Department of Orthodontics, Peking University School and Hospital of Stomatology and National Center of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing, China.
Central Laboratory, Peking University School and Hospital of Stomatology and National Center of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing, China.
Clin Sci (Lond). 2023 Sep 27;137(18):1431-1449. doi: 10.1042/CS20230544.
Skeletal mandibular hypoplasia (SMH) is one of the most common skeletal craniofacial deformities in orthodontics, which was often accompanied by impaired chondrogenesis and increasing apoptosis of condylar chondrocytes. Therefore, protecting chondrocytes from apoptosis and promoting chondrogenesis in condylar growth is vital for treatment of SMH patients. Transferrin (TF) was highly expressed in condylar cartilage of newborn mice and was gradually declined as the condyle ceased growing. Interestingly, serum level of TF in SMH patients was significantly lower than normal subjects. Hence, the aim of our study was to investigate the effect of TF on survival and differentiation of chondrocytes and condylar growth. First, we found that TF protected chondrogenic cell line ATDC5 cells from hypoxia-induced apoptosis and promoted proliferation and chondrogenic differentiation in vitro. Second, TF promoted chondrogenic differentiation and survival through activating autophagic flux. Inhibiting autophagic flux markedly blocked the effects of TF. Third, TF significantly activated ULK1-ATG16L1 axis. Silencing either transferrin receptor (TFRC), ULK1/2 or ATG16 significantly blocked the autophagic flux induced by TF, as well as its effect on anti-apoptosis and chondrogenic differentiation. Furthermore, we established an organoid culture model of mandible ex vivo and found that TF significantly promoted condylar growth. Taken together, our study unraveled a novel function of TF in condylar growth that TF protected chondrocytes from hypoxia-induced apoptosis and promoted chondrogenic differentiation through inducing autophagy via ULK1-ATG16L1 axis, which demonstrated that TF could be a novel growth factor of condylar growth and shed new light on developing treatment strategy of SMH patients.
下颌骨发育不全（SMH）是口腔正畸中最常见的颅面骨骼畸形之一，常伴有软骨生成受损和髁突软骨细胞凋亡增加。因此，保护软骨细胞免受凋亡并促进髁突生长中的软骨生成对于 SMH 患者的治疗至关重要。转铁蛋白（TF）在新生小鼠的髁状突软骨中高度表达，并随着髁突生长的停止而逐渐下降。有趣的是，SMH 患者血清中的 TF 水平明显低于正常对照。因此，我们的研究旨在探讨 TF 对软骨细胞的存活和分化以及髁突生长的影响。首先，我们发现 TF 可保护软骨细胞系 ATDC5 细胞免受缺氧诱导的凋亡，并在体外促进增殖和软骨分化。其次，TF 通过激活自噬流促进软骨分化和存活。抑制自噬流显著阻断了 TF 的作用。第三，TF 显著激活 ULK1-ATG16L1 轴。沉默转铁蛋白受体（TFRC）、ULK1/2 或 ATG16 均可显著阻断 TF 诱导的自噬流及其对抗凋亡和软骨分化的作用。此外，我们建立了下颌骨离体器官样培养模型，发现 TF 可显著促进髁突生长。综上所述，我们的研究揭示了 TF 在髁突生长中的一个新功能，即 TF 通过 ULK1-ATG16L1 轴诱导自噬来保护软骨细胞免受缺氧诱导的凋亡并促进软骨分化，这表明 TF 可能是一种新的髁突生长因子，为 SMH 患者的治疗策略提供了新的思路。
