Sympathetic β1-adrenergic signaling contributes to regulation of human bone metabolism.
Maine Medical Center Research Institute
The Journal of clinical investigation
Adrenergic beta-Antagonists, Adult, Aged, Bone Resorption, Bone and Bones, Cell Line, Collagen Type I, Female, Humans, Middle Aged, Peptides, Receptors, Adrenergic, beta-1, Receptors, Adrenergic, beta-2, Receptors, Adrenergic, beta-3, Signal Transduction, Sympathetic Nervous System
BACKGROUND: Evidence from rodent studies indicates that the sympathetic nervous system (SNS) regulates bone metabolism, principally via β2-adrenergic receptors (β2-ARs). Given the conflicting human data, we used multiple approaches to evaluate the role of the SNS in regulating human bone metabolism.
METHODS: Bone biopsies were obtained from 19 young and 19 elderly women for assessment of ADRB1, ADRB2, and ADRB3 mRNA expression. We examined the relationship of β-blocker use to bone microarchitecture by high-resolution peripheral quantitative CT in a population sample of 248 subjects. A total of 155 postmenopausal women were randomized to 1 of 5 treatment groups for 20 weeks: placebo; propranolol, 20 mg b.i.d.; propranolol, 40 mg b.i.d.; atenolol, 50 mg/day; or nebivolol, 5 mg/day. We took advantage of the β1-AR selectivity gradient of these drugs (propranolol [nonselective] < atenolol [relatively β1-AR selective] < nebivolol [highly β1-AR selective]) to define the β-AR selectivity for SNS effects on bone.
RESULTS: ADRB1 and ADRB2, but not ADRB3, were expressed in human bone; patients treated clinically with β1-AR-selective blockers had better bone microarchitecture than did nonusers, and relative to placebo, atenolol and nebivolol, but not propranolol, reduced the bone resorption marker serum C-telopeptide of type I collagen (by 19.5% and 20.6%, respectively; P < 0.01) and increased bone mineral density of the ultradistal radius (by 3.6% and 2.9%; P < 0.01 and P < 0.05, respectively).
CONCLUSIONS: These 3 independent lines of evidence strongly support a role for adrenergic signaling in the regulation of bone metabolism in humans, principally via β1-ARs.
TRIAL REGISTRATION: ClinicalTrials.gov NCT02467400.
FUNDING: This research was supported by the NIH (AG004875 and AR027065) and a Mayo Clinic Clinical and Translational Science Award (CTSA) (UL1 TR002377).
Khosla, Sundeep; Drake, Matthew T; Volkman, Tammie L; Thicke, Brianne S; Achenbach, Sara J; Atkinson, Elizabeth J; Joyner, Michael J; Rosen, Clifford J; Monroe, David G; and Farr, Joshua N, "Sympathetic β1-adrenergic signaling contributes to regulation of human bone metabolism." (2018). Maine Medical Center. 1402.