Pharmacological intervention of the FGF-PTH axis as a potential therapeutic for craniofacial ciliopathies.
Pharmacological intervention of the FGF-PTH axis as a potential therapeutic for craniofacial ciliopathies.
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DOI：
10.1242/dmm.049611
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发表时间：
2022-08-01
影响因子：
4.3
通讯作者：
中科院分区：
文献类型：
--
作者：
纤毛病代表一种疾病类别，其特征是具有广泛的表型，包括多囊肾和骨骼异常。纤毛病的骨骼表型是最常见和最难治疗的类型之一，因为对导致疾病的病理机制了解很少。使用人类纤毛病的肾脏和骨骼异常(口面部指端综合征14)的禽类模型(Talpid2)，我们发现FGF23-PTH轴的中断导致发育中的下颌骨钙摄取减少和随后的小颌症。尽管美国食品和药物管理局(FDA)批准的泛FGFR抑制剂AZD4547单独进行药物干预可以挽救成纤维细胞生长因子靶标SPRY2的表达，但它并没有显著挽救小颌症。相比之下，AZD4547和醋酸特派(一种甲状旁腺素激动剂，FDA批准的骨质疏松症治疗药物)的鸡尾酒治疗导致了talpid2突变体中纤毛病理性小颌畸形的分子、细胞和表型挽救。总之，这些数据为与纤毛病变骨骼表型相关的病理分子机制提供了新的见解，并为一种仅限于无治疗选择的多效性疾病提供了潜在的治疗策略。摘要：利用禽类动物模型，我们报道了一种新的分子机制(FGF23-PTH轴的破坏导致发育中的下颌骨钙摄取减少)和治疗纤毛病理性小颌症的可能性。
Ciliopathies represent a disease class characterized by a broad range of phenotypes including polycystic kidneys and skeletal anomalies. Ciliopathic skeletal phenotypes are among the most common and most difficult to treat due to a poor understanding of the pathological mechanisms leading to disease. Using an avian model (talpid2) for a human ciliopathy with both kidney and skeletal anomalies (orofaciodigital syndrome 14), we identified disruptions in the FGF23–PTH axis that resulted in reduced calcium uptake in the developing mandible and subsequent micrognathia. Although pharmacological intervention with the U.S. Food and Drug Administration (FDA)-approved pan-FGFR inhibitor AZD4547 alone rescued expression of the FGF target SPRY2, it did not significantly rescue micrognathia. In contrast, treatment with a cocktail of AZD4547 and teriparatide acetate, a PTH agonist and FDA-approved treatment for osteoporosis, resulted in molecular, cellular and phenotypic rescue of ciliopathic micrognathia in talpid2 mutants. Together, these data provide novel insight into pathological molecular mechanisms associated with ciliopathic skeletal phenotypes and a potential therapeutic strategy for a pleiotropic disease class with limited to no treatment options. Summary: Using an avian model, we report a novel molecular mechanism (disruptions in the FGF23–PTH axis resulting in reduced calcium uptake in the developing mandible) and potential treatment for ciliopathic micrognathia.
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影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1002/dvdy.24627
发表时间：
2018-06
期刊：
Developmental dynamics : an official publication of the American Association of Anatomists
影响因子：
--
作者：
Elliott KH;Millington G;Brugmann SA
通讯作者：
Brugmann SA
影响因子：
4.4
作者：
Hebert, K;House, JD;Guenter, W
通讯作者：
Guenter, W
影响因子：
56.9
作者：
HODGES, JH
通讯作者：
HODGES, JH
影响因子：
4.3
作者：
Cordido A;Cernadas E;Fernández-Delgado M;García-González MA
通讯作者：
García-González MA