Decreasing maternal myostatin programs adult offspring bone strength in a mouse model of osteogenesis imperfecta.
Decreasing maternal myostatin programs adult offspring bone strength in a mouse model of osteogenesis imperfecta.
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在成骨不全小鼠模型中，母体肌生长抑制素的减少会影响成年后代的骨强度。
DOI：
10.1073/pnas.1607644113
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发表时间：
2016
影响因子：
11.1
通讯作者：
Phillips,CharlotteL
中科院分区：
文献类型：
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作者：
Oestreich,ArinK;Kamp,WilliamM;McCray,MarcusG;Carleton,StephanieM;Karasseva,Natalia;Lenz,KristinL;Jeong,Youngjae;Daghlas,SalahA;Yao,Xiaomei;Wang,Yong;Pfeiffer,FerrisM;Ellersieck,MarkR;Schulz,LauraC;Phillips,CharlotteL
在胎儿发育过程中，子宫环境对后代骨骼结构和完整性的影响会持续到成年；然而，生物化学和分子机制尚不清楚。肌肉生长抑制素是肌肉质量的负调节因子。亲代肌生长抑制素缺乏（Mstntm1Sjl/+）会增加野生型后代的肌肉质量，表明存在宫内编程效应。在这里，我们假设mstntm1sjl /+水坝也会增加骨强度。在野生型后代中，母体肌生长抑制素缺乏改变了新生小鼠的胎儿生长和颅骨胶原含量，并在4月龄（骨量峰值年龄）时对后代的骨骼几何形状和生物力学完整性产生了持久影响。其次，我们试图将母体肌生长抑制素缺乏应用于具有成骨不完全性（col1a20im）的小鼠模型，这是一种由I型胶原结构和/或合成异常引起的遗传性结缔组织疾病。与年龄、性别和基因型匹配的col1a2im /+坝与col1a2im /+坝自然交配的雄性col1a2im /+后代相比，与col1a2im /+坝自然交配的雄性col1a2im /+后代的股骨抗扭极限强度增加15%，抗拉强度增加29%，破坏能量增加24%。最后，将col1a1sjl /+的后代作为囊胚移植到tomstntm1sjl /+的母鼠体内，其骨骼生物力学强度增加，这表明母体肌生长抑制素缺乏的影响是由移植后的环境所赋予的。因此，靶向妊娠环境，特别是产前肌肉生长抑制素通路，为治疗成骨不全提供了一个潜在的治疗窗口和方法。
During fetal development, the uterine environment can have effects on offspring bone architecture and integrity that persist into adulthood; however, the biochemical and molecular mechanisms remain unknown. Myostatin is a negative regulator of muscle mass. Parental myostatin deficiency (Mstntm1Sjl/+) increases muscle mass in wild-type offspring, suggesting an intrauterine programming effect. Here, we hypothesized thatMstntm1Sjl/+dams would also confer increased bone strength. In wild-type offspring, maternal myostatin deficiency altered fetal growth and calvarial collagen content of newborn mice and conferred a lasting impact on bone geometry and biomechanical integrity of offspring at 4 mo of age, the age of peak bone mass. Second, we sought to apply maternal myostatin deficiency to a mouse model with osteogenesis imperfecta (Col1a2oim), a heritable connective tissue disorder caused by abnormalities in the structure and/or synthesis of type I collagen. Femora of maleCol1a2oim/+offspring from natural mating ofMstntm1Sjl/+dams toCol1a2oim/+sires had a 15% increase in torsional ultimate strength, a 29% increase in tensile strength, and a 24% increase in energy to failure compared with age, sex, and genotype-matched offspring from natural mating ofCol1a2oim/+dams toCol1a2oim/+sires. Finally, increased bone biomechanical strength ofCol1a2oim/+offspring that had been transferred intoMstntm1Sjl/+dams as blastocysts demonstrated that the effects of maternal myostatin deficiency were conferred by the postimplantation environment. Thus, targeting the gestational environment, and specifically prenatal myostatin pathways, provides a potential therapeutic window and an approach for treating osteogenesis imperfecta.