Department of Orthopaedic Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
J Orthop Res. 2010 Jul;28(7):937-41. doi: 10.1002/jor.21086.
Skeletal fracture healing involves a variety of cellular and molecular events; however, the mechanisms behind these processes are not fully understood. In the current study, we investigated the potential involvement of the signal transducer and activator of transcription 1 (STAT1), a critical regulator for both osteoclastogenesis and osteoblast differentiation, in skeletal fracture healing. We used a fracture model and a cortical defect model in mice, and found that fracture callus remodeling and membranous ossification are highly accelerated in STAT1-deficient mice. Additionally, we found that STAT1 suppresses Osterix transcript levels and Osterix promoter activity in vitro, indicating the suppression of Osterix transcription as one of the mechanisms behind the inhibitory effect of STAT1 on osteoblast differentiation. Furthermore, we found that fludarabine, a potent STAT1 inhibitor, significantly increases bone formation in a heterotopic ossification model. These results reveal previously unknown functions of STAT1 in skeletal homeostasis and may have important clinical implications for the treatment of skeletal bone fracture.
骨骼骨折愈合涉及多种细胞和分子事件；然而，这些过程背后的机制尚未完全了解。在本研究中，我们研究了信号转导子和转录激活子 1（STAT1）的潜在参与，STAT1 是破骨细胞生成和成骨细胞分化的关键调节剂，在骨骼骨折愈合中。我们使用了小鼠的骨折模型和皮质缺损模型，发现 STAT1 缺陷型小鼠的骨折痂重塑和膜内成骨过程显著加速。此外，我们发现 STAT1 在体外抑制 Osterix 转录本水平和 Osterix 启动子活性，表明 STAT1 对成骨细胞分化的抑制作用的一种机制是抑制 Osterix 转录。此外，我们发现氟达拉滨，一种有效的 STAT1 抑制剂，在异位骨化模型中显著增加骨形成。这些结果揭示了 STAT1 在骨骼稳态中的以前未知的功能，并且可能对骨骼骨折的治疗具有重要的临床意义。
