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 I 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 Col1a2^oim/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 Col1a2^oim/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 Col1a2^oim/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/osteoprogenitor niche as is a strategy to treat OI.

成骨不全症 (OI) 是一种骨量低、骨折风险增加的疾病，其原因是一系列遗传变异，其中主要包括编码 I 型胶原蛋白的基因突变。众所周知，成骨不全反映了成骨成骨细胞活性的缺陷，但目前尚不清楚成骨不全是否也反映了构成骨的许多其他细胞类型的缺陷，包括骨骼血管内皮或赋予骨骼功能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效用。在这里，我们发现Col1a2 ^oim/oim小鼠（一种经过充分研究的中度至重度 OI 动物模型）中骨骼干细胞 (SSC) 和骨骼动脉内皮细胞 (AEC) 的数量增加，表明血管 SSC 生态位的破坏是 OI 发病机制的一个特点。此外，将Col1a2 ^oim/oim小鼠与缺乏骨骼血管生成和骨形成负调节因子 Schnurri 3 (SHN3) 的小鼠杂交，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 抑制对于治疗 OI 具有强大的治疗效用，因此使用骨靶向 AAV 来介导Shn3敲低，挽救Col1a2 ^oim/oim表型，并为靶向 SHN3 进行治疗提供治疗概念验证的 OI。总体而言，这项工作既提供了抑制 SHN3 通路的概念验证，又更广泛地解决了干/骨祖细胞生态位的缺陷，作为治疗成骨不全的策略。