New bone formation in an osteoblastic tumor model is increased by endothelin-1 overexpression and decreased by endothelin A receptor blockade.
OBJECTIVE
The osteoblastic response of bone to metastatic prostate cancer is both characteristic and enigmatic. The potent vasoconstrictor endothelin-1 (ET-1), produced by prostate cancer, has been identified as a potential factor in new bone formation.


METHODS
Using a novel method to quantitate new bone formation induced by the WISH tumor, we examined the effects of ET-1 overexpression and endothelin receptor antagonists on the osteoblastic response.


RESULTS
WISH, a human tumor cell line derived from amnion, produces ET-1 mRNA and protein and induces abundant new bone formation and splenomegaly in vivo. Stable transfection of WISH with an ET-1 overexpression cDNA construct produced clones that secreted 18-fold more bioactive ET-1 than vector-only controls. After 14 days of growth in the lower leg of nu/nu mice, ET-1 overexpressing tumors produced significantly more new bone than vector-only controls. Conversely, areas of new bone formation were significantly less in animals treated with a selective endothelin A (ET(A)) receptor antagonist A127722.


CONCLUSIONS
The activity of ET-1 in this osteoblastic model provides a unique target for therapy.
Nelson
J B
JB
Department of Orthopaedic Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Nguyen
S H
SH
Wu-Wong
J R
JR
Opgenorth
T J
TJ
Dixon
D B
DB
Chung
L W
LW
Inoue
N
N
D000818:Animals; D001859:Bone Neoplasms / Q000209:etiology* / Q000556:secondary; D015972:Gene Expression Regulation, Neoplastic; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009999:Ossification, Heterotopic; D018215:Osteoblastoma / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000473:pathology; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000502:physiology*
D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin