Endoscopic double line suture repair technique for repairing Iatrogenic dural tear: a technical case report.

PURPOSE: Introducing a suture repair technology, endoscopic double line suture repair technique, for iatrogenic dural injury during Percutaneous Endoscopic Lumbar Discectomy (PELD) surgery. METHODS: A patient with dural injury and cauda equina herniation during PELD surgery was treated with endoscopic double line suture repair technique. RESULTS: A patient with dural injury and cauda equina nerve herniation during PELD surgery was successfully treated using double-line suture technique. After the repair, no obvious cerebrospinal fluid leakage and cauda equina nerve re-herniation was seen. During the postoperative observation period, the wound healed well and there were no complications related to cerebrospinal leakage. During the follow-up period (1 year), the patient reported significant symptom relief and no complications. CONCLUSION: This novel dural repair technology is safe and effective and can be used to treat dural injuries during PELD surgery.

Impaired glucose metabolism underlies articular cartilage degeneration in osteoarthritis.

Osteoarthritis (OA) is the leading joint disease characterized by cartilage destruction and loss of mobility. Accumulating evidence indicates that the incidence and severity of OA increases with diabetes, implicating systemic glucose metabolism in joint health. However, a definitive link between cellular metabolism in articular cartilage and OA pathogenesis is not yet established. Here, we report that in mice surgically induced to develop knee OA through destabilization of medial meniscus (DMM), expression of the main glucose transporter Glut1 is notably reduced in joint cartilage. Inducible deletion of Glut1 specifically in the Prg4-expressing articular cartilage accelerates cartilage loss in DMM-induced OA. Conversely, forced expression of Glut1 protects against cartilage destruction following DMM. Moreover, in mice with type I diabetes, both Glut1 expression and the rate of glycolysis are diminished in the articular cartilage, and the diabetic mice exhibit more severe cartilage destruction than their nondiabetic counterparts following DMM. The results provide proof of concept that boosting glucose metabolism in articular chondrocytes may ameliorate cartilage degeneration in OA.

Echinatin inhibits the growth and metastasis of human osteosarcoma cells through Wnt/ß-catenin and p38 signaling pathways.

Osteosarcoma (OS) is a highly aggressive malignant bone tumor that mainly occurs in adolescents. At present, chemotherapy is the most commonly used method in clinical practice to treat OS. However, due to drug resistance, toxicity and long-term side effects, chemotherapy can't always provide sufficient benefits for OS patients, especially those with metastasis and recurrence. Natural products have long been an excellent source of anti-tumor drug development. In the current study, we evaluated the anti-OS activity of Echinatin (Ecn), a natural active component from the roots and rhizomes of licorice, and explored the possible mechanism. We found that Ecn inhibited the proliferation of human OS cells and blocked cell cycle at S phase. In addition, Ecn suppressed the migration and invasion, while induced the apoptosis of human OS cells. However, Ecn had less cytotoxicity against normal cells. Moreover, Ecn inhibited the xenograft tumor growth of OS cells in vivo. Mechanistically, Ecn inactivated Wnt/ß-catenin signaling pathway while activated p38 signaling pathway. ß-catenin over-expression and the p38 inhibitor SB203580 both attenuated the inhibitory effect of Ecn on OS cells. Notably, we demonstrated that Ecn exhibited synergistic inhibitory effect with cisplatin (DDP) on OS cells in vitro and in vivo. Therefore, our results suggest that Ecn may exert anti-OS effects at least partly through regulating Wnt/ß-catenin and p38 signaling pathways. Most meaningfully, the results obtained suggest a potential strategy to improve the DDP-induced tumor-killing effect on OS cells by combining with Ecn.

Is Helicobacter pylori infection associated with osteoporosis? a systematic review and meta-analysis.

INTRODUCTION: This study used systematic review and meta-analysis to evaluate the association between Helicobacter pylori infection and osteoporosis. MATERIALS AND METHODS: PubMed, Ovid and Web of Science were searched to include observational studies published in English comparing bone mineral density changes between Helicobacter pylori-positive and -negative participants. The quality of the included literature was assessed using the Newcastle-Ottawa Quality Assessment Scale (NOS). R software was used for meta-analysis, and odds ratio (OR) and 95% confidence interval (CI) were calculated to evaluate the relationship between Helicobacter pylori infection and osteoporosis. RESULTS: Twenty-two studies involving 24,176 participants were included in the study. Our meta-analysis showed that Helicobacter pylori infection was significantly associated with the risk of osteoporosis (OR: 1.12, 95%CI: 1.03, 1.22). Participants infected with the CagA-positive Helicobacter pylori strain were more likely to develop osteoporosis (OR = 1.42, 95%CI: 1.09; 1.85). CONCLUSION: Infection with Helicobacter pylori, particularly the CagA-positive strain, has been associated with an increased risk of osteoporosis. The bone health of Helicobacter pylori-positive patients deserves more attention.

Exploration of the Shared Hub Genes and Biological Mechanism in Osteoporosis and Type 2 Diabetes Mellitus based on Machine Learning.

A substantial amount of evidence suggests a close relationship between osteoporosis (OP) and Type 2 Diabetes Mellitus (T2DM), but the mechanisms involved remain unknown. Therefore, we conducted this study with the aim of screening for hub genes common to both diseases and conducting a preliminary exploration of common regulatory mechanisms. In the present study, we first screened genes significantly associated with OP and T2DM by the univariate logistic regression algorithm. And then, based on cross-analysis and random forest algorithm, we obtained three hub genes (ACAA2, GATAD2A, and VPS35) and validated the critical roles and predictive performance of the three genes in both diseases by differential expression analysis, receiver operating characteristic (ROC) curves, and genome wide association study (GWAS) analysis. Finally, based on gene set enrichment analysis (GSEA) and the construction of the miRNA-mRNA regulatory network, we conducted a preliminary exploration of the co-regulatory mechanisms of three hub genes in two diseases. In conclusion, this study provides promising biomarkers for predicting and treating both diseases and offers novel directions for exploring the common regulatory mechanisms of both diseases.

Cement leakage in percutaneous vertebroplasty for spinal metastases: a retrospective study of risk factors and clinical outcomes.

OBJECTIVE: The objective of this research was to investigate the risk factors of cement leakage in patients with metastatic spine tumors following percutaneous vertebroplasty (PVP). METHODS: Sixty-four patients with 113 vertebrae were retrospectively reviewed. Various clinical indexes, including age, sex, body mass index (BMI), smoking history, drinking history, chemotherapy history, radiotherapy history, primary cancer, location, other metastases, collapse, posterior wall defects, the laterality of injection, and the injected cement volume were analyzed as potential risk factors. Multivariate analyses were conducted to identify the independent risk factors. RESULTS: The cement leakage was found 64 in 113 treated vertebrae (56.63%), in which the incidence of each type was shown as below: spinal canal leakage 18 (15.93%), intravascular leakage around the vertebrae 11 (9.73%), and intradiscal and paravertebral leakage 35 (30.97%). Tomita classification (P = 0.019) and posterior wall destruction (P = 0.001) were considered strong risk factors for predicting cement leakage in general. The multivariate logistic analysis showed that defects of the posterior wall (P = 0.001) and injected volume (P = 0.038) were independently related to the presence of spinal canal leakage. The postoperative visual analog scale (VAS) and activities of daily living (ADL) scores showed significant differences compared with the pre-operative parameters (P < 0.05). No significant differences were found in every follow-up time between the leakage group and the non-leakage group for pain management and improvement of activities in daily life. CONCLUSION: In our study, Tomita classification and the destruction of the posterior wall were independent risk factors for leakage in general. The defects of the posterior wall and injected volume were independently related to the presence of spinal canal leakage. The PVP procedure can be an effective way to manage the pain.

Reliability of different smartphones measuring the hallux valgus parameters in a new rapid method: a follow-up study.

OBJECTIVE: This study aimed to further compare the abilities to measure hallux valgus parameters in different smartphones using the intrinsic photograph-editing function. METHODS: We retrospectively reviewed 61 patients (100 feet) of hallux valgus without medical or surgical interventions at our department. The radiographic parameters were assessed and measured via the Picture archiving and communication systems (PACS), iPhone, and Android. The accuracy, reliability, and the time-taken were compared and analyzed between each two methods. RESULTS: The mean value of measured hallux valgus parameters were as follow: hallux valgus angle (HVA): 33.71 ± 7.25°; the first and second intermetatarsal angle (IMA): 12.84 ± 3.62° in PACS; HVA: 33.59 ± 7.18° and IMA: 12.80 ± 3.65° in Android; HVA: 33.63 ± 7.23° and IMA: 12.87 ± 3.60° in iPhone. No significant difference was found among the average results measured by PACS, Android and iPhone (F = 0.008, P = 0.992 in HVA; F = 0.009, P = 0.991 in IMA). For measurements by PACS, Android smartphone, and iPhone, the variability of HVA (F = 0.061, P = 1.000) and IMA (F = 0.133, P = 1.000) was similar. The intraclass correlation coefficients (ICCs) of the mean results of four times measurements of HVA and IMA as follows: PACS vs Android: 0.995 (0.993-0.997) and 0.982 (0.973-0.988); PACS vs iPhone:0.997 (0.995-0.998) and 0.974 (0.962-0.982); Android vs iPhone:0.997 (0.995-0.998) and 0.981 (0.971-0.987). The interobserver and intraobserver reliability was very good for Android smartphones and iPhone in measuring hallux valgus parameters. The mean time of measurement by PACS, Android smartphone, and iPhone were 25.34 ± 1.18 s, 20.10 ± 0.92 s, and 19.92 ± 0.99 s respectively. The measurement time of smartphones is significantly faster than that of PACS by about 5 seconds (P = 0.000). The measurement time of iPhone was slightly faster than that of Android smartphone, while no significant difference was found (P = 0.24). CONCLUSION: It is more convenient and faster to use smartphones when compared with PACS, at the same level of accuracy. Furthermore, the abilities of different smartphone platforms are proven to be of no significant difference.

Clinical results of a lamina with spinous process and an iliac graft as bone grafts in the surgical treatment of single-segment lumbar pyogenic spondylodiscitis: a retrospective cohort study.

BACKGROUND: A retrospective study compared the results of a lamina with spinous process (LSP) and an iliac graft (IG) as bone grafts in single-segment lumbar pyogenic spondylodiscitis (LPS) through one-stage-posterior-only approach with radical debridement and instrumentation. METHODS: A LSP was placed in 17 patients (group A), and an IG was implemented in 20 patients (group B). The surgery time, surgery hemorrhage, hospital stay, drainage, and follow-up (FU) were recorded and compared. The erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, visual analogue scale (VAS), Oswestry Disability Index (ODI), segmental angle, intervertebral height and bony fusion time were compared preoperatively and at the final FU. RESULTS: All patients were followed-up for a mean of 27.94 ± 2.35 months in group A and 30.29 ± 1.89 months in group B, without a difference. The mean age was younger in group A than in group B (P < 0.05). The surgery time, surgery hemorrhage, and hospitalization cost were lower in group A than in group B (P < 0.05), except for the hospital stay and drainage time. 10 patients in group A had fever and 12 patients in group B. The ESR, CRP level, VAS and ODI scores were significantly decreased, and no significant differences were found between the groups at the final FU. The distribution of bacterial agents in blood culture was 1 case of Aerobacter cloacae, 2 of Staphylococcus aureus, 2 of Escherichia coli, and 1 of Streptococcus viridis in group A and 1 of S. aureus, 1 of Staphylococcus warneri and 2 of Klebsiella pneumoniae in group B. Pyogenic infection was observed in the pathological findings of all patients. No significant difference was found in the mean segmental angle or mean intervertebral height preoperation and at the final FU. CONCLUSION: The use of LSP could be an effective bone grafting for surgical management for the LPS while surgery is proposed as a good management strategy for single-segment LPS in carefully selected patients.

A novel rapid measurement of hallux valgus parameters using the built-in photo edit function of smartphones.

OBJECTIVE: The objective of this study was to assess the accuracy and reliability of and time taken by a novel method using the built-in photo-edit function of smartphones compared with PACS in measuring hallux valgus parameters. METHODS: Seventy patients (124 ft) admitted to our hospital with a diagnosis of hallux valgus without previous surgical procedures were retrospectively reviewed. The foot radiographs of all the patients were extracted from PACS. The hallux valgus angle (HVA) and the first and second intermetatarsal angles (IMAs) were measured by PACS and by this novel method using the built-in photo-edit function of a smartphone. The results of these two methods were compared, and the accuracy and reliability were assessed between these two methods. RESULTS: The average parameters measured by PACS were as follows: HVA average: 37.43 ± 9.61°; IMA average: 13.37 ± 4.01°. The average parameters measured by smartphones were as follows: HVA average: 37.09 ± 9.52° and IMA average: 13.49 ± 3.91°. When compared by the independent-samples T test, the average parameters between PACS and smartphones were not significantly different (HVA PACS vs HVA smartphones: P = 0.776; IMA PACS vs IMA smartphones: P = 0.816). The variability of the HVA (F = 0.166, P = 0.992) and IMA (F = 0.215, P = 0.982) measurements was similar for the PACS and smartphones. The ICCs of the average parameters of four measurements of HVA and IMA between PACS and smartphones were 0.995 (0.991-0.997) and 0.970 (0.958-0.979), indicating that the two methods were highly correlated. For the smartphone measurement, the interobserver and intraobserver reliability was very good for HVA and IMA. The average measurement time of PACS was 25.41 ± 0.86 s, and the average measurement time of smartphones was 20.29 ± 1.22 s. The smartphone time was significantly faster than that of PACS by approximately 5 s (P<0.001). CONCLUSION: This novel method using the built-in photo-edit function of smartphones is accurate, reliable, convenient and time-saving in measuring the angles of hallux valgus.

Clinical efficacy of three types of autogenous bone grafts in treatment of single-segment thoracic tuberculosis: A retrospective cohort study.

A retrospective study investigated and compared the results of lamina with spinous process (LSP), transverse process strut (TPS) and iliac graft (IG) as bone graft in thoracic single-segment spinal tuberculosis(TB) with the one-stage posterior approach of debridement, fusion and internal instrumentation. 99 patients treated from January 2012 to December 2015 were reviewed. LSP was performed in 35 patients (group A), TPS was undertaken in 33 patients (group B), and IG was carried out in 31 patients (group C). Surgical time, blood loss, hospitalization time, drainage volume, and follow-up (FU) duration were recorded. The visual analog scale (VAS), Oswestry Disability Index (ODI), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), American Spinal Injury Association (ASIA) grade, segmental angle, intervertebral height and bone fusion time were compared between preoperative and final FU. All the patients were followed up for a mean 43.90±10.39 months in group A, 45.30±6.20 months in group B, 44.32±7.17 months in group C without difference(P>0.05). The mean age was younger, the blood loss was less, the hospitalization time and the surgical time were shorter in group A than those in group B and C (P<0.05). The drainage volume was less in group A than that in group B and group C. The CRP, ESR, VAS, and ODI were significantly decreased and there were no significant difference among the groups at the final FU. The neurological function after surgery was improved compared with preoperation among the groups. The bony fusion at a mean time 12.90±3.91 months in group A was longer than that in group B (6.75±1.55 months) and group C (5.52±1.64 months) (P<0.05). No significant difference was found at the mean segmental angle, mean intervetebral height of preoperation and final FU among the groups (P>0.05). In conclusion, the LSP and TPS as bone graft are reliable, safe, and effective for single-segment stability reconstruction for surgical management of thoracic TB and TPS could be new bone graft methods.

Complications rate of and risk factors for the unplanned reoperation of degenerative lumbar spondylolisthesis in elderly patients: a retrospective single-Centre cohort study of 33 patients.

BACKGROUND: The study was to investigate the complications rate of and risk factors for unplanned reoperation among elderly patients who underwent posterior lumbar fusion (PLF) for degenerative lumbar spondylolisthesis (DLS). METHODS: A total of 1100 DLS patients who were older than 60 years were reviewed from January 2006 to December 2016. 33 patients underwent unplanned reoperations and were analysed and divided into two groups (group A: posterolateral fusion, 650 patients; group B: intervertebral fusion, 450 patients). Sex, body mass index (BMI), radiographic data and clinical outcome data were analysed to evaluate the complications rate of and the risk factors for unplanned reoperations. RESULTS: A total of 33 patients underwent unplanned reoperations (3%). The patients were followed up for an average of 4.20 ± 2.25 years (group A) and 4.32 ± 2.54 years (group B) without a significant difference. Significant differences were found in mean age, levels of involvement, hospital stay, surgery time, and blood loss between the groups. The causes of unplanned operation were wound infection, screw misplacement, neurological deficit, nonunion, and screw fracture, which were significant except for wound infection between the groups. Higher BMI (obesity), diabetes mellitus (DM), more bleeding and sex (female) were risk factors for complications. Cases of screw misplacement, neurological deficit, nonunion and screw fracture in group A were more significant than those in group B. CONCLUSION: Patients with higher BMI, DM, older age, posterolateral fusion, and female sex predicted a higher incidence of unplanned reoperations. Spine surgeons may need to pay more attention to their preoperative training and to improving surgical techniques that could reduce the reoperation rate.

Transverse process strut and titanium mesh cages in the stability reconstruction of thoracic single segment tuberculosis: a retrospective single-center cohort study.

BACKGROUND: A retrospective and comparative study of transverse process strut (TPS, Group A) compared with titanium mesh cages (TMCs, Group B) in the reconstruction of thoracic stability through the one-stage posterior approach to treat single-segment tuberculosis. METHODS: Sixty patients from January 2013 to December 2016 were analyzed and divided into two groups. The following data of clinical and radiographical assessments were observed preoperatively, postoperatively and during follow-up (FU). RESULTS: The patients were followed up for an average of 50.20 ± 25.10 months (Group A) and 48.70 ± 27.30 months(Group B) without significant difference. No significant differences were found in the mean of operation time in minutes, blood loss, hospitalization time, drainage and follow-up duration between the groups. The VAS, ODI, ESR and CRP were reduced significantly at the final FU compared with the preoperation values and there was no significance between the groups. Neurological deficits were improved in all patients at the final FU without significant difference between the groups(P > 0.05). The bony fusion times were 5.85 ± 1.82 months and 8.4 ± 5.1 months with significant difference(P < 0.05). Comparing with the preoperative values, the kyphosis angle significantly improved, but at the final FU the significant difference was found between the groups (P < 0.05). The loss of the angular correction and the fused segmental height in group A was lower than that in group B (P < 0.05). CONCLUSIONS: TPS had a better osseous fusion rate, effective maintenance of fused segment stability which is a good bone graft for surgical management of single-segment thoracic spinal tuberculosis.

Vertebroplasty and vertebroplasty in combination with intermediate bilateral pedicle screw fixation for OF4 in osteoporotic vertebral compression fractures: a retrospective single-Centre cohort study.

BACKGROUND: Although various studies have described the outcomes and complications of each treatment for OF 4 in osteoporotic vertebral compression fractures (OVCFs), there is still no consensus on the optimal treatment regimen. This study aimed to investigate the clinical effect of OF 4 in patients with OVCFs treated with percutaneous vertebroplasty (PV) compared with PV in combination with intermediate bilateral pedicle screw fixation (IBPSF). METHODS: A total of 110 patients with OF 4 in OVCFs from January 2011 to December 2013 were reviewed retrospectively and divided into two groups (group A: PV, group B: PV + IBPSF). According to the guidelines of the German Society for Orthopaedics and Trauma (DGOU), OF 4 consists of 3 fracture types. The clinical and radiographic assessments were observed preoperatively, postoperatively, and during follow-up. RESULTS: The patients were followed for an average of 60.50 ± 15.20 months (group A) and 58.20 ± 17.60 months (group B) without significant differences. No significant differences were found in BMD, BMI and cement volume between the two groups, but differences were found for operation time, blood loss, and hospitalization time. The VAS and ODI scores improved better significantly at the final follow-up in group B but not in group A. Compared with the preoperative values, the postoperative kyphosis angle and loss of fractured segment height significantly improved, but the difference between the groups was significant after 3 months postoperatively. The loss of angular correction and fractured segment height in group A were greater than those in group B. A total of 15 cases of cement leakage were observed in group A and 8 cases in group B, and no complications or revision surgeries were observed in either group. Thirteen new fractures occurred (11 in group A and 2 in group B), which was significant. CONCLUSION: PV with IBPSF could provide effective restoration and maintenance of fractured segment height and segment alignment as well as a lower rate of complications of OF 4 in OVCFs.

BMP9-regulated angiogenic signaling plays an important role in the osteogenic differentiation of mesenchymal progenitor cells.

Mesenchymal stromal progenitor cells (MSCs) are multipotent progenitors that can be isolated from numerous tissues. MSCs can undergo osteogenic differentiation under proper stimuli. We have recently demonstrated that bone morphogenetic protein 9 (BMP9) is one of the most osteogenic BMPs. As one of the least studied BMPs, BMP9 has been shown to regulate angiogenesis in endothelial cells. However, it is unclear whether BMP9-regulated angiogenic signaling plays any important role in the BMP9-initiated osteogenic pathway in MSCs. Here, we investigate the functional role of hypoxia-inducible factor 1α (HIF1α)-mediated angiogenic signaling in BMP9-regulated osteogenic differentiation of MSCs. We find that BMP9 induces HIF1α expression in MSCs through Smad1/5/8 signaling. Exogenous expression of HIF1α potentiates BMP9-induced osteogenic differentiation of MSCs both in vitro and in vivo. siRNA-mediated silencing of HIF1α or HIF1α inhibitor CAY10585 profoundly blunts BMP9-induced osteogenic signaling in MSCs. HIF1α expression regulated by cobalt-induced hypoxia also recapitulates the synergistic effect between HIF1α and BMP9 in osteogenic differentiation. Mechanistically, HIF1α is shown to exert its synergistic effect with BMP9 by inducing both angiogenic signaling and osteogenic signaling in MSCs. Thus, our findings should not only expand our understanding of the molecular basis behind BMP9-regulated osteoblastic lineage-specific differentiation, but also provide an opportunity to harness the BMP9-induced synergy between osteogenic and angiogenic signaling pathways in regenerative medicine.

MicroRNA-212 inhibits osteosarcoma cells proliferation and invasion by down-regulation of Sox4.

BACKGROUND: Multiple MicroRNAs (miRNAs) have been identified in the development and progression of osteosarcoma. However, the expression and roles of miR-212 in osteosarcoma remain largely undefined. METHODS: Real-time PCR assays were used to detect the expression of miR-212 in human osteosarcoma tissues. MiR-212 mimics were introduced into MG63 and U2OS cells. Bioinformatic prediction was used to identify the potential targets of miR-212. Protein expression analysis, luciferase assays and rescue assays were used to confirm the substrate of miR-212. RESULTS: miR-212 was significantly down-regulated in human osteosarcoma tissues, compared with adjacent normal tissues. Introduction of miR-212 mimics into MG63 and U2OS cells inhibited cell proliferation and invasion. Besides, miR-212 overexpression could also inhibit tumor growth in the nude mice. Additionally, bioinformatic prediction suggested that the sex-determining region Y-box 4 (Sox4) is a target gene of miR-212. Sox4 inhibition phenocopied the roles of miR-212, while restored expression of Sox4 dampened miR-212-mediated suppression of tumor progression. CONCLUSION: The miR-212/Sox4 interaction plays an important role of in the osteosarcoma progression.

Casticin induces ferroptosis in human osteosarcoma cells through Fe2+ overload and ROS production mediated by HMOX1 and LC3-NCOA4.

Osteosarcoma is a primary solid bone malignancy, and surgery + chemotherapy is the most commonly used treatment. However, chemotherapeutic drugs can cause a range of side effects. Casticin, a polymethoxyflavonoid, has anti-tumor therapeutic effects. This study is aim to investigate the anti-osteosarcoma activity of casticin and explore the mechanism. Crystal violet staining, MTT assay, colony formation assay, wound healing assay, transwell assay, hoechst 33,258 staining, and flow cytometry analysis were used to investigate the effects of casticin on proliferation, migration, invasion, and apoptosis of osteosarcoma cells in vitro. The intracellular Fe2+, ROS, MDA, GSH/GSSG content changes were detected using the corresponding assay kits. The mRNA sequencing + bioinformatics analysis and western blot were used to detect the possible mechanism. We found that casticin caused G2/M phase cell cycle arrest in human osteosarcoma cells, inhibited the migration and invasion, and induced cell apoptosis and ferroptosis. Mechanistic studies showed the ferroptosis pathway was enriched stronger than apoptosis. Casticin up-regulated the expression of HMOX1, LC3 and NCOA4, meanwhile it activated MAPK signaling pathways. Animal experiments proved that casticin also inhibited the growth and metastasis of osteosarcoma cell xenograft tumor in vivo. In conclusion, casticin can induce ferroptosis in osteosarcoma cells through Fe2+ overload and ROS production mediated by HMOX1 and LC3-NCOA4. This provides a new strategy for osteosarcoma treatment.

Securinine inhibits the tumor growth of human bladder cancer cells by suppressing Wnt/ß-catenin signaling pathway and activating p38 and JNK signaling pathways.

Bladder cancer (BC) is the most common malignant tumor in urinary system. Although chemotherapy is one of the most important adjuvant treatments for BC, drug resistance, non-specific toxicity and severe side effects are the major obstacles to BC chemotherapy. Natural products have always been a leading resource of antitumor drug discovery, with the advantages of excellent effectiveness, low toxicity, multi-targeting potency and easy availability. In this study, we evaluated the potential anti-tumor effect of securinine (SEC), a natural alkaloid from Securinega suffruticosa, on BC cells in vitro and in vivo, and delineated the underlying mechanism. We found that SEC inhibited the proliferation, migration and invasion, induced the apoptosis of BC cells in vitro, and retarded the xenograft tumor growth of BC cell in vivo. Notably, SEC had a promising safety profile because it presented no or low toxicity on normal cells and mice. Mechanistically, SEC inactivated Wnt/ß-catenin signaling pathway while activated p38 and JNK signaling pathway. Moreover, ß-catenin overexpression, the p38 inhibitor SB203580 and the JNK inhibitor SP600125 both mitigated the inhibitory effect of SEC on BC cells. Furthermore, we demonstrated a synergistic inhibitory effect of SEC and gemcitabine (GEM) on BC cells in vitro and in vivo. Taken together, our findings suggest that SEC may exert anti-BC cell effect at least through the activation of p38 and JNK signaling pathways, and the inhibition of Wnt/ß-catenin signaling pathway. More meaningfully, the findings indicate that GEM-induced BC cell killing can be enhanced by combining with SEC.

Mitochondrial-Oriented Injectable Hydrogel Microspheres Maintain Homeostasis of Chondrocyte Metabolism to Promote Subcellular Therapy in Osteoarthritis.

Subcellular mitochondria serve as sensors for energy metabolism and redox balance, and the dynamic regulation of functional and dysfunctional mitochondria plays a crucial role in determining cells' fate. Selective removal of dysfunctional mitochondria at the subcellular level can provide chondrocytes with energy to prevent degeneration, thereby treating osteoarthritis. Herein, to achieve an ideal subcellular therapy, cartilage affinity peptide (WYRGRL)-decorated liposomes loaded with mitophagy activator (urolithin A) were integrated into hyaluronic acid methacrylate hydrogel microspheres through microfluidic technology, named HM@WY-Lip/UA, that could efficiently target chondrocytes and selectively remove subcellular dysfunctional mitochondria. As a result, this system demonstrated an advantage in mitochondria function restoration, reactive oxygen species scavenging, cell survival rescue, and chondrocyte homeostasis maintenance through increasing mitophagy. In a rat post-traumatic osteoarthritis model, the intra-articular injection of HM@WY-Lip/UA ameliorated cartilage matrix degradation, osteophyte formation, and subchondral bone sclerosis at 8 weeks. Overall, this study indicated that HM@WY-Lip/UA provided a protective effect on cartilage degeneration in an efficacious and clinically relevant manner, and a mitochondrial-oriented strategy has great potential in the subcellular therapy of osteoarthritis.

Inhibition of histone deacetylases potentiates BMP9-induced osteogenic signaling in mouse mesenchymal stem cells.

BACKGROUND/AIMS: We have demonstrated that bone morphogenetic protein 9 (BMP9) is one of the most potent BMPs in regulating osteoblast differentiation of mesenchymal stem cells (MSCs) although the molecular mechanism underlying BMP9-induced osteogenesis remains to be fully elucidated. It is known that epigenetic regulations play an important role in regulating the stem cell potency and lineage commitment. Here, we investigate if the inhibition of histone deacetylases (Hdacs) affects BMP9-induced osteogenic differentiation of MSCs. METHODS: Using the Hdac inhibitor trichostatin A (TSA), we assess that TSA enhances BMP9-mediated osteogenic markers and matrix mineralization in MSCs, and bone formation in mouse embryonic limb explants. RESULTS: We find that the endogenous expression of most of the 11 Hdacs is readily detectable in MSCs. BMP9 is shown to induce most Hdacs in MSCs. We demonstrate that TSA potentiates BMP9-induced early osteogenic marker alkaline phosphatase (ALP) activity in MSCs, as well as late osteogenic markers osteopontin (OPN) and osteocalcin (OCN) and matrix mineralization. Fetal limb explant culture studies reveal that TSA potentiates BMP9-induced endochondral bone formation, possibly by expanding hypertrophic chondrocyte zone of growth plate. CONCLUSION: Our findings strongly suggest histone deacetylases may play an important role in fine-tuning BMP9-mediated osteogenic signaling through a negative feedback network in MSCs. Thus, Hdac inhibitors may be used as novel therapeutics for bone fracture healing.