PMID- 23606335
OWN - NLM
STAT- MEDLINE
DCOM- 20140813
LR  - 20131021
IS  - 1523-4681 (Electronic)
IS  - 0884-0431 (Linking)
VI  - 28
IP  - 11
DP  - 2013 Nov
TI  - The G60S connexin 43 mutation activates the osteoblast lineage and results in a 
      resorption-stimulating bone matrix and abrogation of old-age-related bone loss.
PG  - 2400-13
LID - 10.1002/jbmr.1965 [doi]
AB  - We previously isolated a low bone mass mouse, Gja1(Jrt) / + , with a mutation in 
      the gap junction protein, alpha 1 gene (Gja1), encoding for a dominant negative 
      G60S Connexin 43 (Cx43) mutant protein. Similar to other Cx43 mutant mouse models 
      described, including a global Cx43 deletion, four skeletal cell 
      conditional-deletion mutants, and a Cx43 missense mutant (G138R/ +), a reduction 
      in Cx43 gap junction formation and/or function resulted in mice with early onset 
      osteopenia. In contrast to other Cx43 mutants, however, we found that Gja1(Jrt) 
      /+ mice have both higher bone marrow stromal osteoprogenitor numbers and 
      increased appendicular skeleton osteoblast activity, leading to cell autonomous 
      upregulation of both matrix bone sialoprotein (BSP) and membrane-bound receptor 
      activator of nuclear factor-kappaB ligand (mbRANKL). In younger Gja1(Jrt) /+ mice, 
      these contributed to increased osteoclast number and activity resulting in early 
      onset osteopenia. In older animals, however, this effect was abrogated by 
      increased osteoprotegerin (OPG) levels and serum alkaline phosphatase (ALP) so 
      that differences in mutant and wild-type (WT) bone parameters and mechanical 
      properties lessened or disappeared with age. Our study is the first to describe a 
      Cx43 mutation in which osteopenia is caused by increased rather than decreased 
      osteoblast function and where activation of osteoclasts occurs not only through 
      increased mbRANKL but an increase in a matrix protein that affects bone 
      resorption, which together abrogate age-related bone loss in older animals.
CI  - (c) 2013 American Society for Bone and Mineral Research.
FAU - Zappitelli, Tanya
AU  - Zappitelli T
AD  - Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
FAU - Chen, Frieda
AU  - Chen F
FAU - Moreno, Luisa
AU  - Moreno L
FAU - Zirngibl, Ralph A
AU  - Zirngibl RA
FAU - Grynpas, Marc
AU  - Grynpas M
FAU - Henderson, Janet E
AU  - Henderson JE
FAU - Aubin, Jane E
AU  - Aubin JE
LA  - eng
GR  - FRN 69198/Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
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 (Connexin 43)
RN  - 0 (Integrin-Binding Sialoprotein)
RN  - 0 (Osteoprotegerin)
RN  - 0 (RANK Ligand)
SB  - IM
MH  - Animals
MH  - Biomechanical Phenomena
MH  - Bone Density
MH  - Bone Matrix/*metabolism
MH  - Bone Resorption/*metabolism/*pathology
MH  - Cell Count
MH  - *Cell Lineage
MH  - Connexin 43/*genetics
MH  - Female
MH  - Femur/metabolism/pathology/physiopathology
MH  - Integrin-Binding Sialoprotein/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mutation/*genetics
MH  - Osteoblasts/metabolism/*pathology
MH  - Osteoprotegerin/metabolism
MH  - RANK Ligand/metabolism
OTO - NOTNLM
OT  - AGE-RELATED BONE LOSS
OT  - BONE SIALOPROTEIN
OT  - CONNEXIN 43
OT  - OSTEOPENIA
OT  - RANKL-OPG SIGNALING
EDAT- 2013/04/23 06:00
MHDA- 2014/08/15 06:00
CRDT- 2013/04/23 06:00
PHST- 2012/11/12 00:00 [received]
PHST- 2013/04/08 00:00 [revised]
PHST- 2013/04/15 00:00 [accepted]
PHST- 2013/04/23 06:00 [entrez]
PHST- 2013/04/23 06:00 [pubmed]
PHST- 2014/08/15 06:00 [medline]
AID - 10.1002/jbmr.1965 [doi]
PST - ppublish
SO  - J Bone Miner Res. 2013 Nov;28(11):2400-13. doi: 10.1002/jbmr.1965.