Sympathetic β1-adrenergic signaling contributes to regulation of human bone metabolism
Sundeep Khosla, Matthew T Drake, Tammie L Volkman, Brianne S Thicke, Sara J Achenbach, Elizabeth J Atkinson, Michael J Joyner, Clifford J Rosen, David G Monroe, Joshua N Farr, Sundeep Khosla, Matthew T Drake, Tammie L Volkman, Brianne S Thicke, Sara J Achenbach, Elizabeth J Atkinson, Michael J Joyner, Clifford J Rosen, David G Monroe, Joshua N Farr
Abstract
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).
Keywords: Bone Biology; Osteoporosis.
Conflict of interest statement
Conflict of interest: The authors have declared that no conflict of interest exists.
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Source: PubMed