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Cathepsin K Controls Cortical Bone Formation by Degrading Periostin
Nicolas Bonnet1, Julia Brun1, Jean-Charles Rousseau2,3
1Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospital & Faculty of Medicine, Geneva, Switzerland.
Summary
Inhibiting cathepsin K (CatK) boosts bone formation by increasing periostin and beta-catenin signaling, particularly at the periosteum. This mechanism enhances cortical bone volume, offering new insights into bone homeostasis.
Area of Science:
- Bone Biology
- Skeletal Remodeling
- Molecular Mechanisms of Bone Formation
Background:
- Bone resorption and formation are coupled processes.
- Cathepsin K (CatK) inhibition/deletion reduces resorption but paradoxically stimulates bone formation.
- Mechanisms driving increased bone formation, especially at periosteal surfaces, are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanisms by which CatK inhibition/deletion enhances bone formation.
- To investigate the role of CatK in periosteal bone formation.
- To identify molecular targets of CatK involved in bone modeling.
Main Methods:
- Pharmacological inhibition and genetic deletion (Ctsk-/- mice) of CatK.
- Assessment of bone formation and resorption markers.
- Analysis of periostin (Postn) and beta-catenin expression in vivo.
- Investigating the effect of Postn deletion in CatK-deficient mice.
Main Results:
- CatK inhibition/deletion potentiates mechanotransduction signals for cortical bone formation.
- Periostin (Postn) is identified as a direct CatK target.
- CatK deletion increases periosteal Postn and beta-catenin expression.
- Postn deletion abrogates cortical bone formation in CatK-deficient mice.
Conclusions:
- Cathepsin K (CatK) modulates bone modeling-based cortical bone formation by degrading periostin (Postn).
- CatK regulates Wnt-beta-catenin signaling, impacting bone homeostasis.
- These findings reveal novel mechanisms for increased cortical bone volume associated with CatK inhibition.
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