PMID- 23553732
OWN - NLM
STAT- MEDLINE
DCOM- 20140305
LR  - 20211021
IS  - 1523-4681 (Electronic)
IS  - 0884-0431 (Print)
IS  - 0884-0431 (Linking)
VI  - 28
IP  - 9
DP  - 2013 Sep
TI  - Ubiquitin E3 ligase Wwp1 negatively regulates osteoblast function by inhibiting 
      osteoblast differentiation and migration.
PG  - 1925-35
LID - 10.1002/jbmr.1938 [doi]
AB  - Ubiquitin E3 ligase-mediated protein degradation promotes proteasomal degradation 
      of key positive regulators of osteoblast functions. For example, the E3 
      ligases--SMAD-specific E3 ubiquitin protein ligase 1 (Smurf1), Itch, and WW 
      domain-containing E3 ubiquitin protein ligase 1 (Wwp1)--promote degradation of 
      Runt-related transcription factor 2 (Runx2), transcription factor jun-B (JunB), 
      and chemokine (C-X-C) receptor type 4 (CXCR-4) proteins to inhibit their 
      functions. However, the role of E3 ligases in age-associated bone loss is 
      unknown. We found that the expression level of Wwp1, but not Smurf1 or Itch, was 
      significantly increased in CD45-negative (CD45(-)) bone marrow-derived 
      mesenchymal stem cells from 6-month-old and 12-month-old wild-type (WT) mice. 
      Wwp1 knockout (Wwp1(-/-)) mice developed increased bone mass as they aged, 
      associated with increased bone formation rates and normal bone resorption 
      parameters. Bone marrow stromal cells (BMSCs) from Wwp1(-/-) mice formed 
      increased numbers and areas of alkaline phosphatase(+) and Alizarin red(+) 
      nodules and had increased migration potential toward chemokine (C-X-C motif) 
      ligand 12 (CXCL12) gradients. Runx2, JunB, and CXCR-4 protein levels were 
      significantly increased in Wwp1(-/-) BMSCs. Wwp1(-/-) BMSCs had increased amount 
      of ubiquitinated JunB protein, but Runx2 ubiquitination was no change. Knocking 
      down JunB in Wwp1(-/-) BMSCs returned Runx2 protein levels to that in WT cells. 
      Thus, Wwp1 negatively regulates osteoblast functions by affecting both their 
      migration and differentiation. Mechanisms designed to decrease Wwp1 levels in 
      BMSCs may represent a new approach to prevent the decrease in osteoblastic bone 
      formation associated with aging.
CI  - (c) 2013 American Society for Bone and Mineral Research.
FAU - Shu, Lei
AU  - Shu L
AD  - Department of Pathology and Laboratory Medicine, University of Rochester Medical 
      Center, Rochester, NY, USA.
FAU - Zhang, Hengwei
AU  - Zhang H
FAU - Boyce, Brendan F
AU  - Boyce BF
FAU - Xing, Lianping
AU  - Xing L
LA  - eng
GR  - P30 AR061307/AR/NIAMS NIH HHS/United States
GR  - P30AR0613007/AR/NIAMS NIH HHS/United States
GR  - AR43510/AR/NIAMS NIH HHS/United States
GR  - R01 AR043510/AR/NIAMS NIH HHS/United States
GR  - R01 AR048697/AR/NIAMS NIH HHS/United States
GR  - AR48697/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
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 (Chemokine CXCL12)
RN  - 0 (JunB protein, mouse)
RN  - 0 (Receptors, CXCR4)
RN  - 0 (Transcription Factors)
RN  - EC 2.3.2.26 (WWP1 protein, mouse)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 3.1.3.48 (Leukocyte Common Antigens)
SB  - IM
MH  - Aging
MH  - Animals
MH  - *Cell Differentiation/drug effects
MH  - *Cell Movement/drug effects
MH  - Chemokine CXCL12/pharmacology
MH  - Humans
MH  - Leukocyte Common Antigens/metabolism
MH  - Mesenchymal Stem Cells/cytology/drug effects/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Organ Size/drug effects
MH  - Osteoblasts/*cytology/*enzymology
MH  - Osteogenesis/drug effects
MH  - Proteolysis/drug effects
MH  - Receptors, CXCR4/metabolism
MH  - Transcription Factors/metabolism
MH  - Ubiquitin-Protein Ligases/deficiency/*metabolism
PMC - PMC3749248
MID - NIHMS460780
OTO - NOTNLM
OT  - BONE FORMATION
OT  - MESENCHYMAL STEM CELLS
OT  - OSTEOBLASTS
OT  - WWP1
COIS- Disclosure: The authors have nothing to disclose.
EDAT- 2013/04/05 06:00
MHDA- 2014/03/07 06:00
PMCR- 2014/09/01
CRDT- 2013/04/05 06:00
PHST- 2012/10/15 00:00 [received]
PHST- 2013/03/01 00:00 [revised]
PHST- 2013/03/20 00:00 [accepted]
PHST- 2013/04/05 06:00 [entrez]
PHST- 2013/04/05 06:00 [pubmed]
PHST- 2014/03/07 06:00 [medline]
PHST- 2014/09/01 00:00 [pmc-release]
AID - 10.1002/jbmr.1938 [doi]
PST - ppublish
SO  - J Bone Miner Res. 2013 Sep;28(9):1925-35. doi: 10.1002/jbmr.1938.