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.
摘要：
脂联素,脂肪因子,调节代谢过程，包括葡萄糖通量,脂质分解，和胰岛素反应，通过激活脂联素受体1和2（AdipoR1和AdipoR2）。我们之前已经证明球状脂联素(gAd)，脂联素的内源性形式，在绝经后骨量减少的啮齿动物模型中具有骨合成代谢和抗分解代谢作用。此外，我们报道了从脂联素的胶原结构域鉴定出一个13-mer肽（ADP-1），表现出显著的脂联素模拟特性。由于gAd的临床发展受到其大尺寸的制约，在这里，我们研究了ADP-1的成骨特性。ADP-1比gAd更有效地诱导成骨细胞分化。ADP-1通过两个参与脂联素受体参与的下游途径诱导成骨细胞分化。首先,它增强了线粒体生物发生和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，从而增加成骨细胞分化。此外,ADP-1抑制成骨细胞核κB配体受体激活剂的产生，使其能够充当双重作用分子（除了促进成骨细胞功能外，还抑制破骨细胞功能）。在骨质减少的卵巢切除大鼠中，ADP-1通过刺激骨形成和抑制骨吸收来增加骨量和强度并改善小梁完整性。此外，通过增加骨骼中三羧酸循环中产生ATP的中间体，ADP-1可能促进成骨细胞功能。鉴于其双重作用机制和高效力，ADP-1提供了一个独特的机会来解决未满足的临床需求，以将骨质疏松症中的异常骨重塑重置为正常。可能提供改善疾病的影响。
