ATP6V1H Deficiency Impairs Bone Development through Activation of MMP9 and MMP13
Yihan Zhang1,2, Haigen Huang1, Gexin Zhao2,3
1Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen China.
Insights
A mutation in ATP6V1H causes short stature and osteoporosis by disrupting bone formation. Inhibiting MMP9 and MMP13 in zebrafish bone loss models restored bone mass, suggesting therapeutic potential.
Area of Science:
- Genetics
- Molecular Biology
- Bone Biology
Background:
- ATP6V1H is a subunit of vacuolar ATPase (V-ATPase), crucial for cellular processes.
- V-ATPases are highly conserved across species, including humans and zebrafish.
- Mutations in ATP6V1H have been linked to short stature and osteoporosis in humans.
Purpose of the Study:
- To investigate the role of ATP6V1H in bone formation.
- To elucidate the molecular mechanisms underlying ATP6V1H-associated bone disorders.
- To explore potential therapeutic targets for ATP6V1H-related bone diseases.
Main Methods:
- Generated ATP6V1H loss-of-function zebrafish mutants using CRISPR/Cas9.
- Analyzed bone cell development, bone mass, and density in mutant zebrafish.
- Assessed the expression of matrix metalloproteinases (MMPs) 9 and 13.
- Treated mutant zebrafish embryos with MMP9 and MMP13 inhibitors.
Main Results:
- Homozygous atp6v1h mutants showed reduced mature bone cells and increased MMP9/MMP13 expression.
- Heterozygous adults exhibited vertebral deformities, reduced bone mass, and density.
- Inhibition of MMP9/MMP13 significantly improved bone mass in mutant embryos.
Conclusions:
- ATP6V1H plays a critical role in regulating bone formation.
- A novel ATP6V1H-mediated pathway involving MMP9/MMP13 regulates bone homeostasis.
- MMP9 and MMP13 are potential therapeutic targets for rare genetic bone loss diseases.
Abstract:
ATP6V1H is a component of a large protein complex with vacuolar ATPase (V-ATPase) activity. We identified two generations of individuals in which short stature and osteoporosis co-segregated with a mutation in ATP6V1H. Since V-ATPases are highly conserved between human and zebrafish, we generated loss-of-function mutants in atp6v1h in zebrafish through CRISPR/Cas9-mediated gene knockout. Homozygous mutant atp6v1h zebrafish exhibited a severe reduction in the number of mature calcified bone cells and a dramatic increase in the expression of mmp9 and mmp13. Heterozygous adults showed curved vertebra that lack calcified centrum structure and reduced bone mass and density. Treatment of mutant embryos with small molecule inhibitors of MMP9 and MMP13 significantly restored bone mass in the atp6v1h mutants. These studies have uncovered a new, ATP6V1H-mediated pathway that regulates bone formation, and defines a new mechanism of disease that leads to bone loss. We propose that MMP9/MMP13 could be therapeutic targets for patients with this rare genetic disease.
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