title: A mouse model of craniofacial bone lesion of tuberous sclerosis complex.
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.
authors.affiliation: Department of Biologic and Materials Sciences Division of Prosthodontics, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.affiliation: Department of Biologic and Materials Sciences Division of Prosthodontics, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA ; Orthodontic Department, Jilin University College of Dentistry, Changchun, Jilin 130012, China.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Wei
authors.affiliation: Orthodontic Department, Jilin University College of Dentistry, Changchun, Jilin 130012, China.
authors.forename: Min
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Biologic and Materials Sciences Division of Prosthodontics, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
keywords: Tsc1; craniofacial; mTOR; mice; neural crest; osteoblast; tuberous sclerosis