Traumatology & Orthopedics Institute, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P.R. China.
Department of Orthopedic, the Third Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P.R. China.
FASEB J. 2024 Jul 31;38(14):e23810. doi: 10.1096/fj.202400075RR.
Osteofibrous dysplasia (OFD) is a rare, benign, fibro-osseous lesion that occurs most commonly in the tibia of children. Tibial involvement leads to bowing and predisposes to the development of a fracture which exhibit significantly delayed healing processes, leading to prolonged morbidity. We previously identified gain-of-function mutations in the MET gene as a cause for OFD. In our present study, we test the hypothesis that gain-of-function MET mutations impair bone repair due to reduced osteoblast differentiation. A heterozygous Met exon 15 skipping (Met-HET) mouse was created to imitate the human OFD mutation. The mutation results in aberrant and dysregulation of MET-related signaling determined by RNA-seq in the murine osteoblasts extracted from the wide-type and genetic mice. Although no gross skeletal defects were identified in the mice, fracture repair was delayed in Met-HET mice, with decreased bone formation observed 2-week postfracture. Our data are consistent with a novel role for MET-mediated signaling regulating osteogenesis.
骨纤维结构不良（OFD）是一种罕见的良性纤维骨病变，最常发生在儿童的胫骨中。胫骨受累会导致弯曲，并容易发生骨折，这些骨折的愈合过程明显延迟，导致发病率延长。我们之前发现 MET 基因的功能获得性突变是 OFD 的一个原因。在我们目前的研究中，我们测试了这样一个假设，即功能获得性 MET 突变会由于成骨细胞分化减少而损害骨修复。创建了杂合 Met 外显子 15 跳跃（Met-HET）小鼠来模拟人类 OFD 突变。该突变导致了在从野生型和遗传型小鼠中提取的鼠成骨细胞中通过 RNA-seq 确定的异常和失调的 MET 相关信号。尽管在小鼠中未发现明显的骨骼缺陷，但 Met-HET 小鼠的骨折修复延迟，骨折后 2 周观察到骨形成减少。我们的数据与 MET 介导的信号调节成骨作用的新作用一致。
