Center of Craniofacial Orthodontics, Department of Oral and Cranio-maxillofacial Science, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Disease, Shanghai Key Laboratory of Stomatology, Shanghai, 200011, China.
2nd Dental Center, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Disease, Shanghai Key Laboratory of Stomatology, Shanghai, 200011, China.
Nat Commun. 2021 Nov 25;12(1):6891. doi: 10.1038/s41467-021-27273-w.
Skeletal deformities are typical AD-HIES manifestations, which are mainly caused by heterozygous and loss-of-function mutations in Signal transducer and activator of transcription 3 (STAT3). However, the mechanism is still unclear and the treatment strategy is limited. Herein, we reported that the mice with Stat3 deletion in osteoblasts, but not in osteoclasts, induced AD-HIES-like skeletal defects, including craniofacial malformation, osteoporosis, and spontaneous bone fracture. Mechanistic analyses revealed that STAT3 in cooperation with Msh homeobox 1(MSX1) drove osteoblast differentiation by promoting Distal-less homeobox 5(Dlx5) transcription. Furthermore, pharmacological activation of STAT3 partially rescued skeletal deformities in heterozygous knockout mice, while inhibition of STAT3 aggravated bone loss. Taken together, these data show that STAT3 is critical for modulating skeletal development and maintaining bone homeostasis through STAT3-indcued osteogenesis and suggest it may be a potential target for treatments.
骨骼畸形是 AD-HIES 的典型表现，主要由信号转导和转录激活因子 3（STAT3）的杂合和功能丧失突变引起。然而，其机制尚不清楚，治疗策略也有限。在此，我们报道了成骨细胞而非破骨细胞中 Stat3 缺失的小鼠会诱导 AD-HIES 样骨骼缺陷，包括颅面畸形、骨质疏松症和自发性骨折。机制分析表明，STAT3 与同源盒基因 1（MSX1）合作，通过促进远隔同源盒 5（Dlx5）转录来驱动成骨细胞分化。此外，STAT3 的药理学激活部分挽救了杂合敲除小鼠的骨骼畸形，而 STAT3 的抑制则加重了骨质流失。总之，这些数据表明 STAT3 通过 STAT3 诱导的成骨作用对于调节骨骼发育和维持骨稳态至关重要，并表明它可能是一种有治疗潜力的靶点。
