Gregory A. Clines, Khalid S. Mohammad, Jessica M. Grunda, Katrina L. Clines, Maria Niewolna, C. Ryan McKenna, Christopher R. McKibbin, Masashi Yanagisawa, Larry J. Suva, John M. Chirgwin, Theresa A. Guise
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 had 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 vs. 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 compared to WT. Male mice castrated at 8 weeks of age showed the reverse: KO mice had reduced rates of tibial and femoral BMD acquisition compared to WT. 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.