Chondrocyte senescence has recently been proposed as a key pathogenic mechanism in the etiology of osteoarthritis (OA).Nevertheless, the precise molecular mechanisms underlying chondrocyte senescence remain poorly understood.To address this knowledge gap, we conducted an investigation into the involvement of Sirtuin 4 (Sirt4) in chondrocyte senescence.Our experimental findings revealed a downregulation of Sirt4 expression in TBHP-induced senescent chondrocytes in vitro, as well as in mouse OA cartilage.Additionally, we observed that the knockdown of Sirt4 in chondrocytes promoted cellular senescence and cartilage degradation, while the overexpression of Sirt4 protected the cells against TBHP-mediated senescence of chondrocytes and cartilage degradation.Moreover, our findings revealed elevated levels of reactive oxygen species (ROS), abnormal mitochondrial morphology, compromised mitochondrial membrane potential, and reduced ATP production in Sirt4 knockdown chondrocytes, indicative of mitochondrial dysfunction.Conversely, Sirt4 overexpression successfully mitigated TBHP-induced mitochondrial dysfunction.Further analysis revealed that Sirt4 downregulation impaired the cellular capacity to eliminate damaged mitochondria by inhibiting Pink1 in chondrocytes, thereby enhancing the accumulation of ROS and facilitating chondrocyte senescence.Notably, the overexpression of Pink1 counteracted the effects of Sirt4 knockdown on mitochondrial dysfunction.Importantly, our study demonstrated the promise of gene therapy employing a lentiviral vector encoding mouse Sirt4, as it successfully preserved the integrity of articular cartilage in mouse models of OA.In conclusion, our findings provide compelling evidence that the overexpression of Sirt4 enhances mitophagy, restores mitochondrial function, and protects against chondrocyte senescence, thereby offering a novel therapeutic target and potential strategy for the treatment of OA.
Abstract Background The optimal treatment of Pauwels type III femoral neck fracture (FNF) in young patients remains a worldwide challenge in orthopedic surgery. Methods Finite element models of four internal fixations were developed to treat Pauwels type III FNF: a: the traditional inverted triangular parallel cannulated screw (PCS) model, b: the F-technique cannulated screw model, c: the modified F-technique cannulated screw model using a fully threaded screw instead of a partially threaded distally, d: the dynamic hip screw coupled with derotational screw (DHS + DS) model. Under the same conditions, finite element analyses were carried out to compare the displacement and von Mises stress distribution of four internal fixations and femurs, the maximum crack distances of the fracture surfaces, Z axis displacements of four models as well as the stress distribution in the subtrochanteric region. Results The modified F-technique configuration resulted in a more stable fixation as compared to the other three configurations, with respect to the maximum displacement and stress peaks of femur and internal fixations, the maximum crack distances of the fracture surfaces, Z axis displacements of four configurations as well as the stress distribution in the subtrochanteric region. Conclusions Our results suggested that modified F-technique configuration show a better performance in resisting shearing and rotational forces in treating Pauwels type III FNF compared to those using traditional inverted triangular PCS, the F-technique configuration or DHS + DS, providing a new choice for the treatment of FNFs.
Objective Most both‐column acetabular fractures are combined with posterior wall fragments. However, the morphology of this posterior wall is varied, and how to fix this posterior wall remains a controversial topic. To investigate the morphological characteristics of posterior wall fragments of both‐column acetabular fractures and select corresponding fixation methods. Methods Data from 352 patients with acetabular fractures admitted to the level one trauma centre in our hospital between January 2006 and December 2022 were collected. The morphology of posterior wall fragments was observed and analyzed in 83 cases of both‐column acetabular fractures and classified according to the consistency of posterior wall morphology. A fracture map of the posterior wall was created on a normal template according to the three morphological types of posterior wall fragments. Finally, the high‐incidence area of the posterior wall fracture was projected onto the iliac fossa and the medial side of the posterior column to guide the fixation of the posterior wall fragment using the anterior intrapelvic approach. Results Fractures were divided into four types: I, large posterior wall fragment which was high in the ilium bone (34 cases, 41.0%); II, posterior wall fragment in the acetabular parietal region (18 cases, 21.7%); III, posterior wall marginal fracture (10 cases, 12.0%); and IV, non‐combined posterior wall fracture (21 cases, 25.3%). The most common morphologies of the posterior wall fragments of the first two types were mapped and projected onto the anterior iliac inner plate and medial side of the posterior column, where the corresponding area could be used to guide the insertion of the internal fixation. Conclusion Both‐column acetabular fractures combined with posterior wall fractures can be divided into four types according to the morphology of the posterior wall fragment. Understanding the corresponding three‐dimensional morphology and projection position of different types of these fragments can help surgeons determine the position and orientation of internal fixation of posterior wall fractures.
Osteoarthritis (OA) is the most prevalent degenerative joint disease in the elderly. Accumulation of evidence has suggested that chondrocyte senescence plays a significant role in OA development. Here, we show that Krüppel-like factor 10 (Klf10), also named TGFβ inducible early gene-1 (TIEG1), is involved in the pathology of chondrocyte senescence. Knocking down the Klf10 in chondrocytes attenuated the tert-butyl hydroperoxide (TBHP)-induced senescence, inhibited generation of reactive oxygen species (ROS), and maintained mitochondrial homeostasis by activating mitophagy. These findings suggested that knocking down Klf10 inhibited senescence-related changes in chondrocytes and improved cartilage homeostasis, indicating that Klf10 may be a therapeutic target for protecting cartilage against OA.
The transforming growth factor-beta (TGF-β) signaling pathway is an important pathway associated with the pathogenesis of osteoarthritis (OA). This study was to investigate the involvement of circRNAs in the TGF-β signaling pathway.Cell Counting Kit-8 (CCK-8) assay and 5-ethynyl-2'-deoxyuridine (EdU) assay were used to detect the proliferation of primary mouse chondrocytes (PMCs). RNA-sequencing together with bioinformatics analysis were used to systematically clarify TGF-β1 induced alternations of circRNAs in PMCs. The regulatory and functional role of circPhf21a was examined in PMCs. Downstream targets of circPhf21a were explored by RNA-sequencing after overexpression of circPhf21a and verified by RT-qPCR in PMCs. Finally, the role and mechanism of circPhf21a in OA were explored in mouse models.We found that TGF-β1 promoted the proliferation of PMCs. Meanwhile, RT-qPCR and western blotting indicated that TGF-β1 promoted extracellular matrix (ECM) anabolism. RNA-sequencing revealed that a total of 36 circRNAs were differentially expressed between PMCs treated with and without TGF-β1. Of these, circPhf21a was significantly decreased by TGF-β1. Furthermore, circPhf21a knockdown promoted the proliferation and ECM synthesis of PMCs, whereas overexpression of circPhf21a showed the opposite effects. Mechanically, the expression profiles of the mRNAs revealed that Vegfa may be the target of circPhf21a. Additionally, we found that circPhf21a was significantly upregulated in the mouse OA model, and inhibition of circPhf21a significantly relieved the progression of OA.Our results found that TGF-β1 promoted the proliferation and ECM synthesis of PMCs via the circPhf21a-Vegfa axis, which may provide novel therapeutic targets for OA treatment. Video abstract.
Abstract Background The management of Garden IV femoral neck fractures presents a formidable challenge. This study aimed to assess the safety and efficacy of a novel technological approach for treating Garden IV femoral neck fractures, involving intracapsular decompression and the utilization of supported hollow screws. Methods Between October 2018 and October 2021, a cohort of 46 patients, comprising 25 males and 21 females, was admitted for Garden IV femoral neck fractures. The surgical intervention employed a novel methodology, involving closed reduction of femoral neck fractures on a traction bed and percutaneous implantation of decompression support hollow screw internal fixation in the capsule. Operative parameters such as intraoperative bleeding volume, incision length, and fluoroscopy frequency were recorded. Postoperative angiography was performed to evaluate the blood supply to the femoral neck and femoral head, while long-term follow-up records documented femoral neck fracture healing and patient functional recovery. Results The closed reduction and minimally invasive implantation of decompression support screws in the femoral neck capsule proved effective in successfully fixing Garden IV femoral neck fractures. The screw placement time was 20–45 min, with an average of 25.2 min. The number of fluoroscopy was 6–14, with an average of 7. The postoperative follow-up was 20–25 months, with an average duration of 22 months. All patients exhibited uneventful single-stage wound healing, devoid of complications such as nerve, blood vessel, or important tissue structure injuries. While femoral head necrosis occurred in one case and femoral neck shortening in another, all femoral neck fractures exhibited healing. Post-surgery, patients experienced rapid recovery, enabling early functional exercise with satisfactory functional restoration. Conclusion The innovative technology, employing femoral neck capsule decompression support hollow screws, not only offers structural support, but also facilitates capsule decompression post-femoral neck fracture surgery. This approach promotes the restoration of blood flow to the femoral head and neck, accelerates fracture healing, diminishes the likelihood of femoral head necrosis, and enhances the overall therapeutic outcome for Garden IV femoral neck fractures. The merits of this novel technique warrant its widespread adoption and application.
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