Abnormal mechanical stress induced chondrocyte senescence by YAP loss-mediated METTL3 upregulation.

OBJECTIVES: Abnormal mechanical stress is the pivotal risk factor of temporomandibular joint osteoarthritis (TMJOA). This study investigated the pathogenic mechanism by which abnormal mechanical stress induced chondrocyte senescence. MATERIALS AND METHODS: Cellular senescence was investigated in the rodent model of unilateral anterior crossbite and in the chondrocytes subjected to mechanical overloading in vitro. The effects of Yes-associated protein (YAP) in chondrocyte senescence and its correlation with methyltransferase-like 3 (METTL3) and N6 -methyladenosine (m6 A) modification were evaluated. The role of m6 A modification in chondrocyte senescence was determined. The therapeutic effects of m6 A inhibition in TMJOA were investigated. RESULTS: Senescent chondrocytes were accumulated in the mechanically induced TMJOA lesions in rats and mechanical overloading could trigger chondrocyte senescence in vitro. This mechanical stress-induced cellular senescence was revealed to be mediated by YAP deficiency that promoted METTL3-dependent m6 A modification. Moreover, inhibition of m6 A modification rescued chondrocyte senescence in vitro and in vivo, and suppressed TMJOA progression in rats. CONCLUSIONS: This study uncovered the underlying mechanism of mechanically induced senescence in TMJOA from the perspective of epitranscriptomics and revealed the therapeutic potential of m6 A inhibition in TMJOA.

Antibacterial and Angiogenic (2A) Bio-Heterojunctions Facilitate Infectious Ischemic Wound Regeneration via an Endogenous-Exogenous Bistimulatory Strategy.

In infectious ischemic wounds, a lack of blood perfusion significantly worsens microbe-associated infection symptoms and frequently complicates healing. To overcome this daunting issue, antibacterial and angiogenic (2A) bio-heterojunctions (bio-HJs) consisting of CuS/MXene heterojunctions and a vascular endothelial growth factor (VEGF)-mimicking peptide (VMP) are devised and developed to accelerate infectious cutaneous regeneration by boosting angiogenesis via an endogenous-exogenous bistimulatory (EEB) strategy. Assisted by near-infrared irradiation, the bio-HJ platform exhibits versatile synergistic photothermal, photodynamic, and chemodynamic effects for robust antibacterial efficacy. In addition, copper ions liberated from 2A bio-HJs elevate VEGF secretion from fibroblasts, which provokes VEGF receptors (VEGFR) activation through an endogenous pathway, whereas VMP itself promotes an exogenous pathway to facilitate endothelial cell multiplication and tube formation by directly activating the VEGFR signaling pathway. Moreover, employing an in vivo model of infectious ischemic wounds, it is confirmed that the EEB strategy can considerably boost cutaneous regeneration through pathogen elimination, angiogenesis promotion, and collagen deposition. As envisaged, this work leads to the development of a powerful 2A bio-HJ platform that can serve as an effective remedy for bacterial invasion-induced ischemic wounds through the EEB strategy.

YAP/TEAD1 and ß-catenin/LEF1 synergistically induce estrogen receptor α to promote osteogenic differentiation of bone marrow stromal cells.

Bone remodeling is vital to the maintenance of bone homeostasis and may lead to destructive skeletal diseases once the balance is disrupted. Crosstalk between Wnt and estrogen receptor (ER) signaling has been proposed in bone remodeling, but the underlying mechanism remains unclear. This study was designed to explore the effect of Wnt-ER signaling during the osteogenic differentiation of bone marrow stromal cells (BMSCs). Rat BMSCs were isolated and identified using flow cytometry and stimulated with Wnt3a. Wnt3a treatment promoted osteogenic differentiation and mineralization of the BMSCs. Meanwhile, Wnt3a enhanced the expression of ERα as well as the canonical Wnt signaling mediator ß-catenin and the alternative Wnt signaling effector Yes-associated protein 1 (YAP1). Interestingly, DNA pulldown assay revealed direct binding of transcriptional enhanced associate domain 1 (TEAD1) and lymphoid enhancer binding factor 1 (LEF1), transcriptional partners of YAP1 and ß-catenin, respectively, to the promoter region of ERα. In addition, inhibition of TEAD1 and LEF1 suppressed Wnt3-promoted BMSC osteogenic differentiation and blocked Wnt3a-induced ERα expression. Furthermore, an in vivo model of femoral bone defect also supported that Wnt3a facilitated bone healing in an ERα-dependent way. Together, we suggest that Wnt3a promotes the osteogenic activity of BMSCs through YAP1 and ß-catenin-dependent activation of ERα, via direct binding of TEAD1 and LEF1 to the ERα promoter.

A 3D-printed orthopedic implant with dual-effect synergy based on MoS2 and hydroxyapatite nanoparticles for tumor therapy and bone regeneration.

Treatments for malignant bone tumors are urgently needed to be developed due to the dilemma of precise resection of tumor tissue and subsequent bone defects. Although polyether-ether-ketone (PEEK) has widely attracted attention in the orthopedic field, its bioinertness and poor osteogenic properties significantly restrict its applications in bone tumor treatment. To tackle the daunting issue, we use a hydrothermal technique to fabricate novel PEEK scaffolds modified with molybdenum disulfide (MoS2) nanosheets and hydroxyapatite (HA) nanoparticles. Our dual-effect synergistic PEEK scaffolds exhibit perfect photothermal therapeutic (PTT) property dependent on molybdous ion (Mo2+) concentration and laser power density, superior to conventional PEEK scaffolds. Under near-infrared (NIR) irradiation, the viability of MG63 osteosarcoma cells is significantly reduced by modified PEEK scaffolds, indicating a tumor-killing potential in vitro. Furthermore, the incorporation of HA nanoparticles on the surface of PEEK bolsters proliferation and adherence of MC3T3-E1 cells, boosting mineralization for further bone defect repair. The results of micro-computed tomography (micro-CT) and histological analysis of 4-week treated rat femora demonstrate the preeminent photothermal and osteogenesis capacity of 3D-printed modified scaffolds in vivo. In conclusion, the dual-effect synergistic orthopedic implant with photothermal anticancer property and osteogenic induction activity strikes a balance between tumor treatment and bone development promotion, offering a promising future therapeutic option.