Sarsasapogenin inhibits YAP1-dependent chondrocyte ferroptosis to alleviate osteoarthritis.

The involvement of chondrocyte ferroptosis in the development of osteoarthritis (OA) has been observed, and Sarsasapogenin (Sar) has therapeutic promise in a variety of inflammatory diseases. This study investigates the potential influence of Sar on the mechanism of chondrocyte ferroptotic cell death in the progression of osteoarthritic cartilage degradation. An in vivo medial meniscus destabilization (DMM)-induced OA animal model as well as an in vitro examination of chondrocytes in an OA microenvironment induced by interleukin-1ß (IL-1ß) exposure were employed. Histology, immunofluorescence, quantitative RT-PCR, Western blot, cell viability, and Micro-CT analysis were utilized in conjunction with gene overexpression and knockdown to evaluate the chondroprotective effects of Sar in OA progression and the role of Yes-associated protein 1 (YAP1) in Sar-induced ferroptosis resistance of chondrocytes. In this study we found Sar reduced chondrocyte ferroptosis and OA progression. And Sar-induced chondrocyte ferroptosis resistance was mediated by YAP1. Furthermore, infection of siRNA specific to YAP1 in chondrocytes reduced Sar's chondroprotective and ferroptosis-suppressing effects during OA development. The findings suggest that Sar mitigates the progression of osteoarthritis by decreasing the sensitivity of chondrocytes to ferroptosis through the promotion of YAP1, indicating that Sar has the potential to serve as a therapeutic approach for diseases associated with ferroptosis.

Rejuvenation of tendon stem/progenitor cells for functional tendon regeneration through platelet-derived exosomes loaded with recombinant Yap1.

The regenerative capabilities including self-renewal, migration and differentiation potentials shift from the embryonic phase to the mature period of endogenous tendon stem/progenitor cells (TSPCs) characterize restricted functions and disabilities following tendon injuries. Recent studies have shown that tendon regeneration and repair rely on multiple specific transcription factors to maintain TSPCs characteristics and functions. Here, we demonstrate Yap, a Hippo pathway downstream effector, is associated with TSPCs phenotype and regenerative potentials through gene expression analysis of tendon development and repair process. Exosomes have been proven an efficient transport platform for drug delivery. In this study, purified exosomes derived from donor platelets are loaded with recombinant Yap1 protein (PLT-Exo-Yap1) via electroporation to promote the stemness and differentiation potentials of TSPCs in vitro. Programmed TSPCs with Yap1 import maintain stemness and functions after long-term passage in vitro. The increased oxidative stress levels of TSPCs are related to the phenotype changes in duplicative senescent processes. The results show that treatment with PLT-Exo-Yap1 significantly protects TSPCs against oxidative stressor-induced stemness loss and senescence-associated secretory phenotype (SASP) through the NF-κB signaling pathway. In addition, we fabricate an Exos-Yap1-functioned GelMA hydrogel with a parallel-aligned substrate structure to enhance TSPCs adhesion, promote cell stemness and force regenerative cells toward the tendon lineage for in vitro and in vivo tendon regeneration. The application of Exos-Yap1 functioned implant assists new tendon-like tissue formation with good mechanical properties and locomotor functions in a full-cut Achilles tendon defect model. Thus, PLT-Exo-Yap1-functionalized GelMA promotes the rejuvenation of TSPCs to facilitate functional tendon regeneration. STATEMENT OF SIGNIFICANCE: This is the first study to explore that the hippo pathway downstream effector Yap is involved in tendon aging and repair processes, and is associated with the regenerative capabilities of TSPCs. In this syudy, Platelet-derived exosomes (PLT-Exos) act as an appropriate carrier platform for the delivery of recombinant Yap1 into TSPCs to regulate Yap activity. Effective Yap1 delivery inhibit oxidative stress-induced senescence associated phenotype of TSPCs by blocking ROS-mediated NF-κb signaling pathway activation. This study emphasizes that combined application of biomimetic scaffolds and Yap1 loaded PLT-Exos can provide structural support and promote rejuvenation of resident cells to assist functional regeneration for Achilles tendon defect, and has the prospect of clinical setting.

A Novel Suture-Preset Spring Plate System (SSPS) for Comminuted Coronoid Process Fracture in the Elbow.

OBJECTIVE: This study is aimed to investigate the clinical outcomes of a novel SSPS for fixation of the comminuted coronoid fracture. METHODS: A retrospective study was carried out in the patients with comminuted fractures of the coronoid treated by SPSS fixation between January 2014 and December 2018. A total of 17 patients (17 sides) was included in our study, including 11 male and six female, with a mean age range from 18 to 60. All cases started to functional rehabilitation immediately after the operation. Clinical outcomes were evaluated both radiographically and functionally at the follow-up visit, including the elbow instability, range of motion and Mayo elbow performance score (MEPS). RESULTS: According to the O'Driscoll classification system, there was two side of type 1.2, two of type 2.1, four of type 2.2, three of type 2.3, two of 3.1 and four of type 3.2. The surgery was carried out by Kocher and anteromedial approach in 12 patients, posterior and anteromedial approach in four, anterior approach in one. The average operation time and intraoperative blood loss was 129.41±43.87 min and 115.29±104.65 ml. The median follow-up time was 9 months (range, 6 to 15 months). The mean flexion, extension, pronation and supination motion was 138.76±8.67 degrees, 20.00±13.58, 82.94±5.32and 74.12±14.39 respectively at final follow up. The mean MEPS score was 89.76±8.46, including 11 excellent, 3 good and 3 fair result. The mean VAS score was 1.94±0.97. The mean union time of coronoid fractures was 2.77±0.31 months according to the established standard of healing. There were no significant differences in clinical outcomes among groups according to the O'Driscoll classification (P > .05) and ligament repair strategy (P > .05). No patient underwent instability or dislocation of the elbow during follow up. There were two cases with mild ulnar nerve symptoms which recovered totally at follow up. Meanwhile, there were three cases with heterotopic ossification of the elbow. CONCLUSION: Our findings demonstrated that the SSPS can provide a reliable fixation for the comminuted coronoid fracture with satisfactory clinical outcomes.