Endothelin-1 (ET-1) mediates pathological but not normal bone remodeling

K. S. Mohammad, J. J. Yin, B. G. Grubbs, Y. Cui, R. Padley, T. A. Guise

Research output: Contribution to journalArticlepeer-review

Abstract

Osteoblastic metastases cause morbidity in patients with breast and prostate cancer. ET-1 may play a causal role in these metastases. It is unknown whether ET-1 has a function in normal bone remodeling, although expressed in bone. Human breast cancer lines. ZR-75-1, MCF-7 and T47D, cause osteoblastic metastases in nude mice. All secrete ET-1, a peptide first identified as a potent vasoconstrictor. ET-1 is also produced by breast and prostate cancers and is a potent stimulator of osteoblast activity. Selective ETA, and non-selective ETA/B receptor antagonists,completely inhibited ET-1 and ZR-75-1-mediated new bone formation in neonatal mouse calvariae cultured ex vivo, while an ETB antagonist had no effect. In nude mice, administration of an orally active ETA receptor antagonist (ABT-627, 20mg/kg/day) significantly reduced the osteoblastic metastases caused by ZR-75-1. The data suggest that lurnors metastatic to bone cause osteoblastic responses by secreting ET-1, which activates ETA receptors on bone cells. To determine the role of chronic ETA receptor blockade on normal bone remodeling, we measured bone mineral density (BMD) and histomorphometric parameters of bone remodeling in intact female nude mice and those bearing ZR-75-1 mammary fat pad (MFP) tumors. Mice received ABT-627, for 340 days and were given fluorescent labels of tetracycline and calcein 7 days apart and sacrificed 3 days later. Total body, femur and tibia BMD did not differ between normal or ZR-75-1 MFP tumor bearing mice or between those which received ABT-627 vs control. Histomorphometric analysis revealed no differences in trabecularhone volume of tibial secondary spongiosa, osteoclast number, and bone formation rates between ABT-627-treated mice and controls. No metastases from the primary site were detected in mice bearing ZR-75-1 MFP tumors. Taken together, these data indicate that chronic ETA receptor blockade has no effect on normal bone remodeling in intact mice without bone metastases. In mice with breast tumors confined to the MFP, long-term ETA receptor blockade had no effect on BMD. Therefore, the predominant role of ET-1 in bone remodeling appears to be in pathologic states such as those associated with metastatic bone disease. The implications of these findings are: 1) ETA receptor blockade should benefit those patients with osteoblastic bone metastases, 2) ETA receptor blockade should not result in bone loss when used to prevent osteoblastic bone metastases.

Original languageEnglish (US)
Number of pages1
JournalBreast Cancer Research and Treatment
Volume69
Issue number3
StatePublished - Jan 1 2001
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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