The chaperone activity of 4PBA ameliorates the skeletal phenotype of Chihuahua, a zebrafish model for dominant osteogenesis imperfecta.
The chaperone activity of 4PBA ameliorates the skeletal phenotype of Chihuahua, a zebrafish model for dominant osteogenesis imperfecta.
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DOI：
10.1093/hmg/ddx171
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发表时间：
2017-08-01
影响因子：
3.5
通讯作者：
Forlino A
中科院分区：
文献类型：
--
作者：
Gioia R;Tonelli F;Ceppi I;Biggiogera M;Leikin S;Fisher S;Tenedini E;Yorgan TA;Schinke T;Tian K;Schwartz JM;Forte F;Wagener R;Villani S;Rossi A;Forlino A
经典成骨不全症（classical osteogenesis proximata，OI）是由I型胶原蛋白突变引起的骨疾病，其特征在于骨脆性、在没有创伤和生长缺陷的情况下频繁骨折。对于OI没有确定的治愈方法，为了开发新的药物疗法，利用重新定位策略，小型硬骨鱼斑马鱼（Danio rerio）是一种特别有吸引力的模型。斑马鱼体积小，增殖率高，胚胎透明，所需药物量少，使其成为药物筛选研究的首选模型，当有效的疾病模型可用时。我们对斑马鱼突变体奇瓦瓦州进行了深入表征，该突变体在I型胶原蛋白的α1链中携带G574 D（p.G736 D）取代。我们成功地验证了它作为经典OI的模型。与WT相比，突变体的生长延迟。X线、µCT、茜素红/阿辛蓝和钙黄绿素染色显示严重骨骼畸形、存在骨折和延迟矿化。从不同组织中提取的I型胶原蛋白显示异常的电泳迁移和低熔化温度。内质网（ER）扩大的存在下，由于突变体胶原蛋白保留在成骨细胞和成纤维细胞的突变体鱼显示通过电子显微镜和共聚焦显微镜。两种化学伴侣，4PBA和TUDCA，被用来改善细胞应激，并且4PBA确实改善了幼虫的骨矿化和成年的骨骼畸形，主要作用于减少ER池的大小和有利于胶原分泌。总之，我们的数据表明ER应激是改善OI表型的新靶点;化学伴侣（例如4 PBA）单独或组合可能是一类新分子，有待进一步研究用于OI治疗。
Classical osteogenesis imperfecta (OI) is a bone disease caused by type I collagen mutations and characterized by bone fragility, frequent fractures in absence of trauma and growth deficiency. No definitive cure is available for OI and to develop novel drug therapies, taking advantage of a repositioning strategy, the small teleost zebrafish (Danio rerio) is a particularly appealing model. Its small size, high proliferative rate, embryo transparency and small amount of drug required make zebrafish the model of choice for drug screening studies, when a valid disease model is available. We performed a deep characterization of the zebrafish mutant Chihuahua, that carries a G574D (p.G736D) substitution in the α1 chain of type I collagen. We successfully validated it as a model for classical OI. Growth of mutants was delayed compared with WT. X-ray, µCT, alizarin red/alcian blue and calcein staining revealed severe skeletal deformity, presence of fractures and delayed mineralization. Type I collagen extracted from different tissues showed abnormal electrophoretic migration and low melting temperature. The presence of endoplasmic reticulum (ER) enlargement due to mutant collagen retention in osteoblasts and fibroblasts of mutant fish was shown by electron and confocal microscopy. Two chemical chaperones, 4PBA and TUDCA, were used to ameliorate the cellular stress and indeed 4PBA ameliorated bone mineralization in larvae and skeletal deformities in adult, mainly acting on reducing ER cisternae size and favoring collagen secretion. In conclusion, our data demonstrated that ER stress is a novel target to ameliorate OI phenotype; chemical chaperones such as 4PBA may be, alone or in combination, a new class of molecules to be further investigated for OI treatment.
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在主要成骨的鼠模型中，成骨细胞生成受损：成骨的新靶标不完美的药物治疗。
影响因子：
5.2
作者：
Gioia, Roberta;Panaroni, Cristina;Besio, Roberta;Palladini, Giovanni;Merlini, Giampaolo;Giansanti, Vincenzo;Scovassi, Ivana A.;Villani, Simona;Villa, Isabella;Villa, Anna;Vezzoni, Paolo;Tenni, Ruggero;Rossi, Antonio;Marini, Joan C.;Forlino, Antonella
通讯作者：
Forlino, Antonella
影响因子：
2.7
作者：
Duran, I.;Mari-Beffa, M.;Santos-Ruiz, L.
通讯作者：
Santos-Ruiz, L.
影响因子：
14.9
作者：
Flicek P;Amode MR;Barrell D;Beal K;Billis K;Brent S;Carvalho-Silva D;Clapham P;Coates G;Fitzgerald S;Gil L;Girón CG;Gordon L;Hourlier T;Hunt S;Johnson N;Juettemann T;Kähäri AK;Keenan S;Kulesha E;Martin FJ;Maurel T;McLaren WM;Murphy DN;Nag R;Overduin B;Pignatelli M;Pritchard B;Pritchard E;Riat HS;Ruffier M;Sheppard D;Taylor K;Thormann A;Trevanion SJ;Vullo A;Wilder SP;Wilson M;Zadissa A;Aken BL;Birney E;Cunningham F;Harrow J;Herrero J;Hubbard TJ;Kinsella R;Muffato M;Parker A;Spudich G;Yates A;Zerbino DR;Searle SM
通讯作者：
Searle SM
影响因子：
4.2
作者：
Fass, Daniel M.;Shah, Rishita;Ghosh, Balaram;Hennig, Krista;Norton, Stephanie;Zhao, Wen-Ning;Reis, Surya A.;Klein, Peter S.;Mazitschek, Ralph;Maglathlin, Rebecca L.;Lewis, Timothy A.;Haggarty, Stephen J.
通讯作者：
Haggarty, Stephen J.
影响因子：
3.5
作者：
Bianchi, Laura;Gagliardi, Assunta;Forlino, Antonella
通讯作者：
Forlino, Antonella