SAG therapy restores bone growth and reduces enchondroma incidence in a model of skeletal chondrodysplasias caused by Ihh deficiency.

Molecular Therapy. Methods & Clinical Development Pub Date : 2021-10-01 eCollection Date: 2021-12-10 DOI:10.1016/j.omtm.2021.09.015
Xinhua Li, Shuting Yang, Zahra Chinipardaz, Eiki Koyama, Shuying Yang
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引用次数: 3

Abstract

Inactivation mutations in the Indian hedgehog (Ihh) gene in humans cause numerous skeletal chondrodysplasias, including acrocapitofemoral dysplasia, brachydactyly type A1, and human short stature. The lack of an appropriate human-relevant model to accurately represent these chondrodysplasias has hampered the identification of clinically effective treatments. Here, we established a mouse model of human skeletal dysplasia induced by Ihh gene mutations via ablation of Ihh in Aggrecan-positive (Acan+) cells using Aggrecan (Acan)-creERT transgenic mice. Smoothen agonist (SAG) promoted Hh activity and rescued chondrocyte proliferation and differentiation by stimulating smoothened trafficking to the cilium in Ihh-silenced cells. SAG treatment corrected mouse stature and significantly decreased mortality without evidence of toxicity. Moreover, Ihh ablation in Acan+ cells produced enchondroma-like tissues near the growth plates that were significantly reduced by SAG treatment. These results demonstrated that SAG effectively treats skeletal dysplasia caused by Ihh gene mutations in a mouse model, suggesting that SAG may represent a potential drug for the treatment of these diseases and/or enchondromas.

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在Ihh缺乏症引起的骨骼软骨发育不良模型中,SAG治疗可恢复骨生长并减少内生软骨瘤的发生率。
人类印度刺猬(Ihh)基因失活突变导致许多骨骼软骨发育不良,包括肢端股发育不良、A1型短指畸形和人类身材矮小。缺乏适当的人类相关模型来准确地代表这些软骨发育不良阻碍了临床有效治疗方法的确定。在此,我们利用Aggrecan (Acan)-creERT转基因小鼠,通过消融Aggrecan阳性(Acan+)细胞中的Ihh,建立了由Ihh基因突变诱导的人类骨骼发育不良小鼠模型。平滑激动剂(SAG)通过刺激ihh沉默细胞向纤毛的平滑运输,促进Hh活性并挽救软骨细胞增殖和分化。SAG治疗纠正了小鼠的身高,并显著降低了死亡率,没有毒性的证据。此外,Ihh消融在Acan+细胞中产生生长板附近的内生软骨瘤样组织,这种组织在SAG治疗后显著减少。这些结果表明,在小鼠模型中,SAG有效地治疗由Ihh基因突变引起的骨骼发育不良,表明SAG可能是治疗这些疾病和/或内生软骨瘤的潜在药物。
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