Decreasing maternal myostatin programs adult offspring bone strength in a mouse model of osteogenesis imperfecta.
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.
Division of Biological Sciences, University of Missouri, Columbia, MO 65211.
Arin K
AK
Oestreich
Department of Biochemistry, University of Missouri, Columbia, MO 65211.
William M
WM
Kamp
Division of Biological Sciences, University of Missouri, Columbia, MO 65211.
Marcus G
MG
McCray
Department of Biochemistry, University of Missouri, Columbia, MO 65211.
Stephanie M
SM
Carleton
Transgenic Animal Core, University of Missouri, Columbia, MO 65211.
Natalia
N
Karasseva
Department of Biochemistry, University of Missouri, Columbia, MO 65211.
Kristin L
KL
Lenz
Department of Biochemistry, University of Missouri, Columbia, MO 65211.
Youngjae
Y
Jeong
Department of Biochemistry, University of Missouri, Columbia, MO 65211.
Salah A
SA
Daghlas
School of Dentistry, University of Missouri-Kansas City, Kansas City, MO 64108.
Xiaomei
X
Yao
School of Dentistry, University of Missouri-Kansas City, Kansas City, MO 64108.
Yong
Y
Wang
Department of Bioengineering, University of Missouri, Columbia, MO 65211.|Department of Orthopaedic Surgery, University of Missouri, Columbia, MO 65212.
Ferris M
FM
Pfeiffer
Division of Animal Sciences, University of Missouri, Columbia, MO 65211.
Mark R
MR
Ellersieck
Division of Biological Sciences, University of Missouri, Columbia, MO 65211; PhillipsCL@missouri.edu schulzl@missouri.edu.|Department of Obstetrics, Gynecology and Women's Health, University of Missouri, Columbia, MO 65212.
Laura C
LC
Schulz
Department of Biochemistry, University of Missouri, Columbia, MO 65211; PhillipsCL@missouri.edu schulzl@missouri.edu.|Department of Child Health, University of Missouri, Columbia, MO 65212.
Charlotte L
CL
Phillips
D000818:Animals; D015415:Biomarkers / Q000097:blood; D001696:Biomechanical Phenomena; D001835:Body Weight; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D010064:Embryo Implantation; D005260:Female; D005269:Femur / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction; D055435:Myostatin / Q000172:deficiency / Q000378:metabolism*; D010006:Osteoblasts / Q000378:metabolism; D010013:Osteogenesis Imperfecta / Q000097:blood / Q000196:embryology / Q000503:physiopathology*; D013977:Tibia / Q000473:pathology / Q000503:physiopathology
D015415:Biomarkers; D055435:Myostatin; D003094:Collagen
bone health; developmental origins of health and disease; fetal programming; myostatin; osteogenesis imperfecta