Bone Adaptation to Mechanical Loading is Disrupted by Inhibition of Endothelin Receptor a in ex vivo Human Trabecular Bone.

Interactive effects among loading and biochemical signaling on the skeleton are incompletely understood. Endothelin-1 (ET1) is an essential potent autocrine/paracrine signaling molecule recognized for its role in bone mechanotransduction. Ex vivo experiments are a novel alternative method to investigate factors, like ET1, that otherwise would harm organism health. The hypothesis that antagonism of endothelin receptor A (EDNRA) would inhibit mechanotransduction pathways associated with mechanical load adaptation in human trabecular bone was tested in a four-week ex vivo study. Ex vivo trabecular bone cores (n=48, 5 mm x 10 mm) from hip heads donated by two hip arthroplasty patients were subjected to compressive loading in the presence or absence of EDNRA antagonist. Cores were allocated to four groups: control, blocked (10 μM/L BQ-123), loaded (-3000 μe), and loaded+blocked. Data were analyzed with Kruskal-Wallace tests with Dunn?s post hoc test, and Friedman analysis with repeated measures. Microstructural analyses were validated against physical measurements. Pan endothelin (ET) and prostaglandin E2 (PGE2) increased over time, for all groups. Pan ET was higher in blocked in comparison to loaded cores; whereas, PGE2 was higher in the loaded cores in comparison to controls. Percent change in apparent elastic modulus was highest in loaded (26%) and 56% lower in both blocked groups. EDNRA inhibition was found to interact with pathways that respond to mechanical load. This finding suggests that endothelin is required for transduction of mechanical cues into biochemical signals during the anabolic response of bone to mechanical load.