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Protein in womb plays lifelong role in bone health

Researchers find limiting production of the protein myostatin in pregnant mice with osteogenesis imperfecta — or brittle bone disease — results in offspring with stronger, denser bones. This finding might one day provide a new therapy for treating osteogenesis imperfecta.

Fifty to 80 percent of bone density is predicted by genetics. However, University of Missouri School of Medicine (MU) researchers found that the prenatal environment can be manipulated to affect fetal and thus adult bone structure.

Osteogenesis imperfecta, also known as brittle bone disease, is a genetic disorder that causes bones to break easily. Severe cases can result in hundreds of fractures in a person's lifetime — or even death.

"Osteogenesis imperfecta is caused by the body's inability to make strong bones because of mutations affecting production of the protein collagen. No cure exists. However, we know from previous research that prenatal environments can have a lasting effect on cardiovascular and metabolic health — into adulthood. We then studied whether bone health of mice could be improved by optimizing the environment within the womb," explains Charlotte Phillips PhD, associate professor of biochemistry and child health at the MU School of Medicine and a senior author of the study.

Myostatin is a protein that limits muscle growth. However, exercise causes myostatin levels to decrease which allows muscle tissue to develop and results in stronger bones.

Phillips and her team first decreased maternal myostatin levels in pregnant mice confirming that myostatin deficiency can stimulate pups to have stronger bones. Then they identified that pregnant mice with brittle bone disease are responsible for their pups bone health.

"The third part of our study really confirmed our hypothesis.To see if we could reverse this trend, we transplanted embryos from female mice with osteogenesis imperfecta into the wombs of female mice deficient in myostatin.

"The pups from myostatin-deficient mothers with transplanted embryos had stronger, denser bones when they grew up than mice of the same genetic makeup born to osteogenesis imperfecta mice."

Laura Schulz PhD, Associate Professor, Division of Biological Sciences, Department of Obstetrics, Gynecology and Women’s Health, University of Missouri, Columbia, Missouri, USA, and a senior author of the study.

Therefore, they confirm that bone is responsive to developmental programming. In particular, that myostatin can mediate the effects of osteogenesis imperfecta.

"Humans achieve 90 percent of their peak bone mass by age 19. To approximate this timeframe with mice, we re-evaluated their bone strength and density four months after birth. In each case, the mice with stronger, denser adult bones were those whose fetal development involved females deficient in the protein myostatin. This finding shows that the environment within the womb affects bone development not only at birth, but into adulthood."

Charlotte Phillips PhD, Associate Professor, Department of Biochemistry, Department of Child Health, University of Missouri, Columbia, Missouri, USA, and a senior author of the study.

The article is published online at the Proceedings of the National Academy of Sciences, PNAS.

Both researchers believe their work is a paradigm shift in understanding and possibly treating osteogenesis imperfecta. They also feel their findings may prove beneficial to reducing risk for other bone diseases such as osteoporosis later in life for many. However, more research is needed.

"The intrauterine environment is important to bone health. For parents with osteogenesis imperfecta, we may be able to reduce the severity of their unborn child's disease through prenatal treatment. This also may be true for reducing the instances and severity of other bone diseases."

Laura Schulz PhD

Osteogenesis imperfecta (brittle bone disease) is an incurable genetic disorder. We demonstrate that maternal deficiency of myostatin (a negative regulator of muscle growth) can enhance bone biomechanical strength and integrity in control and osteogenesis imperfecta mouse offspring, using three independent approaches. We provide evidence that bone is responsive to developmental programming and that myostatin can mediate these effects. Embryo transfer experiments show that the effects of maternal myostatin deficiency are conferred by the postimplantation environment. These studies represent a paradigm shift in understanding and treating osteogenesis imperfecta—a shift from believing only genetic and postnatal environmental factors control bone health to the inclusion of prenatal/perinatal developmental programming as a modifiable factor controlling adult bone health.

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

The study, "Decreasing Maternal Myostatin Programs Adult Offspring Bone Strength in a Mouse Model of Osteogenesis Imperfecta," recently was published in Proceedings of the National Academy of Sciences. Research reported in this publication was supported by the National Institutes of Health (AR055907), a National Space and Biomedical Research Institute Postdoctoral Fellowship (NCC 9-58), a Leda J. Sears Trust Foundation Grant, a University of Missouri Life Sciences Fellowship and the University of Missouri Interdisciplinary Intercampus Research Program. The researchers have no conflicts of interest to declare related to this study.

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Feb 6, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   

Twins born with Osteogenesis Imperfecta cannot make strong bones because of mutations in their collagen.
Image Credit: The Osteogenesis Imperfecta Foundation



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