JCI：蛋白抑制剂治疗颅骨和皮肤出生缺陷

近日，纽约西奈山医学院的研究人员发现头骨和皮肤患有一种罕见的遗传性疾病叫Beare-Stevenson cutis gyrata综合征（BSS）。利用小鼠模型，研究人员发现，通过抑制蛋白P38能够中断这种出生缺陷疾病的发展如颅或头骨骨骼过早融合、黑棘皮病、色素沉着的皮肤疾病等。

西奈山医学院儿科高级研究员和遗传学和基因组学教授Ethylin Wang Jabs博士说：我们迫切需要确定这些疾病发展的背后分子机制，使我们能够设计有效的治疗手段和防止策略。

研究结果发表在2012年六月Journal of Clinical Investigation杂志上。

使用BSS综合征小鼠模型，研究人员发现细胞内p38信号增加了。当Yingli Wang博士给老鼠腹腔注射p38抑制剂入子宫内，老鼠颅骨和皮肤缺损得到改善。另一项实验中，局部应用p38抑制剂的皮肤缺损情况也得到缓解。研究人员表示P38蛋白抑制剂对颅骨和皮肤出生缺陷可能有潜在治疗作用。（生物谷：Bioon.com）

doi:10.1172/JCI62644
PMC:
PMID:

p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice

Yingli Wang, Xueyan Zhou, Kurun Oberoi1, Robert Phelps, Ross Couwenhoven, Miao Sun, Amélie Rezza, Greg Holmes, Christopher J. Percival, Jenna Friedenthal1, Pavel Krejci, Joan T. Richtsmeier David L. Huso, Michael Rendl and Ethylin Wang Jabs

Beare-Stevenson cutis gyrata syndrome (BSS) is a human genetic disorder characterized by skin and skull abnormalities. BSS is caused by mutations in the FGF receptor 2 (FGFR2), but the molecular mechanisms that induce skin and skull abnormalities are unclear. We developed a mouse model of BSS harboring a FGFR2 Y394C mutation and identified p38 MAPK as an important signaling pathway mediating these abnormalities. Fgfr2^+/Y394C mice exhibited epidermal hyperplasia and premature closure of cranial sutures (craniosynostosis) due to abnormal cell proliferation and differentiation. We found ligand-independent phosphorylation of FGFR2 and activation of p38 signaling in mutant skin and calvarial tissues. Treating Fgfr2^+/Y394C mice with a p38 kinase inhibitor attenuated skin abnormalities by reversing cell proliferation and differentiation to near normal levels. This study reveals the pleiotropic effects of the FGFR2 Y394C mutation evidenced by cutis gyrata, acanthosis nigricans, and craniosynostosis and provides a useful model for investigating the molecular mechanisms of skin and skull development. The demonstration of a pathogenic role for p38 activation may lead to the development of therapeutic strategies for BSS and related conditions, such as acanthosis nigricans or craniosynostosis.