TY - JOUR
T1 - Decreasing maternal myostatin programs adult offspring bone strength in a mouse model of osteogenesis imperfecta
AU - Oestreich, Arin K.
AU - Kamp, William M.
AU - McCray, Marcus G.
AU - Carleton, Stephanie M.
AU - Karasseva, Natalia
AU - Lenz, Kristin L.
AU - Jeong, Youngjae
AU - Daghlas, Salah A.
AU - Yao, Xiaomei
AU - Wang, Yong
AU - Pfeiffer, Ferris M.
AU - Ellersieck, Mark R.
AU - Schulz, Laura C.
AU - Phillips, Charlotte L.
N1 - Funding Information:
This work was supported in part by National Institutes of Health Grant AR055907 (to S.M.C., Y.J., X.Y., Y.W., C.L.P.); National Space and Biomedical Research Institute Postdoctoral Fellowship NCC 9-58 (to S.M.C.); Leda J. Sears Trust Foundation Grant (S.M.C., A.K.O., C.L.P.); University of Missouri Life Sciences Fellowship (A.K.O.); Missouri Mission Enhancement (L.C.S.); and University of Missouri Interdisciplinary Intercampus Research Program (C.L.P., Y.W., A.K.O., L.C.S.).
PY - 2016/11/22
Y1 - 2016/11/22
N2 - 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 musclemass inwild-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.
AB - 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 musclemass inwild-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.
KW - Bone health
KW - Developmental origins of health and disease
KW - Fetal programming
KW - Myostatin
KW - Osteogenesis imperfecta
UR - http://www.scopus.com/inward/record.url?scp=84996533982&partnerID=8YFLogxK
U2 - 10.1073/pnas.1607644113
DO - 10.1073/pnas.1607644113
M3 - Article
C2 - 27821779
AN - SCOPUS:84996533982
SN - 0027-8424
VL - 113
SP - 13522
EP - 13527
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 47
ER -