Gossypol Acetic Acid alleviates the Ferroptosis of Chondrocytes in Osteoarthritis by Inhibiting GPX4 Methylation.

BACKGROUND: Osteoarthritis (OA) is a chronic joint disease, usually accompanied by degeneration of the articular cartilage, fibrosis, bone hyperplasia around the joint, and damage to the entire articular surface. Gossypol is a natural phenolic compound isolated from the seed of cotton plants, and gossypol acetic acid (GAA) is a medicinal form of Gossypol. Recently, various biological activities of GAA, including anti-inflammatory and anti-tumor effects, have been widely reported. However, its effect on chondrocytes in OA has yet to be determined. METHODS: In this study, we investigated the effect of GAA on ferroptosis in OA chondrocytes. The effect of GAA on the cell viability and cytotoxicity of chondrocytes in rat cells was investigated using CCK8. Western blotting, Reverse-transcription PCR (RT-PCR), and immunofluorescence staining were used to elucidate the molecular mechanisms and signaling pathways of GAA inhibition of ferroptosis in OA chondrocytes. The effect of GAA on reactive oxygen species (ROS) production and lipid peroxidation levels in chondrocytes was examined using dihydroethidium (DHE) staining and fluorescent dye BODIPY581/591 C11. in vivo, micro-CT imaging, hematoxylin and eosin staining, Safranin O-Fast staining, and immunohistochemistry were performed to evaluate the effects of GAA on OA cartilage. RESULTS: The results showed that GAA treatment regulated the expression of chondrocyte extracellular matrix (ECM) related factors, including ADAMTS5, MMP13, SOX9, Aggrecan, and COL1A2 and reduced the ROS and lipid peroxidation levels. Besides, Erastin could reverse the effects of GAA on chondrocytes. Similar to GAA, 5-AZA caused the reduction of ROS and lipid peroxidation levels and reversed the effect of IL-1ß on the expression of ECM-related factors in OA chondrocytes. The above results clarified that GAA alleviated the ferroptosis of chondrocytes in OA by inhibiting GPX4 methylation. CONCLUSION: Our findings revealed that GAA might be developed as a drug for treating OA clinically.

CK1ε drives osteogenic differentiation of bone marrow mesenchymal stem cells via activating Wnt/ß-catenin pathway.

The treatment of bone defects is a difficult problem in orthopedics. At present, the treatment mainly relies on autologous or allogeneic bone transplantation, which may lead to some complications such as foreign body rejection, local infection, pain, or numbness at the bone donor site. Local injection of conservative therapy to treat bone defects is one of the research hotspots at present. Bone marrow mesenchymal stem cells (BMSCs) can self-renew, significantly proliferate, and differentiate into various types of cells. Although it has been reported that CK1ε could mediate the Wnt/ß-catenin pathway, leading to the development of the diseases, whether CK1ε plays a role in bone regeneration through the Wnt/ß-catenin pathway has rarely been reported. The purpose of this study was to investigate whether CK1ε was involved in the osteogenic differentiation (OD) of BMSCs through the Wnt/ß-catenin pathway and explore the mechanism. We used quantitative reverse transcription-polymerase chain reaction (qRT-qPCR), Western blots, immunofluorescence, alkaline phosphatase, and alizarin red staining to detect the effect of CK1ε on the OD of BMSCs and the Wnt/ß-catenin signaling pathway. CK1ε was highly expressed in BMSCs with OD, and our study further demonstrated that CK1ε might promote the OD of BMSCs by activating DLV2 phosphorylation, initiating Wnt signaling downstream, and activating ß-catenin nuclear transfer. In addition, by locally injecting a CK1ε-carrying adeno-associated virus (AAV5- CK1ε) into a femoral condyle defect rat model, the overexpression of CK1ε significantly promoted bone repair. Our data show that CK1ε was involved in the regulation of OD by mediating Wnt/ß-catenin. This may provide a new strategy for the treatment of bone defects.

Adipokines regulate mesenchymal stem cell osteogenic differentiation.

Mesenchymal stem cells (MSCs) can differentiate into various tissue cell types including bone, adipose, cartilage, and muscle. Among those, osteogenic differentiation of MSCs has been widely explored in many bone tissue engineering studies. Moreover, the conditions and methods of inducing osteogenic differentiation of MSCs are continuously advancing. Recently, with the gradual recognition of adipokines, the research on their involvement in different pathophysiological processes of the body is also deepening including lipid metabolism, inflammation, immune regulation, energy disorders, and bone homeostasis. At the same time, the role of adipokines in the osteogenic differentiation of MSCs has been gradually described more completely. Therefore, this paper reviewed the evidence of the role of adipokines in the osteogenic differentiation of MSCs, emphasizing bone formation and bone regeneration.

Resistin targets TAZ to promote osteogenic differentiation through PI3K/AKT/mTOR pathway.

Osteogenic differentiation (OD) of bone marrow mesenchymal stem cells (BMSCs) contributes significantly to the regeneration of bone defects. Resistin, an adipose tissue-specific secretory factor, has been shown to involve many different functions, including metabolism, inflammation, cancer, and bone remodeling. However, the effects and mechanisms of resistin on OD of BMSCs remain unclear. Herein, we demonstrated that resistin was highly expressed in BMSCs with OD. Upregulation of resistin contributed to the progression of OD of BMSCs by activating PI3K/AKT/mTOR signaling pathway. In addition, resistin facilitated OD by targeting transcriptional co-activator with PDZ-binding motif (TAZ). In a rat femoral condyle bone defect model, local injection of resistin significantly promoted bone repair and improved bone formation. This work contributes to better understanding the mechanism of resistin directly involved in the OD and might provide a new therapeutic strategy for bone defect regeneration.

Percutaneous Curved Vertebroplasty and Bilateral-Pedicle-Approach Percutaneous Vertebroplasty in the Treatment of Osteoporotic Vertebral Compression Fracture: A Meta-Analysis.

Introduction: The aim of this study was to evaluate the use of percutaneous curved vertebroplasty procedure (PCVP) and bilateral-pedicle-approach percutaneous vertebroplasty (bPVP) for the treatment of osteoporotic vertebral compression fractures (OVCFs) through a systematic review and meta-analysis of the scientific literature. Methods: A systematic review of the scientific literature in PubMed, China National Knowledge Infrastructure (CNKI), Wanfang and other databases was conducted in conjunction with different keywords. Nine studies were included; all but 3 were randomised controlled studies and all were prospective or retrospective cohort studies. Results: We observed statistically significant differences between the PCVP group and the bPCVP group in terms of postoperative visual analogue scale (VAS) scores (mean difference [MD]: -.08; 95% confidence intervals [CI]: -.15 to .00), bone cement leakage rates (OR = .33; 95%CI: .20 to .54), bone cement injection (MD: -1.52; 95%CI: -1.58 to 1.45), operative times (MD: -16.69; 95%CI: -17.40 to -15.99) and intraoperative fluoroscopies (MD: -8.16; 95%CI: -9.56 to -6.67), with the PCVP group being more dominant. There were no statistical differences in postoperative Oswestry Disability Index (ODI) scores (MD: -.72; 95%CI: -2.11 to .67) and overall bone cement distribution rates (MD: 2.14; 95%CI: .99 to 4.65) between the 2 groups. Conclusions: Meta-analysis showed more favourable outcomes in the PCVP group compared to the bPVP group. PCVP might be effective and safe in the treatment of OVCFs because it relieves postoperative patient pain, reduces operative time and cement injection, and decreases the risk of cement leakage and radiation exposure to the surgeon and patient.

Comparison of Complications between Anterior Cervical Diskectomy and Fusion versus Anterior Cervical Corpectomy and Fusion in Two- and Three-Level Cervical Spondylotic Myelopathy: A Meta-analysis.

BACKGROUND: In this study, we systematically analyze the differences in complications between anterior cervical diskectomy and fusion (ACDF) and anterior cervical corpectomy and fusion (ACCF) in two- and three-level cervical spondylotic myelopathy (CSM). METHODS: We performed a systematic search in MEDLINE, EMBASE, PubMed, Web of Science, Cochrane databases, Chinese Biomedical Literature Database, CNKI, and Wan Fang Data for all relevant studies. All statistical analyses were performed using Review Manager version 5.3. RESULTS: A total of 11 articles with 849 study subjects were included, with 474 patients in the ACDF group and 375 patients in the ACCF group. The results of the meta-analysis showed that in C5 palsy (odds ratio [OR]: 0.41; 95% confidence interval [CI]: 0.16-1.06), pseudarthrosis (OR: 1.07; 95% CI: 0.23-5.07), dysphagia (OR: 1.06; 95% CI: 0.60-1.86), infection (OR: 0.41; 95% CI: 0.16-1.09), cerebrospinal fluid leakage (OR: 1.21; 95% CI: 0.39-3.73), graft dislodgment (OR: 0.28; 95% CI: 0.06-1.37), and hematoma (OR: 0.32; 95% CI: 0.06-1.83), there are no significant differences between the ACDF and ACCF groups, whereas total complication (OR: 0.50; 95% CI: 0.31-0.80) showed that the ACDF group had a significantly lower morbidity than the ACCF group. Furthermore, the three-level subgroup of ACDF had significantly better results in C5 palsy (OR: 0.31; 95% CI: 0.11-0.88), infection (OR: 0.22; 95% CI: 0.05-0.94), graft dislodgment (OR: 0.07; 95% CI: 0.01-0.40), and total complication (OR: 0.37; 95% CI: 0.23-0.60) compared with the ACCF subgroup. CONCLUSION: In general, postoperative pseudarthrosis, dysphagia, cerebrospinal fluid leakage, hematoma, C5 palsy, infection, and graft dislodgment did not differ significantly between the two groups. Total complication was significantly less in the ACDF group compared to the ACCF group. In the three-level subgroup, the morbidity of C5 palsy, infection, and graft dislodgment was significantly lower in ACDF than in ACCF.

Unilateral biportal endoscopic versus uniportal full-endoscopic for lumbar degenerative disease: A meta-analysis.

BACKGROUND: Despite the increasing use of unilateral biportal endoscopic (UBE) and uniportal full-endoscopic (UPFE) techniques in lumbar degenerative disease (LDD), few comprehensive and systematic studies have been published comparing UBE and UPFE. Therefore, we conducted a meta-analysis to compare the surgical outcomes of the two procedures. METHODS: We searched all studies that compared operative outcomes of UBE and UPFE for lumbar disc degeneration disease from PubMed, Google Scholar, Web of Science, Chinese Biomedical Literature Database, China National Knowledge Infrastructure (CNKI), Wanfang and other databases up to March 30, 2022. RESULTS: This meta-analysis, which included nine articles, showed that in operative time, (mean difference [MD]: 17.14; 95% confidence intervals [CI]: 6.52 to 27.76), intraoperative bleeding (MD: 59.01; 95% CI: 21.29 to 96.73) and hospital stay (MD: 2.12; 95% CI: 0.35 to 3.90), the UPFE group was more advantageous. UBE had an advantage in terms of postoperative dural expansion area (MD: 59.01; 95% CI: 21.29 to 96.73). These aspects included postoperative clinical score (MD: 0.48; 95% CI: -0.27 to 1.24; MD: -0.07; 95% CI: -0.30 to 0.16; MD: 0.09; 95% CI: -0.09 to 0.26; MD: 0.11; 95% CI: -0.04 to 0.26; MD: -0.81; 95% CI: -3.03 to 1.41; MD: -0.38; 95% CI: -1.02 to 0.26), excellent and good rate (odds ratio [OR] = 1.08; 95% CI: 0.34 to 3.44), complications (OR = 0.82; 95% CI: 0.31 to 2.12), postoperative hospital stay (MD: 1.63; 95% CI: -0.81 to 4.07) and mean number of fluoroscopies (MD: -7.18; 95% CI: -22.84 to 8.48), with no significant difference between the two groups. Meanwhile, the lumbar disc herniation (LDH) subgroup of UPFE had a significantly shorter operation time (MD: 31.67; 95% CI: 12.44 to 50.90) than that of UBE. CONCLUSION: Our study showed that UPFE was associated with shorter operative time, less intraoperative bleeding and shorter hospital stay, whereas UBE was associated with a greater increase in postoperative dural sac area. Postoperative visual analog scale (VAS) scores, Oswestry Disability Index (ODI) scores, satisfaction rates, complications, and mean number of fluoroscopic views were not dramatically dissimilar in UBE and UPFE for LDD. In the LDH subgroup, postoperative hospital stay and operative time were significantly lower in the UPFE group than in the UBE group.

Artemisinin relieves osteoarthritis by activating mitochondrial autophagy through reducing TNFSF11 expression and inhibiting PI3K/AKT/mTOR signaling in cartilage.

Osteoarthritis (OA) is a widespread chronic degenerative joint disease characterized by the degeneration of articular cartilage or inflamed joints. Our findings indicated that treatment with artemisinin (AT) downregulates the protein levels of MMP3, MMP13, and ADAMTS5, which are cartilage degradation-related proteins in OA, and inhibits the expression of inflammatory factors in interleukin-1ß (IL-1ß)-stimulated chondrocytes. However, the mechanism of the role of AT in OA remains unclear. Here, we performed gene sequencing and bioinformatics analysis in control, OA, and OA + AT groups to demonstrate that several mRNA candidates were enriched in the PI3K/AKT/mTOR signaling pathway, and TNFSF11 was significantly downregulated after AT treatment. TNFSF11 was downregulated in the OA + AT group, whereas it was upregulated in rat OA tissues and OA chondrocytes. Therefore, we confirmed that TNFSF11 was the target gene of AT. In addition, our study revealed that AT relieved cartilage degradation and defection by activating mitochondrial autophagy via inhibiting the PI3K/AKT/mTOR signaling pathway in IL-1ß-induced chondrocytes. Furthermore, an OA model was established in rats with medial meniscus destabilization. Injecting AT into the knee joints of OA rat alleviated surgical resection-induced cartilage destruction. Thus, these findings revealed that AT relieves OA by activating mitochondrial autophagy by reducing TNFSF11 expression and inhibiting PI3K/AKT/mTOR signaling.

SEMA6D, Negatively Regulated by miR-7, Contributes to C28/I2 chondrocyte's Catabolic and Anabolic Activities via p38 Signaling Pathway.

MiR-7 has been recognized as an osteoarthritis (OA-)-promoting factor, but the specific downstream pathway of miR-7 still remains unknown. Further investigation of the molecular regulatory mechanism of miR-7 might help develop a novel therapeutic method for OA. In this study, we revealed that Semaphorin 6D (SEMA6D) was a direct target gene of miR-7 and presented a negative regulatory relation with SEMA6D in vitro and in vivo. SEMA6D could improve OA in rat OA models, as indicated by H&E and Safranin O-Fast green staining, and also µCT analysis. Further evaluation of SEMA6D suggested that SEMA6D promotes the anabolism and reduces the catabolism of C28/I2 chondrocytes via inhibiting the activation of the p38 pathway. The present research illustrated that SEMA6D is a negatively regulatory factor of miR-7 and a pivotal mediator of catabolism and anabolism in C28/I2 chondrocytes. SEMA6D exerts its function via inhibiting the activation of the p38 pathway.