Wade Emma M, Goodin Elizabeth A, Wang Yongqiang, Morgan Tim, Callon Karen E, Watson Maureen, Daniel Philip B, Cornish Jillian, McCulloch Christopher A, Robertson Stephen P
Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada.
Bone Rep. 2023 Feb 28;18:101668. doi: 10.1016/j.bonr.2023.101668. eCollection 2023 Jun.
Mutations in , which encodes the cytoskeletal protein FLNA, cause a spectrum of sclerosing skeletal dysplasias. Although many of these genetic variants are recurrent and cluster within the gene, the pathogenic mechanism that underpins the development of these skeletal phenotypes is unknown. To determine if the skeletal dysplasia in -related conditions is due to a cell-autonomous loss-of-function localising to osteoblasts and/or osteocytes, we utilised mouse models to conditionally remove from this cellular lineage. was conditionally knocked out from mature osteocytes using the promoter driven Cre-recombinase expressing mouse, as well as the committed osteoblast lineage using the Cre or -Cre expressing lines. We measured skeletal parameters with μCT and histological methods, as well as gene expression in the mineralised skeleton. We found no measureable differences between the conditional knockout mice, and their control littermate counterparts. Moreover, all of the conditional knockout mice, developed and aged normally. From this we concluded that the skeletal dysplasia phenotype associated with pathogenic variants in is not caused by a cell-autonomous loss-of-function in the osteoblast-osteocyte lineage, adding more evidence to the hypothesis that these phenotypes are due to gain-of-function in
编码细胞骨架蛋白FLNA的基因发生突变会导致一系列硬化性骨骼发育不良。尽管这些基因变异中有许多是反复出现的且聚集在该基因内，但这些骨骼表型发育的致病机制尚不清楚。为了确定与该基因相关疾病中的骨骼发育不良是否是由于成骨细胞和/或骨细胞中细胞自主功能丧失所致，我们利用小鼠模型有条件地从该细胞谱系中去除该基因。使用启动子驱动的表达Cre重组酶的小鼠，以及表达Cre或Osterix-Cre的品系，有条件地从成熟骨细胞以及定向成骨细胞谱系中敲除该基因。我们用μCT和组织学方法测量骨骼参数，以及矿化骨骼中的基因表达。我们发现条件性敲除该基因的小鼠与其对照同窝小鼠之间没有可测量的差异。此外，所有条件性敲除该基因的小鼠都正常发育和衰老。由此我们得出结论，与该基因致病变异相关的骨骼发育不良表型不是由成骨细胞-骨细胞谱系中的细胞自主功能丧失引起的，这为这些表型是由于功能获得这一假说增加了更多证据。
