PMID- 22729283
OWN - NLM
STAT- MEDLINE
DCOM- 20120919
LR  - 20220409
IS  - 1546-170X (Electronic)
IS  - 1078-8956 (Print)
IS  - 1078-8956 (Linking)
VI  - 18
IP  - 7
DP  - 2012 Jul
TI  - Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells.
PG  - 1095-101
LID - 10.1038/nm.2793 [doi]
AB  - Insulin-like growth factor 1 (IGF-1), the most abundant growth factor in the bone 
      matrix, maintains bone mass in adulthood. We now report that IGF-1 released from 
      the bone matrix during bone remodeling stimulates osteoblastic differentiation of 
      recruited mesenchymal stem cells (MSCs) by activation of mammalian target of 
      rapamycin (mTOR), thus maintaining proper bone microarchitecture and mass. Mice 
      with knockout of the IGF-1 receptor (Igf1r) in their pre-osteoblastic cells 
      showed lower bone mass and mineral deposition rates than wild-type mice. Further, 
      MSCs from Igf1rflox/flox mice with Igf1r deleted by a Cre adenovirus in vitro, 
      although recruited to the bone surface after implantation, were unable to 
      differentiate into osteoblasts. We also found that the concentrations of IGF-1 in 
      the bone matrix and marrow of aged rats were lower than in those of young rats 
      and directly correlated with the age-related decrease in bone mass. Likewise, in 
      age-related osteoporosis in humans, we found that bone marrow IGF-1 
      concentrations were 40% lower in individuals with osteoporosis than in 
      individuals without osteoporosis. Notably, injection of IGF-1 plus IGF binding 
      protein 3 (IGFBP3), but not injection of IGF-1 alone, increased the concentration 
      of IGF-1 in the bone matrix and stimulated new bone formation in aged rats. 
      Together, these results provide mechanistic insight into how IGF-1 maintains 
      adult bone mass, while also providing a further rationale for its therapeutic 
      targeting to treat age-related osteoporosis.
FAU - Xian, Lingling
AU  - Xian L
AD  - Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, 
      Baltimore, Maryland, USA.
FAU - Wu, Xiangwei
AU  - Wu X
FAU - Pang, Lijuan
AU  - Pang L
FAU - Lou, Michael
AU  - Lou M
FAU - Rosen, Clifford J
AU  - Rosen CJ
FAU - Qiu, Tao
AU  - Qiu T
FAU - Crane, Janet
AU  - Crane J
FAU - Frassica, Frank
AU  - Frassica F
FAU - Zhang, Liming
AU  - Zhang L
FAU - Rodriguez, Juan Pablo
AU  - Rodriguez JP
FAU - Xiaofeng Jia
AU  - Xiaofeng Jia
FAU - Shoshana Yakar
AU  - Shoshana Yakar
FAU - Shouhong Xuan
AU  - Shouhong Xuan
FAU - Argiris Efstratiadis
AU  - Argiris Efstratiadis
FAU - Mei Wan
AU  - Mei Wan
FAU - Xu Cao
AU  - Xu Cao
LA  - eng
GR  - R01 DK080898/DK/NIDDK NIH HHS/United States
GR  - T32DK007751V/DK/NIDDK NIH HHS/United States
GR  - T32 DK007751/DK/NIDDK NIH HHS/United States
GR  - AR 053973/AR/NIAMS NIH HHS/United States
GR  - K01 AR060433/AR/NIAMS NIH HHS/United States
GR  - R01 AR053973-02/AR/NIAMS NIH HHS/United States
GR  - R01 AR053973-03/AR/NIAMS NIH HHS/United States
GR  - R01 AR045433/AR/NIAMS NIH HHS/United States
GR  - R01 AR053973/AR/NIAMS NIH HHS/United States
GR  - R01 AR053973-05/AR/NIAMS NIH HHS/United States
GR  - R01 AR053973-01A2/AR/NIAMS NIH HHS/United States
GR  - R01 DK057501/DK/NIDDK NIH HHS/United States
GR  - R01 AR053973-04/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Nat Med
JT  - Nature medicine
JID - 9502015
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Insulin-Like Growth Factor Binding Protein 3)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - EC 2.7.10.1 (Receptor, IGF Type 1)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
CIN - Nat Rev Rheumatol. 2012 Aug;8(8):440. PMID: 22782005
MH  - Aging/drug effects/metabolism
MH  - Animals
MH  - Bone Matrix/drug effects/*metabolism
MH  - Bone Resorption/blood/diagnostic imaging/metabolism/pathology
MH  - Bone and Bones/drug effects/metabolism/*pathology
MH  - Cell Count
MH  - Cell Differentiation/drug effects
MH  - Enzyme Activation/drug effects
MH  - Femur/diagnostic imaging/growth & development/pathology
MH  - Humans
MH  - Immunohistochemistry
MH  - Insulin Receptor Substrate Proteins/metabolism
MH  - Insulin-Like Growth Factor Binding Protein 3/administration & 
      dosage/metabolism/pharmacology
MH  - Insulin-Like Growth Factor I/administration & dosage/*metabolism/pharmacology
MH  - Mesenchymal Stem Cells/drug effects/*enzymology/pathology
MH  - Mice
MH  - Mice, Knockout
MH  - Organ Size/drug effects
MH  - Osteoblasts/drug effects/enzymology/pathology
MH  - Osteogenesis/drug effects
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Rats
MH  - Receptor, IGF Type 1/deficiency/metabolism
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - X-Ray Microtomography
PMC - PMC3438316
MID - NIHMS371289
EDAT- 2012/06/26 06:00
MHDA- 2012/09/20 06:00
PMCR- 2013/01/01
CRDT- 2012/06/26 06:00
PHST- 2012/03/07 00:00 [received]
PHST- 2012/04/18 00:00 [accepted]
PHST- 2012/06/26 06:00 [entrez]
PHST- 2012/06/26 06:00 [pubmed]
PHST- 2012/09/20 06:00 [medline]
PHST- 2013/01/01 00:00 [pmc-release]
AID - nm.2793 [pii]
AID - 10.1038/nm.2793 [doi]
PST - ppublish
SO  - Nat Med. 2012 Jul;18(7):1095-101. doi: 10.1038/nm.2793.