PMID- 11159865
OWN - NLM
STAT- MEDLINE
DCOM- 20010329
LR  - 20071114
IS  - 0013-7227 (Print)
IS  - 0013-7227 (Linking)
VI  - 142
IP  - 2
DP  - 2001 Feb
TI  - Receptors for the carboxyl-terminal region of pth(1-84) are highly expressed in 
      osteocytic cells.
PG  - 916-25
AB  - PTH is a potent systemic regulator of cellular differentiation and function in 
      bone. It acts upon cells of the osteoblastic lineage via the G protein-coupled 
      type-1 PTH/PTH-related peptide receptor (PTH1R). Carboxyl fragments of intact 
      PTH(1-84) (C-PTH fragments) are cosecreted with it by the parathyroid glands in a 
      calcium-dependent manner and also are generated via proteolysis of the hormone in 
      peripheral tissues. Receptors that recognize C-PTH fragments (CPTHRs) have been 
      described previously in osteoblastic and chondrocytic cells. To directly study 
      CPTHRs in bone cells, we isolated clonal, conditionally transformed cell lines 
      from fetal calvarial bone of mice that are homozygous for targeted ablation of 
      the PTH1R gene and transgenically express a temperature-sensitive mutant SV40 T 
      antigen. Cells with the highest specific binding of the CPTHR radioligand 
      (125)I-[Tyr(34)]hPTH(19-84) exhibited a stellate, dendritic appearance suggestive 
      of an osteocytic phenotype and expressed 6- to 10-fold more CPTHR sites/cell than 
      did osteoblastic cells previously isolated from the same bones. In these 
      osteocytic (OC) cells, expression of mRNAs for CD44, connexin 43, and osteocalcin 
      was high, whereas that for alkaline phosphatase and cbfa-1/osf-2 was negligible. 
      The CPTHR radioligand was displaced completely by hPTH(1-84), hPTH(19-84) and 
      hPTH(24-84) (IC(50)s = 20-50 nM) and by hPTH(39-84) (IC(50) = 500 nM) but only 
      minimally (24%) by 10,000 nM hPTH(1-34). CPTHR binding was down-regulated dose 
      dependently by hPTH(1-84), an effect mimicked by ionomycin and active phorbol 
      ester. Human PTH(1-84) and hPTH(39-84) altered connexin 43 expression and 
      increased apoptosis in OC cells. Apoptosis induced by PTH(1-84) was blocked by 
      the caspase inhibitor DEVD. We conclude that osteocytes, the most abundant cells 
      in bone, may be principal target cells for unique actions of intact PTH(1-84) and 
      circulating PTH C-fragments that are mediated by CPTHRs.
FAU - Divieti, P
AU  - Divieti P
AD  - Endocrine Unit, Massachusetts General Hospital, and Harvard Medical School, 
      Boston Massachusetts 02114, USA. divieti@helix.mgh.harvard.edu
FAU - Inomata, N
AU  - Inomata N
FAU - Chapin, K
AU  - Chapin K
FAU - Singh, R
AU  - Singh R
FAU - Juppner, H
AU  - Juppner H
FAU - Bringhurst, F R
AU  - Bringhurst FR
LA  - eng
GR  - DK-11794/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Ligands)
RN  - 0 (Parathyroid Hormone)
RN  - 0 (Peptide Fragments)
RN  - 0 (Receptors, Parathyroid Hormone)
RN  - 0 (carboxyl-terminal parathyroid hormone)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Cells, Cultured
MH  - Humans
MH  - Ligands
MH  - Mice
MH  - Mice, Transgenic/genetics
MH  - Osteocytes/*metabolism/physiology/ultrastructure
MH  - Parathyroid Hormone/*genetics/*metabolism/pharmacology
MH  - Peptide Fragments/genetics/*metabolism
MH  - Receptors, Parathyroid Hormone/*metabolism
EDAT- 2001/02/13 11:00
MHDA- 2001/04/03 10:01
CRDT- 2001/02/13 11:00
PHST- 2001/02/13 11:00 [pubmed]
PHST- 2001/04/03 10:01 [medline]
PHST- 2001/02/13 11:00 [entrez]
AID - 10.1210/endo.142.2.7955 [doi]
PST - ppublish
SO  - Endocrinology. 2001 Feb;142(2):916-25. doi: 10.1210/endo.142.2.7955.