Robert and Arlene Kogod Center on Aging and Division of Endocrinology.
Department of Health Sciences Research, and.
J Clin Invest. 2018 Nov 1;128(11):4832-4842. doi: 10.1172/JCI122151. Epub 2018 Oct 2.
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.
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.
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).
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.
ClinicalTrials.gov NCT02467400.
This research was supported by the NIH (AG004875 and AR027065) and a Mayo Clinic Clinical and Translational Science Award (CTSA) (UL1 TR002377).
啮齿动物研究的证据表明，交感神经系统（SNS）通过β2-肾上腺素能受体（β2-AR）调节骨代谢。鉴于人类数据存在冲突，我们使用多种方法来评估 SNS 在调节人类骨代谢中的作用。
为了评估 ADRB1、ADRB2 和 ADRB3 mRNA 的表达，我们从 19 名年轻女性和 19 名老年女性中获取了骨活检样本。我们在 248 名受试者的人群样本中，通过高分辨率外周定量 CT 检查，研究了β受体阻滞剂的使用与骨微结构的关系。共有 155 名绝经后妇女被随机分配到 5 个治疗组中的 1 个，进行 20 周的治疗：安慰剂；普萘洛尔，20mg，每日 2 次；普萘洛尔，40mg，每日 2 次；阿替洛尔，50mg/天；或比索洛尔，5mg/天。我们利用这些药物的β1-AR 选择性梯度（普萘洛尔[非选择性]<<阿替洛尔[相对β1-AR 选择性] <比索洛尔[高度β1-AR 选择性]）来定义 SNS 对骨作用的β-AR 选择性。
ADRB1 和 ADRB2，但不是 ADRB3，在人类骨中表达；临床上接受β1-AR 选择性阻滞剂治疗的患者，其骨微结构优于未使用者，与安慰剂相比，阿替洛尔和比索洛尔，但不是普萘洛尔，降低了血清 I 型胶原 C 端肽（CTX）的骨吸收标志物（分别降低 19.5%和 20.6%；P<0.01），并增加了桡骨远端的骨矿物质密度（分别增加 3.6%和 2.9%；P<0.01 和 P<0.05）。
这 3 条独立的证据线强烈支持肾上腺素能信号在人类骨代谢调节中的作用，主要通过β1-AR 发挥作用。
ClinicalTrials.gov NCT02467400。
本研究由美国国立卫生研究院（NIH）（AG004875 和 AR027065）和梅奥诊所临床与转化科学奖（CTSA）（UL1 TR002377）资助。
