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Proc Natl Acad Sci U S A. 2016 Nov 22;113(47):13522-13527. Epub 2016 Nov 7.

Decreasing maternal myostatin programs adult offspring bone strength in a mouse model of osteogenesis imperfecta.

Author information

1
Division of Biological Sciences, University of Missouri, Columbia, MO 65211.
2
Department of Biochemistry, University of Missouri, Columbia, MO 65211.
3
Transgenic Animal Core, University of Missouri, Columbia, MO 65211.
4
School of Dentistry, University of Missouri-Kansas City, Kansas City, MO 64108.
5
Department of Bioengineering, University of Missouri, Columbia, MO 65211.
6
Department of Orthopaedic Surgery, University of Missouri, Columbia, MO 65212.
7
Division of Animal Sciences, University of Missouri, Columbia, MO 65211.
8
Division of Biological Sciences, University of Missouri, Columbia, MO 65211; PhillipsCL@missouri.edu schulzl@missouri.edu.
9
Department of Obstetrics, Gynecology and Women's Health, University of Missouri, Columbia, MO 65212.
10
Department of Biochemistry, University of Missouri, Columbia, MO 65211; PhillipsCL@missouri.edu schulzl@missouri.edu.
11
Department of Child Health, University of Missouri, Columbia, MO 65212.

Abstract

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 that Mstntm1Sjl/+ 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 male Col1a2oim/+ offspring from natural mating of Mstntm1Sjl/+ dams to Col1a2oim/+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 of Col1a2oim/+ dams to Col1a2oim/+ sires. Finally, increased bone biomechanical strength of Col1a2oim/+ offspring that had been transferred into Mstntm1Sjl/+ 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.

KEYWORDS:

bone health; developmental origins of health and disease; fetal programming; myostatin; osteogenesis imperfecta

PMID:
27821779
PMCID:
PMC5127318
DOI:
10.1073/pnas.1607644113
[Indexed for MEDLINE]
Free PMC Article

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