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Schnurri-3 inhibition rescues skeletal fragility and vascular skeletal stem cell niche pathology in the OIM model of osteogenesis imperfecta

Authors :
Na Li
Baohong Shi
Zan Li
Jie Han
Jun Sun
Haitao Huang
Alisha R. Yallowitz
Seoyeon Bok
Shuang Xiao
Zuoxing Wu
Yu Chen
Yan Xu
Tian Qin
Rui Huang
Haiping Zheng
Rong Shen
Lin Meng
Matthew B. Greenblatt
Ren Xu
Source :
Bone Research, Vol 12, Iss 1, Pp 1-14 (2024)
Publication Year :
2024
Publisher :
Nature Publishing Group, 2024.

Abstract

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 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.

Details

Language :
English
ISSN :
20956231
Volume :
12
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Bone Research
Publication Type :
Academic Journal
Accession number :
edsdoj.0c95e2dd8b644fdaa77b85915215f7db
Document Type :
article
Full Text :
https://doi.org/10.1038/s41413-024-00349-1