开发一流的单分子双 GIP/GLP-2 类似物 GL-0001，用于治疗骨脆性,Journal of Bone and Mineral Research

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开发一流的单分子双 GIP/GLP-2 类似物 GL-0001，用于治疗骨脆性
Journal of Bone and Mineral Research ( IF 5.1 ) Pub Date : 2023-02-27 , DOI: 10.1002/jbmr.4792
Benoit Gobron _{1,

2} , Malory Couchot _{1,

3} , Nigel Irwin ₄ , Erick Legrand _{1,

2} , Béatrice Bouvard _{1,

2} , Guillaume Mabilleau _{1,

5}

Affiliation

由于人口老龄化，全球骨质疏松症急剧增加。尽管存在一些治疗选择，但它们不能完全保护或预防新骨折的发生。目前批准用于治疗骨脆性的所有药物都以骨量为目标。然而，骨对骨折的抵抗力不仅仅取决于骨量，还取决于骨细胞外基质 (ECM) 材料特性，即骨基质成分的质量。在这里，我们介绍了一流的单分子双葡萄糖依赖性促胰岛素多肽/胰高血糖素样肽-2 (GIP/GLP-2) 类似物 GL-0001，它同时激活葡萄糖依赖性促胰岛素多肽受体 (GIPr)和胰高血糖素样肽-2 受体 (GLP-2r)。GL-0001 通过环磷酸腺苷-赖氨酰氧化酶途径协同作用，以增强胶原蛋白的成熟度。此外，在 32 只 12 周龄的 BALB/c 小鼠中进行了双侧卵巢切除术，然后随机分配到生理盐水、双重 GIP/GLP-2 类似物（GL-0001 或 GL-0007）或唑来膦酸组（n = 8/组）。4 周后开始使用双 GIP/GLP-2 类似物进行治疗，持续 8 周。在器官水平，GL-0001 通过增加皮质骨的极限载荷、屈服后位移和断裂能量来修改生物力学参数。GL-0001 还通过降低矿物质与基质的比例和增强酶促胶原蛋白交联，防止四肢骨骼处过度的骨小梁降解，并增强皮质骨中的骨 ECM 材料特性。这些结果表明，靶向骨 ECM 材料特性是增强骨强度的可行选择，并为治疗骨脆性患者开辟了一条创新途径。© 2023 作者。骨骼与矿物质研究杂志由 Wiley Periodicals LLC 代表美国骨骼和矿物研究协会 (ASBMR) 出版。

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Development of a First-in-Class Unimolecular Dual GIP/GLP-2 Analogue, GL-0001, for the Treatment of Bone Fragility

Due to aging of the population, bone frailty is dramatically increasing worldwide. Although some therapeutic options exist, they do not fully protect or prevent against the occurrence of new fractures. All current drugs approved for the treatment of bone fragility target bone mass. However, bone resistance to fracture is not solely due to bone mass but relies also on bone extracellular matrix (ECM) material properties, i.e., the quality of the bone matrix component. Here, we introduce the first-in-class unimolecular dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-2 (GIP/GLP-2) analogue, GL-0001, that activates simultaneously the glucose-dependent insulinotropic polypeptide receptor (GIPr) and the glucagon-like peptide-2 receptor (GLP-2r). GL-0001 acts synergistically through a cyclic adenosine monophosphate-lysyl oxidase pathway to enhance collagen maturity. Furthermore, bilateral ovariectomy was performed in 32 BALB/c mice at 12 weeks of age prior to random allocation to either saline, dual GIP/GLP-2 analogues (GL-0001 or GL-0007) or zoledronic acid groups (n = 8/group). Treatment with dual GIP/GLP-2 analogues was initiated 4 weeks later for 8 weeks. At the organ level, GL-0001 modified biomechanical parameters by increasing ultimate load, postyield displacement, and energy-to-fracture of cortical bone. GL-0001 also prevented excess trabecular bone degradation at the appendicular skeleton and enhanced bone ECM material properties in cortical bone through a reduction of the mineral-to-matrix ratio and augmentation in enzymatic collagen cross-linking. These results demonstrate that targeting bone ECM material properties is a viable option to enhance bone strength and opens an innovative pathway for the treatment of patients suffering from bone fragility. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

更新日期：2023-02-27

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