PDF(Pubmed)
Abstract：
Osteogenesis imperfecta (OI) is a disorder of low bone mass and increased fracture risk due to a range of genetic variants that prominently include mutations in genes encoding type collagen. While it is well known that OI reflects defects in the activity of bone-forming osteoblasts, it is currently unclear whether OI also reflects defects in the many other cell types comprising bone, including defects in skeletal vascular endothelium or the skeletal stem cell populations that give rise to osteoblasts and whether correcting these broader defects could have therapeutic utility. Here, we find that numbers of skeletal stem cells (SSCs) and skeletal arterial endothelial cells (AECs) are augmented in Col1a2oim/oim mice, a well-studied animal model of moderate to severe OI, suggesting that disruption of a vascular SSC niche is a feature of OI pathogenesis. Moreover, crossing Col1a2oim/oim mice to mice lacking a negative regulator of skeletal angiogenesis and bone formation, Schnurri 3 (SHN3), not only corrected the SSC and AEC phenotypes but moreover robustly corrected the bone mass and spontaneous fracture phenotypes. As this finding suggested a strong therapeutic utility of SHN3 inhibition for the treatment of OI, a bone-targeting AAV was used to mediate Shn3 knockdown, rescuing the Col1a2oim/oim phenotype and providing therapeutic proof-of-concept for targeting SHN3 for the treatment of OI. Overall, this work both provides proof-of-concept for inhibition of the SHN3 pathway and more broadly addressing defects in the stem/osteoprogentior niche as is a strategy to treat OI.
摘要：
成骨不全症（OI）是一种低骨量和骨折风险增加的疾病，由于一系列遗传变异，主要包括编码Ⅰ型胶原蛋白的基因突变。虽然众所周知，OI反映了骨形成成骨细胞活性的缺陷，目前尚不清楚OI是否也反映了骨骼中许多其他细胞类型的缺陷，包括骨骼血管内皮或产生成骨细胞的骨骼干细胞群的缺陷，以及纠正这些更广泛的缺陷是否具有治疗作用。这里,我们发现，在Col1a2oim/oim小鼠中，骨骼干细胞（SSC）和骨骼动脉内皮细胞（AECs）的数量增加，研究良好的中度至重度OI动物模型，表明血管SSC生态位的破坏是OI发病机制的特征。此外，将Col1a2oim/oim小鼠与缺乏骨骼血管生成和骨形成负调节剂的小鼠交叉，Schnurri3(SHN3),不仅纠正了SSC和AEC表型，而且还有力地纠正了骨量和自发性骨折表型。由于这一发现表明SHN3抑制用于治疗OI的强大治疗效用，骨靶向AAV用于介导Sn3敲低，挽救Col1a2oim/oim表型，并提供靶向SHN3治疗OI的治疗概念证明。总的来说,这项工作既为抑制SHN3通路提供了概念验证,也更广泛地解决了茎/骨祖细胞生态位的缺陷,这是治疗OI的一种策略.
