Signalling interaction between ß-catenin and other signalling molecules during osteoarthritis development.

Osteoarthritis (OA) is the most prevalent disorder of synovial joint affecting multiple joints. In the past decade, we have witnessed conceptual switch of OA pathogenesis from a 'wear and tear' disease to a disease affecting entire joint. Extensive studies have been conducted to understand the underlying mechanisms of OA using genetic mouse models and ex vivo joint tissues derived from individuals with OA. These studies revealed that multiple signalling pathways are involved in OA development, including the canonical Wnt/ß-catenin signalling and its interaction with other signalling pathways, such as transforming growth factor ß (TGF-ß), bone morphogenic protein (BMP), Indian Hedgehog (Ihh), nuclear factor κB (NF-κB), fibroblast growth factor (FGF), and Notch. The identification of signalling interaction and underlying mechanisms are currently underway and the specific molecule(s) and key signalling pathway(s) playing a decisive role in OA development need to be evaluated. This review will focus on recent progresses in understanding of the critical role of Wnt/ß-catenin signalling in OA pathogenesis and interaction of ß-catenin with other pathways, such as TGF-ß, BMP, Notch, Ihh, NF-κB, and FGF. Understanding of these novel insights into the interaction of ß-catenin with other pathways and its integration into a complex gene regulatory network during OA development will help us identify the key signalling pathway of OA pathogenesis leading to the discovery of novel therapeutic strategies for OA intervention.

Updated roles of cGAS-STING signaling in autoimmune diseases.

Natural immunity, the first line for the body to defense against the invasion of pathogen, serves as the body's perception of the presence of pathogens depends on nucleic acid recognition mechanisms. The cyclic GMP-AMP synthase-stimulator of the interferon gene (cGAS-STING) signaling pathway is considered an essential pattern recognition and effector pathway in the natural immune system and is mainly responsible for recognizing DNA molecules present in the cytoplasm and activating downstream signaling pathways to generate type I interferons and some other inflammatory factors. STING, a crucial junction protein in the innate immune system, exerts an essential role in host resistance to external pathogen invasion. Also, STING, with the same character of inflammatory molecules, is inseparable from the body's inflammatory response. In particular, when the expression of STING is upregulated or its related signaling pathways are overactivated, the body may develop serious infectious disorders due to the generation of excessive inflammatory responses, non-infectious diseases, and autoimmune diseases. In recent years, accumulating studies indicated that the abnormal activation of the natural immune cGAS-STING signaling pathway modulated by the nucleic acid receptor cGAS closely associated with the development and occurrence of autoimmune diseases (AID). Thereof, to explore an in-depth role of STING and its related signaling pathways in the diseases associated with inflammation may be helpful to provide new avenues for the treatment of these diseases in the clinic. This article reviews the activation process of the cGAS-STING signaling pathways and its related important roles, and therapeutic drugs in AID, aiming to improve our understanding of AID and achieve better diagnosis and treatment of AID.

Anterior debridement combined with autogenous iliac bone graft fusion for the treatment of lower cervical tuberculosis: a multicenter retrospective study.

BACKGROUND: This study aimed to analyze the clinical efficacy of one-stage anterior debridement of lower cervical tuberculosis using iliac crest bone graft fusion and internal fixation. MATERIALS AND METHODS: A retrospective analysis was performed on 48 patients with lower cervical tuberculosis admitted to multiple medical centers from June 2018 to June 2021. Among them, 36 patients had lesions involving two vertebrae and 12 patients had lesions involving more than three vertebrae. All patients were treated with quadruple antituberculosis drugs for more than 2 weeks before the operation, and then treated with one-stage anterior debridement and autogenous iliac bone graft fusion combined with titanium plate internal fixation. After the operation, antituberculosis drugs were continued for 12-18 months. The patients were followed-up to observe the improvement in clinical symptoms, bone graft fusion, Cobb angle, visual analog score (VAS), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), wound healing, and neurological function. RESULTS: The patients were followed-up for 13-43 months, with an average of 21.46 ± 1.52 months. The clinical symptoms significantly improved after the operation. The bone graft was completely fused in all patients, and the bone fusion time was 3-6 months, with an average of 4.16 ± 0.47 months. At the last follow-up, the Cobb angle, VAS, ESR, and CRP level were significantly lower than those before surgery (P < 0.05). None of the patients had loosening, detachment, or rupture of the internal fixation, and no recurrence occurred. All surgical incisions healed in one stage without infection or sinus formation. The preoperative Frankel neurological function classification was grade B in 7 cases, grade C in 13, grade D in 18, and grade E in 10. At the last follow-up, 8 cases recovered to grade D and 40 recovered to grade E. CONCLUSIONS: For patients with lower cervical tuberculosis, based on oral treatment with quadruple antituberculosis drugs, direct decompression through anterior debridement, followed by autologous iliac bone graft fusion combined with internal fixation can completely remove tuberculosis foci, rebuild the stability of the cervical spine, and obtain good clinical efficacy. Level of evidence Level 3.

LncRNA MEG3 promotes chemosensitivity of osteosarcoma by regulating antitumor immunity via miR-21-5p/p53 pathway and autophagy.

This study aimed to investigate the role of long non-coding RNA maternally expressed gene 3 (lncRNA MEG3) in chemosensitivity of osteosarcoma (OS), and to reveal the possible underlying mechanisms. In this study, we found that the expression of lncRNA MEG3 was significantly lower in OS tissues and cell lines. Furthermore, lncRNA MEG3 overexpression enhanced chemosensitivity of OS by inhibiting cell proliferation, migration, autophagy, and promoting antitumor immunity. LncRNA MEG3 functioned as miR-21-5 sponge to regulate p53 expression in OS. Mechanically, lncRNA MEG3 promoted OS chemosensitivity by regulating antitumor immunity via miR-21-5p/p53 pathway and autophagy. Collectively, this study provided the evidence that lncRNA MEG3 might be a promising therapeutic target for OS chemoresistance.

Clinical efficacy of customized modular prosthesis in the treatment of femoral shaft metastases.

Purpose: To examine clinical outcomes of a specialized modular prosthesis used to fill a bone deficiency following removal of femoral shaft metastases. Methods: Eighteen patients with femoral shaft metastases who underwent en bloc resection and implantation of a personalized modular prosthesis between December 2014 and December 2019 were retrospectively analyzed. Pain, limb function, and quality of life were evaluated using the visual analog scale (VAS), Musculoskeletal Tumor Society (MSTS) scale, International Society of Limb Salvage (ISOLS) scoring system, Karnofsky Performance Status (KPS) scale, and Nottingham Health Profile (NHP) scale. The Kaplan-Meier technique was used to analyze patient survival. Results: The operation duration was 90-150 min (mean, 115 min), and the osteotomy length was 9-16 cm (mean, 11.72 cm). The patients were followed for 12-62 months (mean, 25.28 months). The VAS and NHP ratings were lower at 3, 6, and 12 months after surgery than before surgery, while the MSTS, ISOLS, and KPS scores were higher after surgery than they had been before. These differences were statistically significant (P<0.05). The survival period was between 7 and 62 months (mean, 20.89 months), and the rates of survival at 1-year and 2-year were 72.22% and 27.78%, respectively. Except for two patients with aseptic prosthesis loosening during the follow-up period, there were no problems. Conclusion: En bloc excision and implantation of a personalized modular prosthesis can reduce pain and improve the ability of patients with femoral shaft metastases to perform daily activities, thereby improving their quality of life.

Research and Application of Medical Polyetheretherketone as Bone Repair Material.

Polyetheretherketone (PEEK) can potentially be used for bone repair because its elastic modulus is similar to that of human natural bone and good biocompatibility and chemical stability. However, its hydrophobicity and biological inertness limit its application in the biomedical field. Inspired by the composition, structure, and function of bone tissue, many strategies are proposed to change the structure and functionality of the PEEK surface. In this review, the applications of PEEK in bone repair and the optimization strategy for PEEK's biological activity are reviewed, which provides a direction for the development of multifunctional bone repair materials in the future.

Clinical effect of surgical resection on primary malignant and invasive bone tumours of the proximal fibula.

There is no unified surgical plan for fibular proximal malignant tumours; therefore, the present study retrospectively analysed the medical records of 19 patients with primary malignant and invasive tumours in the proximal fibula and discussed the postoperative oncological results, complications and postoperative functions of limb salvage surgery. According to pathological classification, there were 10 osteosarcoma cases, 3 chondrosarcoma cases, 2 invasive giant cell osteosarcoma tumour cases, 1 epithelioid sarcoma case, 1 leiomyosarcoma case, 1 fibrosarcoma case and 1 lymphoma case. According to the Enneking instalment, IB stage was found in 2 cases, IIA in 2 cases and IIB in 15 cases. A total of 3 patients underwent Malawer I resection, and 16 patients underwent Malawer II resection. The follow-up period was 11-174 months, with an average of 76.58 months. Local recurrence occurred in three patients and distant metastasis in seven patients; 4 patients succumbed and 15 survived. After biceps femoris tendon reconstruction and lateral collateral ligament insertion, 18 patients had good knee stability. The Musculoskeletal Tumour Society scale ranged between 23 and 29 points, with an average of 27.26 points; the Lysholm Knee Score was 65-84 points, with an average of 83 points. After the resection of proximal fibula primary and invasive tumours, the biceps femoris tendon and lateral collateral ligament insertion point was reconstructed. The data show that this technique can effectively reconstruct stability and restore knee function.

Association between total cholesterol and total bone mineral density in US adults: National Health and Nutrition Examination Survey (NHANES), 2011-2018.

BACKGROUND: Accumulated evidence indicates that cholesterol is offensive to bone metabolism. Therefore, we examined the real-world study among total cholesterol and total bone mineral density (BMD). We investigated the relationship between total cholesterol and total BMD among 10,039 US participants aged 20-59 years old over the period 2011-2018 from the NHANES. METHODS: To analyze the relationship among total cholesterol and total BMD, multivariate linear regression models were used. Fitted smoothing curves, generalized additive models, and threshold effect analysis were also conducted. RESULTS: After adjusting for additional covariates, weighted multivariable linear regression models indicated total cholesterol concentration levels exhibited a negative relationship with total BMD, particularly among participants aged 20-29 years. Concerning subgroup analysis, stratified by gender, race/ethnicity and age group, the negative correlation of total cholesterol with total BMD dwelled in both female and male as well as in whites and other races (including Hispanic and Multi-Racial), but not in non-Hispanic blacks and Mexican American. In other races, this relationship presented a nonlinear association (inflection point: 6.7 mmol/L) with a U-shaped curve. Among participants aged 40 to 49 years, this relationship also followed a nonlinear association (inflection point: 5.84 mmol/L), indicating a saturation effect. Moreover, the three types of diabetes status were found to have negative, U-shaped, and positive relationships. In participants with borderline diabetes status, the relationship of total cholesterol with total BMD was a U-shaped curve (inflection point: 4.65 mmol/L). CONCLUSIONS: For US young adults (20-29 years old), our study revealed a negative relationship between total cholesterol and total BMD. This association followed a U-shaped curve (inflection point: 4.65 mmol/L) in borderline diabetes status participants, a saturation curve (inflection point: 5.84 mmol/L) in participants aged 40-49 years and a nonlinear curve (inflection point: 6.7 mmol/L) in other races (including Hispanic and Multi-Racial). Therefore, keeping total cholesterol concentration at a reasonable level for young adults and diabetic population might be an approach to prevent osteoporosis or osteopenia.

2-Hydroxy-3-methylanthraquinone inhibits homologous recombination repair in osteosarcoma through the MYC-CHK1-RAD51 axis.

BACKGROUND: Osteosarcoma is a malignant bone tumor that usually affects adolescents aged 15-19 y. The DNA damage response (DDR) is significantly enhanced in osteosarcoma, impairing the effect of systemic chemotherapy. Targeting the DDR process was considered a feasible strategy benefitting osteosarcoma patients. However, the clinical application of DDR inhibitors is not impressive because of their side effects. Chinese herbal medicines with high anti-tumor effects and low toxicity in the human body have gradually gained attention. 2-Hydroxy-3-methylanthraquinone (HMA), a Chinese medicine monomer found in the extract of Oldenlandia diffusa, exerts significant inhibitory effects on various tumors. However, its anti-osteosarcoma effects and defined molecular mechanisms have not been reported. METHODS: After HMA treatment, the proliferation and metastasis capacity of osteosarcoma cells was detected by CCK-8, colony formation, transwell assays and Annexin V-fluorescein isothiocyanate/propidium iodide staining. RNA-sequence, plasmid infection, RNA interference, Western blotting and immunofluorescence assay were used to investigate the molecular mechanism and effects of HMA inhibiting osteosarcoma. Rescue assay and CHIP assay was used to further verified the relationship between MYC, CHK1 and RAD51. RESULTS: HMA regulate MYC to inhibit osteosarcoma proliferation and DNA damage repair through PI3K/AKT signaling pathway. The results of RNA-seq, IHC, Western boltting etc. showed relationship between MYC, CHK1 and RAD51. Rescue assay and CHIP assay further verified HMA can impair homologous recombination repair through the MYC-CHK1-RAD51 pathway. CONCLUSION: HMA significantly inhibits osteosarcoma proliferation and homologous recombination repair through the MYC-CHK1-RAD51 pathway, which is mediated by the PI3K-AKT signaling pathway. This study investigated the exact mechanism of the anti-osteosarcoma effect of HMA and provided a potential feasible strategy for the clinical treatment of human osteosarcoma.

Three-dimensional-printed titanium prostheses with bone trabeculae enable mechanical-biological reconstruction after resection of bone tumours.

Reconstruction after resection has always been an urgent problem in the treatment of bone tumours. There are many methods that can be used to reconstruct bone defects; however, there are also many complications, and it is difficult to develop a safe and effective reconstruction plan for the treatment of bone tumours. With the rapid development of digital orthopaedics, three-dimensional printing technology can solve this problem. The three-dimensional printing of personalised prostheses has many advantages. It can be used to print complex structures that are difficult to fabricate using traditional processes and overcome the problems of stress shielding and low biological activity of conventional prostheses. In this study, 12 patients with bone tumours were selected as research subjects, and based on individualised reverse-engineering design technology, a three-dimensional model of each prosthesis was designed and installed using medical image data. Ti6Al4V was used as the raw material to prepare the prostheses, which were used to repair bone defects after surgical resection. The operation time was 266.43 ± 21.08 minutes (range 180-390 minutes), and intraoperative blood loss was 857.26 ± 84.28 mL (range 800-2500 mL). One patient had delayed wound healing after surgery, but all patients survived without local tumour recurrence, and no tumour metastasis was found. No aseptic loosening or structural fracture of the prosthesis, and no non-mechanical prosthesis failure caused by infection, tumour recurrence, or progression was observed. The Musculo-Skeletal Tumour Society (MSTS) score of limb function was 22.53 ± 2.09 (range 16-26), and ten of the 12 patients scored ≥ 20 and were able to function normally. The results showed that three-dimensional printed prostheses with an individualised design can achieve satisfactory short-term clinical efficacy in the reconstruction of large bone defects after bone tumour resection.

Targeted Delivery of PD-L1-Derived Phosphorylation-Mimicking Peptides by Engineered Biomimetic Nanovesicles to Enhance Osteosarcoma Treatment.

Osteosarcoma is a rare malignant bone-originating tumor that usually occurs in young people. Programmed cell death 1 ligand 1 (PD-L1), an immune checkpoint protein, is highly expressed in osteosarcoma tissues. Several recent studies have indicated that the tumor-related role of PD-L1 in tumors, especially non-plasma membrane (NPM)-localized PD-L1, is not limited to immune regulation in osteosarcoma. Here, mass spectrometry analysis is combined with RNA-seq examination to identify the intracellular binding partners of PD-L1 and elucidate the underlying mechanism of its action. It is found that the NPM-localized PD-L1 interacted with Insulin-like growth factor binding protein-3 (IGFBP3) to promote osteosarcoma tumor growth by activating mTOR signaling. This interaction is enforced after phosphoglyceratekinase1 (PGK1)-mediated PD-L1 phosphorylation. Based on these findings, a phosphorylation-mimicking peptide is designed from PD-L1 and it is encapsulated with a Cyclic RGD (cRGD)-modified red blood cell membrane (RBCM) vesicle (Peptide@cRGD-M). The Peptide@cRGD-M precisely delivers the PD-L1-derived phosphorylation-mimicking peptide into osteosarcoma lesions and significantly promotes its therapeutic effect on the tumor. Therefore, this investigation not only highlights the function of NPM-localized PD-L1, but also uses an engineering approach to synthesize a small molecular peptide capable of inhibiting osteosarcoma growth.

Engineered biomimetic nanoreactor for synergistic photodynamic-chemotherapy against hypoxic tumor.

Photodynamic therapy (PDT) can produce a large amount of reactive oxygen species (ROS) in the radiation field to kill tumor cells. However, the sustainable anti-tumor efficacy of PDT is limited due to the hypoxic microenvironment of tumor. In this study, classic PDT agent indocyanine green (ICG) and hypoxia-activated chemotherapeutic drug tirapazamine (TPZ) were loaded on mesoporous polydopamine (PDA) to construct PDA@ICG-TPZ nanoparticles (PIT). Then, PIT was camouflaged with cyclic arginine-glycine-aspartate (cRGD) modified tumor cell membranes to obtain the engineered membrane-coated nanoreactor (cRGD-mPIT). The nanoreactor cRGD-mPIT could achieve the dual-targeting ability via tumor cell membrane mediated homologous targeting and cRGD mediated active targeting. With the enhanced tumor-targeting and penetrating delivery system, PIT could efficiently accumulate in hypoxic tumor cells and the loaded drugs were quickly released in response to near-infrared (NIR) laser. The nanoreactor might produce cytotoxic ROS under NIR and further enhance hypoxia within tumor to activate TPZ, which efficiently inhibited hypoxic tumor by synergistic photodynamic-chemotherapy. Mechanically, hypoxia-inhibitory factor-1α (HIF-1α) was down-regulated by the synergistic therapy. Accordingly, the cRGD-mPIT nanoreactor with sustainable and cascade anti-tumor effects and satisfied biosafety might be a promising strategy in hypoxic tumor therapy.

[Risk factors of adjacent vertebral refracture after percutaneous vertebroplasty for osteoporotic vertebral compression fractures in super-old patients].

OBJECTIVE: To analyze the risk factors for refracture of adjacent vertebrae after percutaneous vertebroplasty (PVP) in super-old patients with osteoporotic vertebral compression fractures(OVCFs). METHODS: A retrospective analysis was performed on 40 patients(age≥90 years) with OVCFs who underwent PVP between June 2012 and June 2019. There were 7 males and 33 females, age from 90 to 101 years old with an average of (94.6±1.6) years. Patients were divided into two groups according to whether adjacent vertebral refracture occurred after PVP. Among them, 20 patients occurred refracture after PVP (refracture group) and 20 patients did not occur it(control group). The general information, radiological data and pelvic parameters of the two groups were collected. The items included age, gender, body mass index (BMI), fracture site and bone mineral density(BMD) T-value, fracture to operation time, compression degree of injured vertebra, recovery degree of anterior edge of injured vertebra, bone cement injection amount, bone cement leakage, pelvic index(PI), pelvic tilt angle (PT), sacral angle(SS), et al. Factors that may be related to refracture were included in the single-factor study, and multivariate Logistic regression analysis was performed on the risk factors with statistical significance in the single-factor analysis to further clarify the independent risk factors for refracture of adjacent vertebral bodies after PVP. RESULTS: There were no significant differences in age, gender, fracture site, fracture to operation time, compression degree of injured vertebra and recovery degree of anterior edge of injured vertebra between two groups (P>0.05). There were significant differences in BMI, BMD T-value, bone cement injection amount and bone cement leakage rate between two groups(P<0.05). The PI and PT values of the refracture group were higher than those of the control group(P<0.05). There was no significant difference in SS between two groups (P>0.05). Multivariate Logistic regression analysis showed that decreased BMD T-value, bone cement leakage, increased PT and PI values increased the risk of recurrence of adjacent vertebral fractures in OVCFs (P<0.05). CONCLUSION: There are many risk factors for the recurrence of adjacent vertebral fractures in super-old patients with OVCFs. Patients with high PI and PT values may be one of the risk factors.

[Clinical application of three-dimensional printed osteotomy guide plate and personalized prosthesis in knee-preserving tumor resection].

Objective: To investigate the mid-term effectiveness of three-dimensional (3D) printed osteotomy guide plate and personalized prosthesis in knee-preserving tumor resection. Methods: The clinical data of 12 patients who underwent knee-preserving tumor resection and reconstruction with 3D printed osteotomy guide plate and personalized prosthesis between September 2016 and October 2018 were retrospectively analyzed. There were 7 males and 5 females. The age ranged from 7 to 59 years, with a median of 44.5 years. There were 11 cases of osteosarcoma and 1 case of fibrosarcoma, all of which were Enneking grade ⅡB. The distance from the tumor to the joint surface was 5.5-8.2 cm, with an average of 6.94 cm. Incision healing, tumor recurrence, periprosthetic fracture, and aseptic loosening were observed after operation. The Musculoskeletal Tumor Society (MSTS) scoring system was used to evaluate the function of the patients, and the knee flexion range of motion was measured. Results: The 12 patients were followed up 41-66 months, with an average of 54.5 months. The length of osteotomy ranged from 14 to 26 cm, with an average of 22.08 cm. Except for 2 patients with superficial infection of incision tissue, no deep infection involving the prosthesis occurred, no patient underwent revision surgery because of prosthesis infection. During the follow-up, local recurrence occurred in 2 cases and distant metastasis occurred in 3 cases. The overall disease-free survival rate was 58.3%. Two patients died of lung metastasis, and the overall survival rate was 83.3%. One patient underwent amputation due to local recurrence, and 1 patient underwent total knee arthroplasty due to prosthesis rupture. No aseptic loosening of the prosthesis and periprosthetic fracture occurred during the follow-up, and the overall prosthesis survival rate was 83.3%. At last follow-up, 10 patients obtained satisfactory knee flexion range of motion that ranged from 95° to 125°, with an average of 110°. Two children could not cooperate with early rehabilitation treatment due to pain, and the knee flexion range of motion was not ideal (50°, 75°). All patients achieved acceptable lower limb function with MSTS scores ranged from 26 to 30, with an average of 28. All patients walked without crutches. Conclusion: The treatment of malignant bone tumors around the knee joint with 3D printed osteotomy guide plate and personalized prosthesis can preserve the articular surface, obtain good limb function, reduce the risk of aseptic loosening of prosthesis, and achieve better mid-term effectiveness.

Pan-sarcoma characterization of lncRNAs in the crosstalk of EMT and tumour immunity identifies distinct clinical outcomes and potential implications for immunotherapy.

The epithelial-to-mesenchymal transition (EMT) is a reversible process that may interact with tumour immunity through multiple approaches. There is increasing evidence demonstrating the interconnections among EMT-related processes, the tumour microenvironment, and immune activity, as well as its potential influence on the immunotherapy response. Long non-coding RNAs (lncRNAs) are emerging as critical modulators of gene expression. They play fundamental roles in tumour immunity and act as promising biomarkers of immunotherapy response. However, the potential roles of lncRNA in the crosstalk of EMT and tumour immunity are still unclear in sarcoma. We obtained multi-omics profiling of 1440 pan-sarcoma patients from 19 datasets. Through an unsupervised consensus clustering approach, we categorised EMT molecular subtypes. We subsequently identified 26 EMT molecular subtype and tumour immune-related lncRNAs (EILncRNA) across pan-sarcoma types and developed an EILncRNA signature-based weighted scoring model (EILncSig). The EILncSig exhibited favourable performance in predicting the prognosis of sarcoma, and a high-EILncSig was associated with exclusive tumour microenvironment (TME) characteristics with desert-like infiltration of immune cells. Multiple altered pathways, somatically-mutated genes and recurrent CNV regions associated with EILncSig were identified. Notably, the EILncSig was associated with the efficacy of immune checkpoint inhibition (ICI) therapy. Using a computational drug-genomic approach, we identified compounds, such as Irinotecan that may have the potential to convert the EILncSig phenotype. By integrative analysis on multi-omics profiling, our findings provide a comprehensive resource for understanding the functional role of lncRNA-mediated immune regulation in sarcomas, which may advance the understanding of tumour immune response and the development of lncRNA-based immunotherapeutic strategies for sarcoma.

Quercetin encapsulated in folic acid-modified liposomes is therapeutic against osteosarcoma by non-covalent binding to the JH2 domain of JAK2 Via the JAK2-STAT3-PDL1.

Osteosarcoma (OS) is a malignant solid tumor prone to lung metastasis that occurs in adolescents aged 15-19 years. Neoadjuvant chemotherapy and surgical treatment aimed at curing OS have gained limited progress over the last 30 years. Exploring new effective second-line therapies for OS patients is a serious challenge for researchers. Quercetin, a multiple biologically active polyphenolic flavonoid, has been used in tumor therapy. However, the exact mechanism of quercetin is still unknown, which limits the application of quercetin. In the current study, we found that quercetin could inhibit JAK2 through the JH2 domain in a non-covalent manner, resulting in the inhibition of OS proliferation and immune escape via the JAK2-STAT3-PD-L1 signaling axis. More importantly, to overcome the shortcomings of quercetin, including low water solubility and low oral availability, we encapsulated it with folic acid-modified liposomes. The transportation of quercetin by folic acid-modified liposomes may provide a feasible strategy to cure OS.

LncCCAT1 interaction protein PKM2 upregulates SREBP2 phosphorylation to promote osteosarcoma tumorigenesis by enhancing the Warburg effect and lipogenesis.

Pyruvate kinase M2 (PKM2) plays an important role in the consumption of glucose and the production of lactic acid, the striking feature of cancer metabolism. The association of PKM2 with osteosarcoma (OS) has been reported but its role in OS has yet to be elucidated. To study this, PKM2­bound RNAs in HeLa cells, a type of cancer cells widely used in the study of molecular function and mechanism, were obtained. Peak calling analysis revealed that PKM2 binds to long noncoding RNAs (lncRNAs), which are associated with cancer pathogenesis and development. Validation of the PKM2­lncRNA interaction in the human OS cell line revealed that lncRNA colon cancer associated transcript­1 (lncCCAT1) interacted with PKM2, which upregulated the phosphorylation of sterol regulatory element­binding protein 2 (SREBP2). These factors promoted the Warburg effect, lipogenesis, and OS cell growth. PKM2 appears to be a key regulator in OS by binding to lncCCAT1. This further extends the biological functions of PKM2 in tumorigenesis and makes it a novel potential therapeutic for OS.