Wang Yidi, Wen Xi, Guo Yutong, Wang Yixiang, Gu Yan
Department of Orthodontics, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, No. 22, Zhongguancun Avenue South, Haidian District, Beijing 100081, China.
Central Laboratory, Peking University School and Hospital of Stomatology, No. 22, Zhongguancun Avenue South, Haidian District, Beijing 100081, China.
Int J Mol Sci. 2025 Mar 18;26(6):2724. doi: 10.3390/ijms26062724.
The mandibular condyle cartilage serves as a principal zone for mandible growth, and any dysplasia could contribute to skeletal mandibular hypoplasia (SMH). The aim of the study was to further explore how TFRC signaling regulates condylar cartilage development. In this study, TFRC, SLC39A14, chondrogenic markers and ferroptosis-related signals were detected in the condylar cartilage of postnatal mice and cartilage conditional knockout (-cKO) mice at different time points through immunofluorescence, immunohistochemical staining and qPCR assays. The overexpression and knockdown of TFRC in the ATDC5 cell line were used to investigate its role in a specific biological process. Co-immunoprecipitation was used to verify protein-protein interaction in vitro. Ferroptosis inhibitor Fer1, Ac-Met-OH and DFP were used for an in vitro rescue assay. The temporomandibular joint injection of DFP was used to rescue the cartilage phenotype in vivo. Our results verified that TFRC was crucial for condylar cartilage development. TFRC ablation led to condylar cartilage thickness and condyle length alterations and induced the ferroptosis of chondrocyte by upregulating SLC39A14. Mitochondrial p53 translocation was involved in the TFRC-SLC39A14 switch by SLC39A14 ubiquitination degradation. Fer1, Ac-Met-OH and DFP inhibited ferroptosis and restored chondrogenic differentiation in vivo. The temporomandibular joint injection of DFP could rescue the cartilage phenotype. In summary, this study reveals that TFRC influences postnatal condylar cartilage development through mitochondrial p53 translocation-mediated ferroptosis, which provides insights into the etiology, pathogenesis, and therapy of mandibular hypoplasia and even systemic articular cartilage dysplasia.
下颌髁突软骨是下颌骨生长的主要区域，任何发育异常都可能导致下颌骨骨骼发育不全（SMH）。本研究的目的是进一步探讨TFRC信号通路如何调节髁突软骨发育。在本研究中，通过免疫荧光、免疫组织化学染色和qPCR检测，在出生后小鼠和软骨条件性敲除（-cKO）小鼠不同时间点的髁突软骨中检测TFRC、SLC39A14、软骨生成标志物和铁死亡相关信号。利用ATDC5细胞系中TFRC的过表达和敲低来研究其在特定生物学过程中的作用。采用免疫共沉淀法体外验证蛋白质-蛋白质相互作用。使用铁死亡抑制剂Fer1、Ac-Met-OH和DFP进行体外挽救实验。通过颞下颌关节注射DFP来挽救体内软骨表型。我们的结果证实TFRC对髁突软骨发育至关重要。TFRC缺失导致髁突软骨厚度和髁突长度改变，并通过上调SLC39A14诱导软骨细胞铁死亡。线粒体p53易位通过SLC39A14泛素化降解参与TFRC-SLC39A14转换。Fer1、Ac-Met-OH和DFP在体内抑制铁死亡并恢复软骨生成分化。颞下颌关节注射DFP可挽救软骨表型。总之，本研究揭示TFRC通过线粒体p53易位介导的铁死亡影响出生后髁突软骨发育，这为下颌发育不全甚至全身关节软骨发育异常的病因、发病机制和治疗提供了见解。
