PMID- 33900666
OWN - NLM
STAT- MEDLINE
DCOM- 20210809
LR  - 20230504
IS  - 1523-4681 (Electronic)
IS  - 0884-0431 (Linking)
VI  - 36
IP  - 8
DP  - 2021 Aug
TI  - Phosphate restriction impairs mTORC1 signaling leading to increased bone marrow 
      adipose tissue and decreased bone in growing mice.
PG  - 1510-1520
LID - 10.1002/jbmr.4312 [doi]
AB  - Bone marrow stromal cells (BMSCs) are multipotent cells that differentiate into 
      cells of the osteogenic and adipogenic lineage. A striking inverse relationship 
      between bone marrow adipose tissue (BMAT) and bone volume is seen in several 
      conditions, suggesting that differentiation of BMSCs into bone marrow adipocytes 
      diverts cells from the osteogenic lineage, thereby compromising the structural 
      and mechanical properties of bone. Phosphate restriction of growing mice acutely 
      decreases bone formation, blocks osteoblast differentiation and increases BMAT. 
      Studies performed to evaluate the cellular and molecular basis for the effects of 
      acute phosphate restriction demonstrate that it acutely increases 5' adenosine 
      monophosphate-activated protein kinase (AMPK) phosphorylation and inhibits 
      mammalian target of rapamycin complex 1 (mTORC1) signaling in osteoblasts. This 
      is accompanied by decreased expression of Wnt10b in BMSCs. Phosphate restriction 
      also promotes expression of the key adipogenic transcription factors, peroxisome 
      proliferator-activated receptor gamma (PPARgamma) and CCAAT-enhancer binding protein alpha 
      (CEBPalpha), in CXCL12 abundant reticular (CAR) cells, which represent 
      undifferentiated BMSCs and are the main source of BMAT and osteoblasts in the 
      adult murine skeleton. Consistent with this, lineage tracing studies reveal that 
      the BMAT observed in phosphate-restricted mice is of CAR cell origin. To 
      determine whether circumventing the decrease in mTORC1 signaling in maturing 
      osteoblasts attenuates the osteoblast and BMAT phenotype, phosphate-restricted 
      mice with OSX-Cre(ERT2) -mediated haploinsufficiency of the mTORC1 inhibitor, 
      TSC2, were generated. TSC2 haploinsufficiency in preosteoblasts/osteoblasts 
      normalized bone volume and osteoblast number in phosphate-restricted mice and 
      attenuated the increase in BMAT observed. Thus, acute phosphate restriction leads 
      to decreased bone and increases BMAT by impairing mTORC1 signaling in 
      osterix-expressing cells. (c) 2021 American Society for Bone and Mineral Research 
      (ASBMR).
CI  - (c) 2021 American Society for Bone and Mineral Research (ASBMR).
FAU - Ko, Frank C
AU  - Ko FC
AD  - Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
AD  - Harvard Medical School, Boston, Massachusetts, USA.
FAU - Kobelski, Margaret M
AU  - Kobelski MM
AD  - Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
FAU - Zhang, Wanlin
AU  - Zhang W
AD  - Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
FAU - Grenga, Gina M
AU  - Grenga GM
AD  - Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
FAU - Martins, Janaina S
AU  - Martins JS
AD  - Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
AD  - Harvard Medical School, Boston, Massachusetts, USA.
FAU - Demay, Marie B
AU  - Demay MB
AUID- ORCID: 0000-0001-5845-5479
AD  - Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
AD  - Harvard Medical School, Boston, Massachusetts, USA.
LA  - eng
GR  - T32 DK007028/DK/NIDDK NIH HHS/United States
GR  - R01 AR061376/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20210604
PL  - England
TA  - J Bone Miner Res
JT  - Journal of bone and mineral research : the official journal of the American 
      Society for Bone and Mineral Research
JID - 8610640
RN  - 0 (Phosphates)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
SB  - IM
MH  - Adipose Tissue
MH  - Animals
MH  - *Bone Marrow
MH  - Bone Marrow Cells
MH  - Cell Differentiation
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Osteoblasts
MH  - Osteogenesis
MH  - *Phosphates
OTO - NOTNLM
OT  - BONE HISTOMORPHOMETRY
OT  - BONE QCT/muCT
OT  - GENETIC ANIMAL MODELS
OT  - OSTEOBLAST
OT  - mTORC1
EDAT- 2021/04/27 06:00
MHDA- 2021/08/10 06:00
CRDT- 2021/04/26 12:32
PHST- 2021/04/14 00:00 [revised]
PHST- 2020/10/30 00:00 [received]
PHST- 2021/04/17 00:00 [accepted]
PHST- 2021/04/27 06:00 [pubmed]
PHST- 2021/08/10 06:00 [medline]
PHST- 2021/04/26 12:32 [entrez]
AID - 10.1002/jbmr.4312 [doi]
PST - ppublish
SO  - J Bone Miner Res. 2021 Aug;36(8):1510-1520. doi: 10.1002/jbmr.4312. Epub 2021 Jun 
      4.