Granting immunity to FOP and catching heterotopic ossification in the Act

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• 作者：Frederick S. Kaplan^a ; ^b ; ^d ; ^{frederick.kaplan@uphs.upenn.edu" class="auth_mail" title="E-mail the corresponding author} ; Robert J. Pignolo^a ; ^b ; ^d ; ^{pignolo@mail.med.upenn.edu" class="auth_mail" title="E-mail the corresponding author} ; Eileen M. Shore^a ; ^c ; ^d ; ^{shore@mail.med.upenn.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Fibrodysplasia ossificans progressiva (FOP) ; Heterotopic ossification ; Bone morphogenetic protein (BMP) ; Bone morphogenetic protein signaling ; Innate immune system ; ACVR1 ; Activin A ; Toll-like receptor (TLR)
• 刊名：Seminars in Cell & Developmental Biology
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：49
• 期：Complete
• 页码：30-36
• 全文大小：333 K

文摘

The progressive transformation of one organ system into another is a fundamental signature of fibrodysplasia ossificans progressiva (FOP), the most catastrophic form of extraskeletal bone formation in humans. In all affected individuals, FOP is caused by heterozygous missense gain-of-function mutations in Activin receptor A type I (ACVR1), a bone morphogenetic protein (BMP) type I receptor. Loss of autoinhibition of the mutant receptor (mACVR1) results in dysregulated BMP pathway signaling, and is necessary for the myriad developmental features of FOP, but does not appear sufficient to induce the episodic flare-ups that lead to disabling post-natal heterotopic endochondral ossification (HEO) and that are a hallmark of the disease. Post-natal FOP flare-ups strongly implicate an underlying immunological trigger involving inflammation and the innate immune system. Recent studies implicate canonical and non-canonical TGFβ/BMP family ligands in the amplification of mACVR1 signaling leading to the formation of FOP lesions and resultant HEO. BMP and Activin ligands that stimulate mACVR1 signaling also have critical regulatory functions in the immune system. Cross-talk between the morphogenetic and immunological pathways that regulate tissue maintenance and wound healing identifies potential robust therapeutic targets for FOP. Here we review current evidence for an immunological trigger for flare-ups and HEO in FOP, propose a working schema for the pathophysiology of observed phenomena, and highlight outstanding questions under investigation.