Regulation of postnatal trabecular bone formation by the osteoblast endothelin A receptor

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

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2523-2536
Number of pages14
JournalJournal of Bone and Mineral Research
Volume26
Issue number10
DOIs
StatePublished - Oct 2011

Fingerprint

Endothelin A Receptors
Osteoblasts
Osteogenesis
Endothelin-1
Bone and Bones
Thigh
Knockout Mice
Hypogonadism
Cancellous Bone
Dihydrotestosterone
Bone Remodeling
Castration
Endothelins
Osteocalcin
Vasoconstrictor Agents
Androgens
Homeostasis
Ligands

Keywords

  • bone
  • endothelin A receptor
  • endothelin-1
  • osteoblast
  • sex steroids

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Clines, G. A., Mohammad, K. S., Grunda, J. M., Clines, K. L., Niewolna, M., McKenna, C. R., ... Guise, T. A. (2011). Regulation of postnatal trabecular bone formation by the osteoblast endothelin A receptor. Journal of Bone and Mineral Research, 26(10), 2523-2536. https://doi.org/10.1002/jbmr.450

Regulation of postnatal trabecular bone formation by the osteoblast endothelin A receptor. / 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.

In: Journal of Bone and Mineral Research, Vol. 26, No. 10, 10.2011, p. 2523-2536.

Research output: Contribution to journalArticle

Clines, GA, Mohammad, KS, Grunda, JM, Clines, KL, Niewolna, M, McKenna, CR, McKibbin, CR, Yanagisawa, M, Suva, LJ, Chirgwin, JM & Guise, TA 2011, 'Regulation of postnatal trabecular bone formation by the osteoblast endothelin A receptor', Journal of Bone and Mineral Research, vol. 26, no. 10, pp. 2523-2536. https://doi.org/10.1002/jbmr.450
Clines GA, Mohammad KS, Grunda JM, Clines KL, Niewolna M, McKenna CR et al. Regulation of postnatal trabecular bone formation by the osteoblast endothelin A receptor. Journal of Bone and Mineral Research. 2011 Oct;26(10):2523-2536. https://doi.org/10.1002/jbmr.450
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. / Regulation of postnatal trabecular bone formation by the osteoblast endothelin A receptor. In: Journal of Bone and Mineral Research. 2011 ; Vol. 26, No. 10. pp. 2523-2536.
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