Department of Medicine, Division of Endocrinology and Metabolism, Duke University Medical Center, Durham, North Carolina, USA.
Prog Mol Biol Transl Sci. 2013;118:335-58. doi: 10.1016/B978-0-12-394440-5.00013-9.
Parathyroid hormone (PTH) is the principle regulator of calcium-phosphorus metabolism and bone turnover. Because of its central role in bone remodeling, recombinant human PTH (i.e., Forteo®; PTH(1-34)) has been developed for the treatment of osteoporosis. PTH(1-34) acts principally through the type I PTH/PTH-related peptide receptor (PTH1R), a classic seven transmembrane G protein-coupled receptor (GPCR). Intermittent treatment with PTH(1-34) promotes osteoblast and osteoclast recruitment through activation of PTH1R with resultant net bone gain. Recent studies have demonstrated that the complex metabolic effects induced by PTH1R stimulation are not entirely a consequence of conventional GPCR signaling. β-Arrestins, in addition to their desensitizing actions, also serve as multifunctional scaffolding proteins linking the PTH1R to signaling molecules independent of classic G protein-mediated second messenger-dependent pathways. In vitro, D-Trp(12), Tyr(34)-bPTH(7-34) [bPTH(7-34)], a β-arrestin-selective biased agonist for the PTH1R, antagonizes G protein signaling but activates arrestin-dependent signaling. In vivo, intermittent administration of bPTH(7-34) to mice induces anabolic bone formation independent of classic G protein-coupled signaling mechanisms. While both the conventional PTH1R agonists, PTH(1-34) and bPTH(7-34), stimulate anabolic bone formation in mice, the latter does not induce hypercalcemia nor does it increase markers of bone resorption. This newly recognized ability of β-arrestins to serve as signal transducers for the PTH1R independent of classic GPCR signaling represents a novel paradigm with therapeutic potential. Exploitation of β-arrestin-biased agonism may offer therapeutic benefit for the treatment of metabolic bone diseases such as osteoporosis with an improved side effect profile.
甲状旁腺激素（PTH）是钙磷代谢和骨转换的主要调节剂。由于其在骨重建中的核心作用，重组人甲状旁腺激素（即 Forteo®；PTH(1-34)）已被开发用于治疗骨质疏松症。PTH(1-34) 主要通过 I 型甲状旁腺素/PTH 相关肽受体（PTH1R）发挥作用，这是一种经典的七跨膜 G 蛋白偶联受体（GPCR）。间歇性使用 PTH(1-34) 通过激活 PTH1R 促进成骨细胞和破骨细胞募集，从而导致净骨量增加。最近的研究表明，PTH1R 刺激引起的复杂代谢效应并非完全是传统 GPCR 信号传导的结果。β-arrestin 除了具有脱敏作用外，还作为多功能支架蛋白，将 PTH1R 与独立于经典 G 蛋白介导的第二信使依赖途径的信号分子连接起来。在体外，D-Trp(12), Tyr(34)-bPTH(7-34)[bPTH(7-34)]，一种 PTH1R 的β-arrestin 选择性偏激动剂，拮抗 G 蛋白信号，但激活 arrestin 依赖性信号。在体内，间歇性给予 bPTH(7-34) 可诱导小鼠产生合成代谢性骨形成，而无需经典 G 蛋白偶联信号机制。虽然传统的 PTH1R 激动剂 PTH(1-34)和 bPTH(7-34)都能刺激小鼠的合成代谢性骨形成，但后者不会引起高钙血症，也不会增加骨吸收标志物。β-arrestin 作为 PTH1R 的信号转导物的这种新发现能力独立于经典 GPCR 信号，代表了一种具有治疗潜力的新范式。利用β-arrestin 偏性激动剂可能为治疗代谢性骨疾病（如骨质疏松症）带来治疗益处，并改善副作用谱。
