BMP type I receptor inhibition reduces heterotopic [corrected] ossification.
BMP type I receptor inhibition reduces heterotopic [corrected] ossification.
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进行性骨化性纤维发育不良 (FOP) 是一种先天性软组织进行性、广泛的产后骨化性疾病，目前尚无有效的治疗方法。受影响的个体在 ACVR1 基因中存在保守突变，这些突变被认为会导致骨形态发生蛋白 (BMP) I 型受体、激活素受体样激酶 2 (ALK2) 的组成型激活。在此，我们表明，编码组成型活性 ALK2 (caALK2) 的诱导型转基因在小鼠中肌肉内表达，该转基因是由于第 207 位氨基酸从谷氨酰胺变为天冬氨酸而引起的，导致异位软骨内骨形成、关节融合和功能损伤，从而模拟了人类 FOP 的关键方面。 BMP I 型受体激酶的选择性抑制剂 LDN-193189（参考文献）可抑制由特异腺病毒 Cre (Ad.Cre) 诱导表达 caALK2 的组织中 BMP 信号传导效应器 SMAD1、SMAD5 和 SMAD8 的激活。这种治疗减少了异位骨化和功能障碍。与 Ad.Cre 局部诱导 caALK2（引起炎症）相反，caALK2 的出生后整体表达（不使用 Ad.Cre 诱导，因此没有炎症）不会导致异位骨化。然而，如果在这种情况下用对照腺病毒提供炎症刺激，则会诱导异位骨形成。与 LDN-193189 一样，皮质类固醇治疗可抑制注射 Ad.Cre 的突变小鼠的骨化，表明 caALK2 表达和炎症环境都是该模型中异位骨化发展所必需的。这些结果支持 ALK2 激酶活性失调在 FOP 发病机制中的作用，并表明 BMP I 型受体活性的小分子抑制可能有助于治疗 FOP 和与过度 BMP 信号传导相关的异位骨化综合征。
Fibrodysplasia ossificans progressiva (FOP) is a congenital disorder of progressive and widespread postnatal ossification of soft tissues and is without known effective treatments. Affected individuals harbor conserved mutations in the ACVR1 gene that are thought to cause constitutive activation of the bone morphogenetic protein (BMP) type I receptor, activin receptor-like kinase-2 (ALK2). Here we show that intramuscular expression in the mouse of an inducible transgene encoding constitutively active ALK2 (caALK2), resulting from a glutamine to aspartic acid change at amino acid position 207, leads to ectopic endochondral bone formation, joint fusion and functional impairment, thus phenocopying key aspects of human FOP. A selective inhibitor of BMP type I receptor kinases, LDN-193189 (ref.), inhibits activation of the BMP signaling effectors SMAD1, SMAD5 and SMAD8 in tissues expressing caALK2 induced by adenovirus specifying Cre (Ad.Cre). This treatment resulted in a reduction in ectopic ossification and functional impairment. In contrast to localized induction of caALK2 by Ad.Cre (which entails inflammation), global postnatal expression of caALK2 (induced without the use of Ad.Cre and thus without inflammation) does not lead to ectopic ossification. However, if in this context an inflammatory stimulus was provided with a control adenovirus, ectopic bone formation was induced. Like LDN-193189, corticosteroid treatment inhibits ossification in Ad.Cre-injected mutant mice, suggesting caALK2 expression and an inflammatory milieu are both required for the development of ectopic ossification in this model. These results support the role of dysregulated ALK2 kinase activity in the pathogenesis of FOP and suggest that small molecule inhibition of BMP type I receptor activity may be useful in treating FOP and heterotopic ossification syndromes associated with excessive BMP signaling.
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DOI：
10.1097/01.blo.0000129557.38803.26
发表时间：
2004-06-01
影响因子：
4.2
作者：
Scarlett, RF;Rocke, DM;Kaplan, FS
通讯作者：
Kaplan, FS
DOI：
10.1016/j.berh.2007.11.007
发表时间：
2008-03-01
影响因子：
5.2
作者：
Kaplan, Frederick S.;Le Merrer, Martine;Groppe, Jay
通讯作者：
Groppe, Jay
影响因子：
12.4
作者：
Koefoed, M;Ito, H;Schwarz, EM
通讯作者：
Schwarz, EM
影响因子：
2.2
作者：
Corriere, Matthew A.;Rogers, Chris M.;Guzman, Raul J.
通讯作者：
Guzman, Raul J.
影响因子：
2.1
作者：
Shimizu, A;Kato, M;Miyazono, K
通讯作者：
Miyazono, K