating nuclear factor kappa-Β ligand (RANKL)-induced osteoclastogenesis. Here, we demonstrated that proanthocyanidins (PACs) target Irf-3 to alleviate breast cancer-induced activation of osteoclasts. We also found that PACs induced apoptosis of osteoclast precursors by upregulating the ratio of bax/bcl-2 and activating caspase-3 activity. Such bone protective effect also could be observed in a bone metastasis model of breast cancer. These findings provided a novel therapeutic intervention targeting abnormal bone metabolism to alleviate bone metastasis of breast cancer.

Long non-coding RNA MEG3 inhibits chondrogenic differentiation of synovium-derived mesenchymal stem cells by epigenetically inhibiting TRIB2 via methyltransferase EZH2.

Osteoarthritis (OA) is a highly prevalent skeletal disease. Mesenchymal stem cell-derived cartilage tissue engineering is a clinical method used for OA treatment. Investigations on the molecular regulatory mechanisms of the chondrogenic differentiation of synovium-derived mesenchymal stem cells(SMSCs) will help promote its clinical applications. In this study, bioinformatics analysis from three different databases indicated that the long non-coding RNA (lncRNA) MEG3 may regulate the chondrogenic differentiation of SMSCs by targeting TRIB2. We then performed assays and found that both knockdown of MEG3 or overexpression of TRIB2 can stimulate the chondrogenic differentiation of SMSCs and increase Col2A1 and aggrecan expression. Knockdown of MEG3 can induce the expression of TRIB2; conversely, overexpression of MEG3 can inhibit the expression of TRIB2. Futhermore, knockdown of the TRIB2 can rescue the MEG3 silencing-mediated promotion of chondrogenic differentiation. Moreover, RNA immunoprecipitation(RIP) and RNA pull-down assays demonstrated that MEG3 can interact with EZH2, thus recruiting it to induce H3K27me3, which promotes the methylation of TRIB2 by binding with the promoter of TRIB2 in SMSCs. Additionally, EZH2 silencing significantly rescued the MEG3 overexpression-mediated inhibition of TRIB2 expression and chondrogenic differentiation of SMSCs. Taken together, these data indicated that MEG3 regulates chondrogenic differentiation by inhibiting TRIB2 expression through EZH2-mediated H3K27me3.