Secreted frizzled related protein 1 is a target to improve fracture healing.
Secreted frizzled related protein 1 is a target to improve fracture healing.
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DOI：
10.1002/jcp.21747
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发表时间：
2009-07
影响因子：
5.6
通讯作者：
Lian, Jane B.
中科院分区：
文献类型：
--
作者：
Gaur, Tripti;Wixted, John J.;Hussain, Sadiq;O'Connell, Shannon L.;Morgan, Elise F.;Ayers, David C.;Komm, Barry S.;Bodine, Peter V.;Stein, Gary S.;Lian, Jane B.
遗传研究已经确定了当经典Wnt信号传导增加时，人和小鼠的表型的高骨量。分泌型卷曲相关蛋白1（sFRP 1）是几种Wnt拮抗剂之一，也是32周龄小鼠表现出高骨量表型的功能丧失小鼠模型之一。在这里，我们表明，在年轻（8周）sFRP 1 −/−小鼠的生理水平上增加Wnt信号的小鼠模型中，冲击性骨折愈合得到了增强，这些小鼠尚未表现出BMD的显着增加。体内sFRP 1功能的丧失通过促进早期骨愈合来改善骨折修复，而不会对骨组织质量产生不良影响，这反映在机械强度增加上。我们观察到sFRP 1 −/−小鼠在14天的骨折修复过程中，软骨硬结显著减少，膜内骨形成增加，骨桥接，早期骨重建。我们对基因标记物的分子分析表明，sFRP 1功能丧失在骨折修复过程中的作用是通过引导间充质干细胞通过经典途径进入成骨细胞谱系来加速初始血肿形成后的骨愈合。支持这一结论的进一步证据是在WT小鼠的软骨愈伤组织中观察到最大sFRP 1水平，因此在sFRP 1 −/−小鼠中，祖细胞直接转变为成骨细胞谱系。因此，开发特异性抑制sFRP 1的拮抗剂代表了在代谢性骨病、骨质疏松症和衰老中刺激骨折修复和骨形成的安全靶点。
Genetic studies have identified a high bone mass of phenotype in both human and mouse when canonical Wnt signaling is increased. Secreted frizzled related protein1 (sFRP1) is one of several Wnt antagonists and among the loss-of-function mouse models in which 32-week old mice exhibit a high bone mass phenotype. Here we show that impact fracture healing is enhanced in this mouse model of increased Wnt signaling at a physiologic level in young (8 week) sFRP1−/− mice which do not yet exhibit significant increase in BMD. The loss of sFRP1 function in vivo improves fracture repair by promoting early bone union without adverse effects on the quality of bone tissue reflected by increased mechanical strength. We observe a dramatic reduction of the cartilage callous, increased intramembranous bone formation with bone bridging by 14 days, and early bone remodeling during the 28 day fracture repair process in the sFRP1−/− mice. Our molecular analyses of gene markers indicate that the effect of sFRP1 loss-of-function during fracture repair is to accelerate bone healing after formation of the initial hematoma by directing mesenchymal stem cells into the osteoblast lineage via the canonical pathway. Further evidence to support this conclusion is the observation of maximal sFRP1 levels in the cartilaginous callus of a WT mouse, hence in sFRP1−/− mouse progenitor cells are shifted directly into osteoblast lineage. Thus, developing an antagonist to specifically inhibit sFRP1 represents a safe target for stimulating fracture repair and bone formation in metabolic bone disorders, osteoporosis and aging.
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影响因子：
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