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Updated: Jul 17, 2026
Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model
Published on: July 3, 2020
Novel pycnodysostosis mouse model uncovers cathepsin K function as a potential regulator of osteoclast apoptosis and
Wei Chen1, Shuying Yang, Yoke Abe
1Department of Cytokine Biology, The Forsyth Institute and Harvard School of Dental Medicine, 140 The Fenway, Boston, MA 02115, USA.
Abstract:
Pycnodysostosis is a genetic bone disease featuring the unique bone homeostasis disorders of osteolysis and osteopetrosis in the same organism. The pathomechanism for pycnodysostosis has been largely unknown due to the unavailability of a pycnodysostosis mouse model with all the traits of the disease. We generated cathepsin K(-/-) mouse strains in the 129/Sv and C57BL/6J backgrounds and found that, only in the 129/Sv background, cathepsin K(-/-) mice exhibit many characteristics of the human pycnodysostosis-like phenotype. Our data indicated that 129/Sv cathepsin K(-/-) osteoclasts (OCs) lacked normal apoptosis and senescence and exhibited over-growth both in vitro and in vivo. These abnormalities resulted in an unusually high OC number, which is consistent with a recent case study of human pycnodysostosis. Our results show that cathepsin K function has different effects around the skeleton due to site-specific variations in bone homeostasis, such as phenotypes of osteopetrosis in tibiae and osteolysis in calvariae as a result of cathepsin K mutation. Our data demonstrated that the expression levels of p19, p53 and p21 were significantly reduced in 129/Sv cathepsin K(-/-) OCs and forced expression of cathepsin K in pre-OCs induced premature senescence and increased expression of p19, p53 and p21. This is the first evidence that cathepsin K plays a key role in OC apoptosis and senescence, revealing the importance of OC senescence in bone homeostasis. The finding of this novel cathepsin K function provides insight into the pathomechanism of pycnodysostosis and may provide new drug targets for diseases involved in OC-related abnormal bone homeostasis.
Insights
Cathepsin K deficiency in mice causes pycnodysostosis-like bone disease by impairing osteoclast apoptosis and senescence. This study identifies a key role for cathepsin K in regulating bone homeostasis and suggests new therapeutic targets.
Area of Science:
- Genetics
- Bone Biology
- Pathomechanisms of Genetic Diseases
Background:
- Pycnodysostosis is a rare genetic disorder characterized by impaired bone resorption and increased bone density.
- The precise pathomechanism of pycnodysostosis has remained elusive due to the lack of suitable animal models.
- Osteoclast (OC) dysfunction is implicated in pycnodysostosis, but the underlying molecular mechanisms are not fully understood.
Purpose of the Study:
- To develop and characterize a mouse model that recapitulates the key features of human pycnodysostosis.
- To investigate the role of cathepsin K in osteoclast biology and bone homeostasis.
- To elucidate the molecular mechanisms by which cathepsin K influences osteoclast apoptosis and senescence.
Main Methods:
- Generation of cathepsin K-deficient (cathepsin K-/-) mouse strains on different genetic backgrounds (129/Sv and C57BL/6J).
- Phenotypic analysis of cathepsin K-/- mice, including bone density, osteoclast number, and skeletal abnormalities.
- In vitro and in vivo studies of osteoclast apoptosis, senescence, and proliferation.
- Analysis of key regulatory proteins involved in apoptosis and senescence pathways (p19, p53, p21).
Main Results:
- Cathepsin K-/- mice on the 129/Sv background exhibited a pycnodysostosis-like phenotype, including osteopetrosis and osteolysis.
- 129/Sv cathepsin K-/- osteoclasts displayed impaired apoptosis and senescence, leading to increased osteoclast numbers.
- Cathepsin K deficiency resulted in reduced expression of p19, p53, and p21 in osteoclasts.
- Forced expression of cathepsin K induced premature senescence and increased p19, p53, and p21 expression in osteoclasts.
Conclusions:
- Cathepsin K plays a critical role in regulating osteoclast apoptosis and senescence, essential processes for maintaining bone homeostasis.
- The 129/Sv background is crucial for the manifestation of a pycnodysostosis-like phenotype in cathepsin K-/- mice, highlighting genetic background effects.
- This study provides novel insights into the pathomechanism of pycnodysostosis and identifies cathepsin K as a potential therapeutic target for bone diseases characterized by osteoclast dysfunction.
