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Updated: Aug 5, 2025
Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model
Published on: July 3, 2020
Effect of sclerostin inactivation in a mouse model of severe dominant osteogenesis imperfecta
Juliana Marulanda1,2, Josephine T Tauer1, Iris Boraschi-Diaz2
1Shriners Hospital for Children, 1003 Decarie, Montreal, QC, H4A 0A9, Canada.
Abstract:
Osteogenesis imperfecta (OI) is a rare bone disease that is associated with fractures and low bone mass. Sclerostin inhibition is being evaluated as a potential approach to increase bone mass in OI. We had previously found that in Col1a1Jrt/+ mice, a model of severe OI, treatment with an anti-sclerostin antibody had a minor effect on the skeletal phenotype. In the present study, we assessed the effect of genetic sclerostin inactivation in the Col1a1Jrt/+ mouse. We crossed Col1a1Jrt/+ mice with Sost knockout mice to generate Sost-deficient Col1a1Jrt/+ mice and assessed differences between Col1a1Jrt/+ mice with homozygous Sost deficiency and Col1a1Jrt/+ mice with heterozygous Sost deficiency. We found that Col1a1Jrt/+ mice with homozygous Sost deficiency had higher body mass, femur length, trabecular bone volume, cortical thickness and periosteal diameter as well as increased biomechanical parameters of bone strength. Differences between genotypes were larger at the age of 14 weeks than at 8 weeks of age. Transcriptome analysis of RNA extracted from the tibial diaphysis revealed only 5 differentially regulated genes. Thus, genetic inactivation of Sost increased bone mass and strength in the Col1a1Jrt/+ mouse. It appears from these observations that the degree of Sost suppression that is required for eliciting a beneficial response can vary with the genetic cause of OI.
Insights
Genetic inactivation of sclerostin (Sost) significantly improved bone mass and strength in a mouse model of severe Osteogenesis imperfecta (OI). This suggests Sost suppression may be a viable therapeutic strategy for OI patients.
Area of Science:
- Biochemistry
- Genetics
- Orthopedics
Background:
- Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by brittle bones and low bone mass.
- Sclerostin (Sost) is a protein that inhibits bone formation, and its inhibition is being explored as a treatment for bone diseases like OI.
- Previous studies showed limited efficacy of anti-sclerostin antibodies in a severe OI mouse model (Col1a1Jrt/+).
Purpose of the Study:
- To investigate the therapeutic potential of genetic sclerostin inactivation in the Col1a1Jrt/+ mouse model of severe OI.
- To assess the impact of complete (homozygous) versus partial (heterozygous) Sost deficiency on skeletal parameters in OI mice.
Main Methods:
- Generation of Sost-deficient Col1a1Jrt/+ mice by crossing Col1a1Jrt/+ mice with Sost knockout mice.
- Comparison of skeletal and biomechanical properties between homozygous Sost-deficient, heterozygous Sost-deficient, and control Col1a1Jrt/+ mice at 8 and 14 weeks of age.
- Transcriptome analysis of tibial diaphysis RNA to identify gene expression changes.
Main Results:
- Homozygous Sost deficiency in Col1a1Jrt/+ mice led to increased body mass, femur length, and bone dimensions (cortical thickness, periosteal diameter).
- Significant improvements in trabecular bone volume and bone strength (biomechanical parameters) were observed in homozygous Sost-deficient OI mice.
- The beneficial effects were more pronounced at 14 weeks compared to 8 weeks, and transcriptome analysis revealed minimal changes in gene expression.
Conclusions:
- Genetic inactivation of Sost effectively increases bone mass and strength in a severe mouse model of Osteogenesis imperfecta.
- The findings suggest that the required level of Sost suppression for therapeutic benefit may depend on the specific genetic cause of OI.
- Complete genetic inactivation of Sost demonstrates a potent positive effect on the skeletal phenotype in this OI model.
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