PMID- 26052552
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201001
IS  - 2378-5551 (Print)
IS  - 2378-5551 (Electronic)
IS  - 2378-5551 (Linking)
VI  - 1
IP  - 1
DP  - 2015
TI  - A mouse model of craniofacial bone lesion of tuberous sclerosis complex.
LID - e814 [pii]
AB  - 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.
FAU - Fang, Fang
AU  - Fang F
AD  - Department of Biologic and Materials Sciences Division of Prosthodontics, 
      University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
FAU - Wei, Xiaoxi
AU  - Wei X
AD  - 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.
FAU - Hu, Min
AU  - Hu M
AD  - Orthodontic Department, Jilin University College of Dentistry, Changchun, Jilin 
      130012, China.
FAU - Liu, Fei
AU  - Liu F
AD  - Department of Biologic and Materials Sciences Division of Prosthodontics, 
      University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
LA  - eng
GR  - R01 AR062030/AR/NIAMS NIH HHS/United States
GR  - R03 DE021718/DE/NIDCR NIH HHS/United States
PT  - Journal Article
PL  - United States
TA  - Musculoskelet Regen
JT  - Musculoskeletal regeneration
JID - 101659130
PMC - PMC4456023
MID - NIHMS690479
OTO - NOTNLM
OT  - Tsc1
OT  - craniofacial
OT  - mTOR
OT  - mice
OT  - neural crest
OT  - osteoblast
OT  - tuberous sclerosis
COIS- Conflict of Interest The author declares that they have no conflict of interest.
EDAT- 2015/06/09 06:00
MHDA- 2015/06/09 06:01
PMCR- 2015/06/04
CRDT- 2015/06/09 06:00
PHST- 2015/06/09 06:00 [entrez]
PHST- 2015/06/09 06:00 [pubmed]
PHST- 2015/06/09 06:01 [medline]
PHST- 2015/06/04 00:00 [pmc-release]
AID - e814 [pii]
AID - 10.14800/mr.814 [doi]
PST - ppublish
SO  - Musculoskelet Regen. 2015;1(1):e814. doi: 10.14800/mr.814.