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Transient inhibition of the Hedgehog pathway in young mice causes permanent defects in bone structure
Hiromichi Kimura1, Jessica M Y Ng, Tom Curran
1Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105, USA.
Abstract:
The Hedgehog (Hh) pathway plays critical roles in normal development and in tumorigenesis. We generated Gli-luciferase transgenic mice to evaluate the Smo inhibitor, HhAntag, by whole animal functional imaging. HhAntag rapidly reduced systemic luciferase activity in 10- to 14-day-old mice following oral dosing. Although pathway activity was restored 2 days after drug removal, brief inhibition caused permanent defects in bone growth. HhAntag inhibited proliferation and promoted differentiation of chondrocytes, leading to dramatic expansion of the hypertrophic zone. After drug removal, osteoblasts invaded the cartilage plate, mineralization occurred, and there was premature fusion of the growth plate resulting in permanent disruption of bone epiphyses.
Insights
Short-term inhibition of the Hedgehog (Hh) pathway using HhAntag in young mice caused permanent bone growth defects. This Smo inhibitor disrupted chondrocyte development and led to premature growth plate fusion.
Area of Science:
- Developmental biology
- Pharmacology
- Skeletal biology
Background:
- The Hedgehog (Hh) signaling pathway is crucial for embryonic development and implicated in various cancers.
- Dysregulation of the Hh pathway contributes to abnormal growth and disease states.
- Targeting the Hh pathway with inhibitors is a therapeutic strategy for Hh-dependent tumors.
Purpose of the Study:
- To evaluate the efficacy and long-term effects of a Smo inhibitor, HhAntag, on the Hh pathway in vivo.
- To assess the impact of Hh pathway inhibition on bone development using functional imaging in transgenic mice.
Main Methods:
- Generation of Gli-luciferase transgenic mice to monitor Hh pathway activity.
- Whole animal functional imaging to track systemic luciferase activity following HhAntag administration.
- Oral dosing of HhAntag in 10- to 14-day-old mice.
- Analysis of bone growth and development post-drug withdrawal.
Main Results:
- HhAntag rapidly and effectively reduced systemic Hh pathway activity upon oral administration.
- Hh pathway activity was restored within 2 days after cessation of HhAntag treatment.
- Transient Hh inhibition resulted in significant and permanent defects in bone growth.
- HhAntag treatment led to chondrocyte proliferation inhibition, differentiation promotion, and expansion of the hypertrophic zone.
- Post-treatment, osteoblast invasion of the cartilage plate, mineralization, and premature growth plate fusion were observed, causing permanent disruption of bone epiphyses.
Conclusions:
- Brief inhibition of the Hedgehog pathway with HhAntag can induce lasting skeletal abnormalities.
- The timing of Hh pathway inhibition during development is critical, as transient disruption leads to permanent bone growth defects.
- HhAntag's effects on chondrocytes and growth plate dynamics highlight its potential for unintended skeletal consequences.
- These findings underscore the importance of considering developmental timing and potential off-target effects when using Hh pathway inhibitors.
