在细胞层面,骨质疏松症(OP)是骨重建不平衡的结果,其中破骨细胞骨吸收超过成骨细胞骨形成。目前可用的OP药物包括抗再吸收和骨形成药物。然而,它们在OP患者中的长期使用,主要是绝经后的妇女,伴随着严重的副作用。值得注意的是,骨吸收和形成过程之间的基本耦合是存在不良的次要结果的基础,即骨合成代谢或抗吸收药物也会减少骨形成。该缺点需要开发能够选择性刺激成骨细胞生成并伴随减少破骨细胞生成的抗OP药物。我们建议应用成骨细胞受体的小型合成偏向和变构调节剂,属于G蛋白偶联受体(GPCR)家族,可能是解决不希望的抗OP药物选择性的关键。这种方法是基于这些GPCR调节剂的能力,与天然配体不同,触发信号通路,促进对骨骼重建的有益作用,同时阻断潜在的有害作用。在OP的设置下,最佳的抗OP药物应提供对下游效应的微调调节,例如,间歇性循环AMP(cAMP)升高,保持Ca2+平衡,刺激骨保护素(OPG)和雌激素的产生,抑制硬化蛋白分泌,和/或保留/增强的经典β-连环蛋白/Wnt信号通路。因此,参与骨重建的GPCRs的选择性调节在OP治疗中提出了有希望的方法。这篇综述的重点是我们假设有效性的证据。
On the cellular level, osteoporosis (OP) is a result of imbalanced bone remodeling, in which osteoclastic bone resorption outcompetes osteoblastic bone formation. Currently available OP medications include both antiresorptive and bone-forming drugs. However, their long-term use in OP patients, mainly in postmenopausal women, is accompanied by severe side effects. Notably, the fundamental coupling between bone resorption and formation processes underlies the existence of an undesirable secondary outcome that bone anabolic or anti-resorptive drugs also reduce bone formation. This drawback requires the development of anti-OP drugs capable of selectively stimulating osteoblastogenesis and concomitantly reducing osteoclastogenesis. We propose that the application of small synthetic biased and allosteric modulators of bone cell receptors, which belong to the G-protein coupled receptors (GPCR) family, could be the key to resolving the undesired anti-OP drug selectivity. This approach is based on the capacity of these GPCR modulators, unlike the natural ligands, to trigger signaling pathways that promote beneficial effects on bone remodeling while blocking potentially deleterious effects. Under the settings of OP, an optimal anti-OP drug should provide fine-tuned regulation of downstream effects, for example, intermittent cyclic AMP (cAMP) elevation, preservation of Ca2+ balance, stimulation of osteoprotegerin (OPG) and estrogen production, suppression of sclerostin secretion, and/or preserved/enhanced canonical β-catenin/Wnt signaling pathway. As such, selective modulation of GPCRs involved in bone remodeling presents a promising approach in OP treatment. This review focuses on the evidence for the validity of our hypothesis.