Osteogenic effect of an adiponectin-derived short peptide that rebalances bone remodeling: a potential disease-modifying approach for postmenopausal osteoporosis therapy

IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL
Swati Rajput, Chirag Kulkarni, Shivani Sharma, Manendra Singh Tomar, Shamima Khatoon, Arvind Gupta, Sabyasachi Sanyal, Ashutosh Shrivastava, Jimut Kanti Ghosh, Naibedya Chattopadhyay
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引用次数: 0

Abstract

Adiponectin, an adipokine, regulates metabolic processes, including glucose flux, lipid breakdown, and insulin response, by activating adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2). We have previously shown that globular adiponectin (gAd), an endogenous form of adiponectin, has osteoanabolic and anti-catabolic effects in rodent models of postmenopausal osteopenia. Moreover, we reported the identification of a 13-mer peptide (ADP-1) from the collagen domain of adiponectin, which exhibited significant adiponectin-mimetic properties. Since the clinical development of gAd is constrained by its large size, here, we investigated the osteogenic property of ADP-1. ADP-1 induced osteoblast differentiation more potently than gAd. ADP-1 elicited osteoblast differentiation through two downstream pathways that involved the participation of adiponectin receptors. Firstly, it enhanced mitochondrial biogenesis and OxPhos, leading to osteoblast differentiation. Secondly, it activated the Akt-glycogen synthase kinase 3β-Wnt pathway, thereby increasing osteoblast differentiation. Additionally, ADP-1 suppressed the production of receptor–activator of nuclear kappa B ligand from osteoblasts, enabling it to act as a dual-action molecule (suppressing osteoclast function besides promoting osteoblast function). In osteopenic ovariectomized rats, ADP-1 increased bone mass and strength and improved trabecular integrity by stimulating bone formation and inhibiting bone resorption. Furthermore, by increasing ATP-producing intermediates within the tricarboxylic acid cycle in bones, ADP-1 likely fueled osteoblast function. Given its dual-action mechanism and high potency, ADP-1 offers a unique opportunity to address the unmet clinical need to reset the aberrant bone remodeling in osteoporosis to normalcy, potentially offering a disease-modifying impact.

Abstract Image

重新平衡骨重塑的脂肪连接素衍生短肽的成骨效应:绝经后骨质疏松症治疗的潜在疾病调节方法。
脂肪连通素是一种脂肪因子,它通过激活脂肪连通素受体 1 和 2(AdipoR1 和 AdipoR2)来调节新陈代谢过程,包括葡萄糖通量、脂质分解和胰岛素反应。我们之前已经证明,球状脂肪粘连素(gAd)是脂肪粘连素的一种内源性形式,在绝经后骨质疏松症的啮齿动物模型中具有促进骨合成和抗代谢的作用。此外,我们还报告了从脂肪连通素的胶原蛋白结构域中鉴定出的一种 13-mer肽(ADP-1),它具有显著的脂肪连通素模拟特性。由于 gAd 的临床开发受到其巨大体积的限制,我们在此研究了 ADP-1 的成骨特性。ADP-1 比 gAd 更能诱导成骨细胞分化。ADP-1 通过两个下游途径诱导成骨细胞分化,这两个途径都有脂肪素受体的参与。首先,它增强了线粒体的生物生成和 OxPhos,导致成骨细胞分化。其次,它激活了 Akt-糖原合成酶激酶 3β-Wnt 通路,从而促进了成骨细胞的分化。此外,ADP-1 还能抑制成骨细胞产生核卡巴 B 受体激活剂配体,使其成为一种双重作用分子(除了促进成骨细胞功能外,还能抑制破骨细胞功能)。在骨质疏松的卵巢切除大鼠身上,ADP-1 通过刺激骨形成和抑制骨吸收,增加了骨量和骨强度,改善了骨小梁的完整性。此外,通过增加骨骼三羧酸循环中产生 ATP 的中间产物,ADP-1 还可能促进成骨细胞的功能。鉴于 ADP-1 的双重作用机制和高效力,它提供了一个独特的机会来满足尚未得到满足的临床需求,将骨质疏松症中异常的骨重塑重置为正常状态,从而有可能产生改变疾病的影响。
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来源期刊
CiteScore
13.40
自引率
9.00%
发文量
48
审稿时长
3.3 months
期刊介绍: Archives of Pharmacal Research is the official journal of the Pharmaceutical Society of Korea and has been published since 1976. Archives of Pharmacal Research is an interdisciplinary journal devoted to the publication of original scientific research papers and reviews in the fields of drug discovery, drug development, and drug actions with a view to providing fundamental and novel information on drugs and drug candidates.
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