Bi Ruiye, Luo Xueting, Li Qianli, Li Peiran, Li Haohan, Fan Yi, Ying Binbin, Zhu Songsong
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthognathic and TMJ Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Department of Stomatology, Ningbo First Hospital, Ningbo, China.
J Bone Miner Res. 2023 Apr;38(4):556-567. doi: 10.1002/jbmr.4782. Epub 2023 Feb 13.
Temporomandibular joint (TMJ) growth requires orchestrated interactions between various cell types. Recent studies revealed that fibrocartilage stem cells (FCSCs) in the TMJ cartilage play critical roles as cell resources for joint development and repair. However, the detailed molecular network that influences FCSC fate during TMJ cartilage development remains to be elucidated. Here, we investigate the functional role of Igf1 in FCSCs for TMJ cartilage growth and homeostasis by lineage tracing using Gli1-CreER ; Tm mice and conditional Igf1 deletion using Gli1-/Col2-CreER ; Igf1 mice. In Gli1-CreER ; Tm mice, red fluorescence (RFP ) FCSCs show a favorable proliferative capacity. Igf1 deletion in Gli1 /Col2 cell lineages leads to distinct pathological changes in TMJ cartilage. More serious cartilage thickness and cell density reductions are found in the superficial layers in Gli1-CreER ; Igf1 mice. After long-term Igf1 deletion, a severe disordered cell arrangement is found in both groups. When Igf1 is conditionally deleted in vivo, the red fluorescent protein-labeled Gli1 FCSC shows a significant disruption of chondrogenic differentiation, cell proliferation, and apoptosis leading to TMJ cartilage disarrangement and subchondral bone loss. Immunostaining shows that pAkt signaling is blocked in all cartilage layers after the Gli1 -specific deletion of Igf1. In vitro, Igf1 deletion disrupts FCSC capacities, including proliferation and chondrogenesis. Moreover, the deletion of Igf1 in FCSCs significantly aggravates the joint osteoarthritis phenotype in the unilateral anterior crossbite mouse model, characterized by decreased cartilage thickness and cell numbers as well as a loss of extracellular matrix secretions. These findings uncover Igf1 as a regulator of TMJ cartilage growth and repair. The deletion of Igf1 disrupts the progenitor capacity of FCSCs, leading to a disordered cell distribution and exaggerating TMJ cartilage dysfunction. © 2023 American Society for Bone and Mineral Research (ASBMR).
颞下颌关节（TMJ）的生长需要多种细胞类型之间协调的相互作用。最近的研究表明，TMJ软骨中的纤维软骨干细胞（FCSCs）作为关节发育和修复的细胞资源发挥着关键作用。然而，在TMJ软骨发育过程中影响FCSC命运的详细分子网络仍有待阐明。在这里，我们通过使用Gli1-CreER;Tm小鼠进行谱系追踪以及使用Gli1-/Col2-CreER;Igf1小鼠进行条件性Igf1缺失，来研究Igf1在FCSCs中对TMJ软骨生长和稳态的功能作用。在Gli1-CreER;Tm小鼠中，红色荧光（RFP）FCSCs显示出良好的增殖能力。Gli1/Col2细胞谱系中Igf1的缺失导致TMJ软骨出现明显的病理变化。在Gli1-CreER;Igf1小鼠的表层发现更严重的软骨厚度和细胞密度降低。长期缺失Igf1后，两组均出现严重的细胞排列紊乱。当在体内条件性缺失Igf1时，红色荧光蛋白标记的Gli1 FCSC显示软骨生成分化、细胞增殖和凋亡受到显著破坏，导致TMJ软骨排列紊乱和软骨下骨丢失。免疫染色显示，在Gli1特异性缺失Igf1后，所有软骨层中的pAkt信号均被阻断。在体外，Igf1的缺失破坏了FCSC的能力，包括增殖和成软骨能力。此外，FCSCs中Igf1的缺失显著加重了单侧前牙反咬合小鼠模型中的关节骨关节炎表型，其特征是软骨厚度和细胞数量减少以及细胞外基质分泌丧失。这些发现揭示了Igf1是TMJ软骨生长和修复的调节因子。Igf1的缺失破坏了FCSCs的祖细胞能力，导致细胞分布紊乱并加剧TMJ软骨功能障碍。©2023美国骨与矿物质研究学会（ASBMR）
