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Regulation of postnatal trabecular bone formation by the osteoblast endothelin A receptor
Author(s) -
Clines Gregory A,
Mohammad Khalid S,
Grunda Jessica M,
Clines Katrina L,
Niewolna Maria,
McKenna C Ryan,
McKibbin Christopher R,
Yanagisawa Masashi,
Suva Larry J,
Chirgwin John M,
Guise Theresa A
Publication year - 2011
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.450
Subject(s) - osteoblast , endocrinology , medicine , bone remodeling , osteocalcin , chemistry , endothelin receptor , endothelin 1 , receptor , biology , in vitro , alkaline phosphatase , biochemistry , enzyme
Abstract Endothelin‐1 (ET‐1) is a potent vasoconstrictor that also stimulates cells in the osteoblast lineage by binding to the endothelin A receptor (ETAR). ET‐1 ligand is widely secreted, particularly by the vasculature. However, the contributions of ETAR signaling to adult bone homeostasis have not been defined. ETAR was inactivated in osteoblasts by crossing ETAR‐floxed and osteocalcin‐ Cre mice. Histomorphometric analyses were performed on 4‐, 8‐, and 12‐week‐old osteoblast‐targeted ETAR knockout (KO) and wild‐type (WT) male and female mice. Tibial trabecular bone volume was significantly lower from 12 weeks in KO versus WT mice in both males and females. Bone‐formation rate, osteoblast density, and in vitro osteoblast differentiation were reduced by targeted inactivation of ETAR. A separate longitudinal analysis was performed between 8 and 64 weeks to examine the effect of aging and castration on bone metabolism in ETAR KO mice. Hypogonadism did not change the rate of bone accrual in WT or KO females. However, eugonadal KO males had a significantly larger increase in tibial and femoral bone acquisition than WT mice. Male mice castrated at 8 weeks of age showed the reverse: KO mice had reduced rates of tibial and femoral BMD acquisition compared with WT mice. In vitro, ET‐1 increased osteoblast proliferation, survival, and differentiation. Dihydrotestosterone also increased osteoblast differentiation using a mechanism distinct from the actions of ET‐1. These results demonstrate that endothelin signaling in osteoblasts is an important regulator of postnatal trabecular bone remodeling and a modulator of androgen effects on bone. © 2011 American Society for Bone and Mineral Research