# Maternal Anti-myostatin (GDF8) Therapy to Enhance Offspring Musculoskeletal Health in Mouse Models of Osteogenesis Imperfecta

> **NIH NIH R21** · UNIVERSITY OF MISSOURI-COLUMBIA · 2021 · $164,451

## Abstract

Summary
Osteogenesis imperfecta (OI) is a genetically and clinically heterogeneous connective tissue disorder
resulting in muscle weakness, bone deformity and increased fragility, primarily due to type I collagen
gene mutations. Currently there is no cure. Genetic and clinical heterogeneity (> 1500 mutations) and
growing evidence of mutation specific pathogenesis further challenges drug discovery. Deficiency in
myostatin, a circulating negative regulator of muscle growth, results in increased muscle mass and
physiological loading on the skeleton with concomitant increases in bone mass and biomechanical
integrity. Developmental programming by the prenatal environment is hypothesized to play a significant
role in lifelong bone health and promises to provide a novel modality for therapeutic intervention.
Congenital myostatin null mice demonstrate both myofiber hyperplasia and hypertrophy, while mice
with postnatal myostatin deficiency exhibit only hypertrophy, indicating some aspects of adult physiology
are irreversibly determined during prenatal development. Previously, by three independent approaches
we demonstrated that reduced maternal myostatin during pregnancy improves bone geometry and
biomechanical integrity in offspring: 1) Wildtype (Wt) offspring born to dams with reduced myostatin
(+/mstn) had stronger bones than Wt offspring born to Wt dams; 2) Mice with osteogenesis imperfecta
(+/oim) had stronger bones when born to +/mstn dams than when born to +/oim dams; and 3) +/oim
blastocysts transferred to +/mstn recipient dams had stronger bones as adults than those transferred to
+/oim dams. Importantly, the last approach through embryo transfer experiments demonstrated that
the maternal +/mstn effect on offspring bone was conferred by the uteroplacental environment during
pregnancy. Based on these findings, we will test the efficacy of pharmacological inhibition of maternal
and fetal myostatin during pregnancy via maternal anti-myostatin (GDF8) monoclonal antibody
treatment as a prenatal therapeutic approach for OI using two molecularly distinct OI mouse models. The
primary outcomes measures and indicators of efficacy are improved musculoskeletal health (skeletal
muscle and bone mass and function) of Wt and OI offspring at the age of peak bone mass (4 month old).
OI can be diagnosed prenatally, whether genetically or by ultrasound, yet we have no prenatal
treatment options and, are thus missing a critical therapeutic window. This high risk study represents a
more than incremental leap towards establishing the translational potential of a prenatal treatment for
OI, it is a paradigm shift in understanding and treating OI; a shift from believing only genetic and
postnatal factors control bone health, to the inclusion of the prenatal/perinatal period as an important
and modifiable window for controlling adult bone health.

## Key facts

- **NIH application ID:** 10216181
- **Project number:** 5R21AR077813-02
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** CHARLOTTE L PHILLIPS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $164,451
- **Award type:** 5
- **Project period:** 2020-07-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10216181

## Citation

> US National Institutes of Health, RePORTER application 10216181, Maternal Anti-myostatin (GDF8) Therapy to Enhance Offspring Musculoskeletal Health in Mouse Models of Osteogenesis Imperfecta (5R21AR077813-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10216181. Licensed CC0.

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