Cortical-Bone Fragility--Insights from sFRP4 Deficiency in Pyle's Disease.
Cortical-Bone Fragility--Insights from sFRP4 Deficiency in Pyle's Disease.
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DOI：
10.1056/nejmoa1509342
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发表时间：
2016-06-30
期刊：
影响因子：
--
通讯作者：
Baron R
中科院分区：
文献类型：
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作者：
Kiper POS;Saito H;Gori F;Unger S;Hesse E;Yamana K;Kiviranta R;Solban N;Liu J;Brommage R;Boduroglu K;Bonafé L;Campos-Xavier B;Dikoglu E;Eastell R;Gossiel F;Harshman K;Nishimura G;Girisha KM;Stevenson BJ;Takita H;Rivolta C;Superti-Furga A;Baron R
皮质骨脆性是骨质疏松症的常见特征，与非椎骨骨折有关。皮质骨稳态的调节已被证明是难以捉摸的。骨骼遗传疾病的研究可以产生的见解，燃料实验治疗方法来治疗罕见疾病和常见的骨骼疾病。我们评估了4例Pyle病患者，这是一种遗传性疾病，其特征是皮质骨变薄、肢体畸形和骨折; 2例患者通过外显子组测序进行了检查，2例通过桑格测序进行了检查。在确定候选基因后，我们产生了一个敲除小鼠模型，该模型表现出表型，并研究了骨结构改变的机制。在所有受影响的患者中，我们发现SFRP 4中的双等位基因截短突变，SFRP 4是编码分泌型卷曲相关蛋白4（可溶性Wnt抑制剂）的基因。缺乏Sfrp 4的小鼠，像患有派尔氏病的人一样，由于Wnt和骨形态发生蛋白（BMP）信号在这两个骨区室中的差异调节，具有增加量的骨小梁和异常薄的皮质骨。用可溶性Bmp 2受体（RAP-661）或sclerostin抗体治疗Sfrp 4缺陷小鼠，纠正了皮质骨缺陷。我们的研究表明，派尔氏病是由sFRP 4缺乏引起的，皮质骨和小梁骨稳态由不同的机制控制，sFRP 4介导的Wnt和BMP信号之间的交叉调节对于实现适当的皮质骨厚度和稳定性至关重要。（由瑞士国家基金会和美国国立卫生研究院资助。
Cortical-bone fragility is a common feature in osteoporosis that is linked to nonvertebral fractures. Regulation of cortical-bone homeostasis has proved elusive. The study of genetic disorders of the skeleton can yield insights that fuel experimental therapeutic approaches to the treatment of rare disorders and common skeletal ailments. We evaluated four patients with Pyle’s disease, a genetic disorder that is characterized by cortical-bone thinning, limb deformity, and fractures; two patients were examined by means of exome sequencing, and two were examined by means of Sanger sequencing. After a candidate gene was identified, we generated a knockout mouse model that manifested the phenotype and studied the mechanisms responsible for altered bone architecture. In all affected patients, we found biallelic truncating mutations in SFRP4, the gene encoding secreted frizzled-related protein 4, a soluble Wnt inhibitor. Mice deficient in Sfrp4, like persons with Pyle’s disease, have increased amounts of trabecular bone and unusually thin cortical bone, as a result of differential regulation of Wnt and bone morphogenetic protein (BMP) signaling in these two bone compartments. Treatment of Sfrp4-deficient mice with a soluble Bmp2 receptor (RAP-661) or with antibodies to sclerostin corrected the cortical-bone defect. Our study showed that Pyle’s disease was caused by a deficiency of sFRP4, that cortical-bone and trabecular-bone homeostasis were governed by different mechanisms, and that sFRP4-mediated cross-regulation between Wnt and BMP signaling was critical for achieving proper cortical-bone thickness and stability. (Funded by the Swiss National Foundation and the National Institutes of Health.)