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Updated: Apr 11, 2026
Analysis of Craniomaxillofacial Malformations in Mice Using Three-dimensional Microcomputed Tomography
Published on: January 17, 2025
A mouse model of craniofacial bone lesion of tuberous sclerosis complex
Fang Fang1, Xiaoxi Wei2, Min Hu3
1Department of Biologic and Materials Sciences Division of Prosthodontics, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
Abstract:
The mammalian/mechanistic target of rapamycin (mTOR) signaling pathway plays critical roles in skeletal development. The impact and underlying mechanisms of its dysregulation in bone homeostasis is poorly defined. The best known and characterized mTOR signaling dysregulation in human disease is called Tuberous Sclerosis Complex (TSC). TSC is an autosomal dominant neurocutaneous syndrome with a high frequency (>66%) of osseous manifestations such as sclerotic lesions in the craniofacial region. TSC is caused by mutations of TSC1 or TSC2, the heterodimer protein inhibitor of mTORC1 signaling. The underlying mechanism of bone lesions in TSC is unclear. We generated a TSC mouse model with TSC1 deletion in neural crest derived (NCD) cells, which recapitulated the sclerotic craniofacial bone lesion in TSC patients. We demonstrated that TSC1 null NCD osteoblasts overpopulated the NCD bones and the resultant increased bone formation is responsible for the sclerotic bone phenotype. Mechanistically, osteoblast number increase is due to the hyperproliferation of osteoprogenitor cells at an early postnatal stage. Noteworthy, administration of rapamycin, an mTORC1 inhibitor at early postnatal stage can completely rescue the excess bone acquisition, but late treatment cannot. Altogether, our data suggested that enhanced mTORC1 signaling in NCD cells can enlarge the osteoprogenitor pool and lead to the excess bone acquisition, which is likely the underlying mechanism of sclerotic bone lesion observed in TSC patients.
Insights
Enhanced mechanistic target of rapamycin (mTOR) signaling in neural crest cells causes excess bone formation in Tuberous Sclerosis Complex (TSC). Early rapamycin treatment rescues this bone overgrowth, revealing a potential therapeutic window.
Area of Science:
- Molecular Biology
- Developmental Biology
- Genetics
- Bone Biology
Background:
- The mechanistic target of rapamycin (mTOR) pathway is crucial for skeletal development, but its dysregulation in bone homeostasis is not well understood.
- Tuberous Sclerosis Complex (TSC), caused by TSC1 or TSC2 mutations, is linked to significant bone abnormalities, particularly sclerotic craniofacial lesions.
Purpose of the Study:
- To investigate the role of mTOR signaling in neural crest-derived (NCD) cells in the pathogenesis of bone lesions observed in TSC.
- To elucidate the mechanisms underlying the sclerotic craniofacial bone phenotype in a TSC mouse model.
Main Methods:
- Generation of a mouse model with TSC1 deletion specifically in neural crest-derived (NCD) cells.
- Analysis of bone formation and osteoblast populations in the TSC mouse model.
- Treatment with rapamycin, an mTORC1 inhibitor, at different postnatal stages.
Main Results:
- TSC1 deletion in NCD cells led to osteoblast overpopulation and increased bone formation, mimicking sclerotic craniofacial lesions in TSC patients.
- The excess bone formation was attributed to hyperproliferation of osteoprogenitor cells in early postnatal stages.
- Early postnatal rapamycin administration completely rescued the excessive bone acquisition, while late treatment was ineffective.
Conclusions:
- Enhanced mTORC1 signaling in NCD cells expands the osteoprogenitor pool, driving excess bone acquisition and sclerotic lesions characteristic of TSC.
- Early postnatal intervention with mTORC1 inhibitors like rapamycin shows therapeutic potential for TSC-associated bone abnormalities.
