In vivo somatic cell gene transfer of an engineered noggin mutein prevents BMP4-induced heterotopic ossification
In vivo somatic cell gene transfer of an engineered noggin mutein prevents BMP4-induced heterotopic ossification
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DOI：
10.2106/00004623-200312000-00010
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发表时间：
2003-12-01
影响因子：
5.3
通讯作者：
Shore, EM
中科院分区：
文献类型：
--
作者：
Glaser, DL;Economides, AN;Shore, EM
背景：骨骼的形成需要在高度调控的负反馈系统中与其拮抗者平衡的诱导信号。骨形态发生蛋白或其拮抗剂的不适当或过度表达会导致影响骨骼的遗传性疾病，如进行性骨纤维发育不良。BMP信号通过与其受体结合而介导，是诱导异常骨化的关键步骤。因此，我们假设，设计更有效的BMP信号传递过程的抑制剂可能会导致此类疾病的治疗方法的发展。方法：以BMP4诱导的异位成骨为模型，测试BMP拮抗剂Noggin通过局部或全身给药阻止新骨形成的能力。由于Noggin天然起局部作用，因此设计了一种Noggin突变体hNOGDeltaB2，并证明其可系统循环，并通过腺病毒介导体细胞基因转移在小鼠模型中检测其阻断异位成骨的能力。结果：建立了BMP4诱导的小鼠异位成骨模型。局部注射野生型NOG可抑制异位骨化，但全身给药无效。相反，全身注射编码hNOGDeltaB2的腺病毒导致全身水平持续两周以上，足以阻断BMP4诱导的异位成骨。结论：局部注射野生型Noggin或体细胞基因转移Noggin突变体hNOGDeltaB2可在体内预防BMP4诱导的异位成骨。此外，本研究中的数据提供了概念上的证据，即自然发生的因子可以被设计成系统地传递到理想的药理学结果。临床相关性：阻止骨形成与人类异位骨化障碍临床相关，例如进行性骨纤维发育不良。此外，BMP拮抗剂作为治疗药物的发展可能为治疗因BMP异常表达和/或缺乏其拮抗剂而引起的其他病理情况提供方法。
Background: The formation of the skeleton requires inductive signals that are balanced with their antagonists in a highly regulated negative feedback system. Inappropriate or excessive expression of BMPs (bone morphogenetic proteins) or their antagonists results in genetic disorders affecting the skeleton, such as fibrodysplasia ossificans progressiva. BMP signaling mediated through binding to its receptors is a critical step in the induction of abnormal ossification. Therefore, we hypothesized that engineering more effective inhibitors of this BMP-signaling process may lead to the development of therapies for such conditions.Methods: BMP4-induced heterotopic ossification was used as a model for testing the ability of the BMP antagonist Noggin to block de novo bone formation, either by local or systemic delivery. Since Noggin naturally acts locally, a Noggin mutein, hNOGDeltaB2, was engineered and was shown to circulate systemically, and its ability to block heterotopic ossification was tested in a mouse model with use of adenovirus-mediated somatic cell gene transfer.Results: A mouse model of BMP4-induced heterotopic ossification was developed. Local delivery of wild-type NOG inhibited heterotopic ossification, but systemic administration was ineffective. In contrast, systemic delivery of the adenovirus encoding hNOGDeltaB2 resulted in systemic levels that persisted for more than two weeks and were sufficient to block BMP4-induced heterotopic ossification.Conclusions: BMP4-induced heterotopic ossification can be prevented in vivo either by local delivery of wild-type Noggin or after somatic cell gene transfer of a Noggin mutein, hNOGDeltaB2. Furthermore, the data in the present study provide proof of concept that a naturally occurring factor can be engineered for systemic delivery toward a desirable pharmacological outcome.Clinical Relevance: Blocking bone formation is clinically relevant to disorders of heterotopic ossification in humans, such as fibrodysplasia ossificans progressiva. Furthermore, development of BMP antagonists as therapeutic agents may provide modalities for the treatment of other pathologic conditions that arise from aberrant expression of BMPs and/or from a lack of their antagonists.