人硬化蛋白激发的短肽通过相反的Wnt通路逆转骨质疏松症并抑制骨关节炎的关节变性

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy Pub Date : 2025-09-01 DOI:10.1016/j.biopha.2025.118501

Shivani Sharma , Chirag Kulkarni , Neeraj K. Verma , Swati Srivastava , Rosebin Babu , Anupam Ghosh , Nandita Dasgupta , Arvind Gupta , Simran Preet Kaur , Leena Sapra , Swati Rajput , Sreyanko Sadhukhan , Konica Porwal , Devesh P. Verma , Mohd. Sayeed , Asit R. Mridha , Madan M. Godbole , Kumaravelu Jagavelu , Rupesh K. Srivastava , Aravind S. Kshatri , Naibedya Chattopadhyay

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引用次数: 0

摘要

硬化蛋白（Sclerostin）是Wnt/β-catenin信号的关键调节因子，在骨疾病中表现出双重治疗潜力：它的抑制作用促进骨质疏松症的骨形成，而它的模拟作用抑制骨关节炎（OA）的异常骨生长。利用核磁共振研究的结构见解，我们鉴定了两种硬化蛋白衍生的肽：来自环2的SC-1 （18-mer）和来自环3的SC-3 （14-mer）。分子模型显示SC-1结合LRP6的第一外畴，可能通过竞争性抑制取代硬化蛋白，激活Wnt信号。相反，SC-3占据第二外域的硬化蛋白/ wnt结合位点，从而模仿硬化蛋白的抑制功能。在去卵巢（OVX）大鼠中，SC-1（100 µg/kg）将骨矿物质密度（BMD）、小梁结构和机械强度恢复到假手术水平，通过将骨形成与再吸收抑制结合起来，其效果优于特立帕肽。在慢性肾脏疾病引起的骨质疏松症中，SC-1逆转骨软化并改善肾脏参数。安全性评估显示SC-1缺乏免疫原性（CD11b+细胞不增加）和心血管风险（在ApoE毒血症中没有hERG抑制或主动脉瘤），将其与临床使用的抗硬化蛋白抗体romosozumab区分开来。对于OA， SC-3抑制软骨下骨形成（通过Runx2和BMP-2下调）并增强软骨基质合成（通过Sox-9和Col-II上调）。在大鼠OA模型中，连续8周每周关节内注射SC-3（50 µg/kg）可阻止OA进展并使骨体积正常化。单剂量SC-3（50 µg/kg）在剪切稀释水凝胶中递送，与多剂量疗效相匹配，解决了依从性挑战。该研究确定了两种不同的硬化蛋白衍生肽：SC-1，一种安全的双作用（合成代谢和抗分解代谢）肽，用于骨质疏松症，SC-3用于OA，具有水凝胶激活的缓释增强其治疗潜力。

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Human sclerostin-inspired short peptides reverse osteoporosis and suppress joint degeneration in osteoarthritis via opposing Wnt pathways

Sclerostin, a key regulator of Wnt/β-catenin signaling, exhibits dual therapeutic potential in bone disorders: its inhibition promotes bone formation in osteoporosis, while its mimicry suppresses aberrant bone growth in osteoarthritis (OA). Using structural insights from NMR studies, we identified two sclerostin-derived peptides: SC-1 (an 18-mer) from loop 2, and SC-3 (a 14-mer) from loop 3. Molecular modeling showed that SC-1 binds to the first ectodomain of LRP6, potentially displacing sclerostin through competitive inhibition to activate Wnt signaling. In contrast, SC-3 occupies the sclerostin/Wnt-binding site on the second ectodomain, thereby mimicking sclerostin's inhibitory function. In ovariectomized (OVX) rats, SC-1 (100 µg/kg) restored bone mineral density (BMD), trabecular architecture, and mechanical strength to sham levels, outperforming teriparatide by coupling bone formation with resorption suppression. In chronic kidney disease-induced osteoporosis, SC-1 reversed osteomalacia and improved renal parameters. Safety assessments showed that SC-1 lacked immunogenicity (no increase in CD11b+ cells) and cardiovascular risks (no hERG inhibition or aortic aneurysms in ApoE⁻/⁻ mice), distinguishing it from romosozumab, a clinically used anti-sclerostin antibody. For OA, SC-3 suppressed subchondral bone formation (via Runx2 and BMP-2 downregulation) and enhanced cartilage matrix synthesis (via Sox-9 and Col-II upregulation). In a rat OA model, weekly SC-3 intra-articular injections (50 µg/kg) for 8 weeks prevented OA progression and normalized bone volume. A single dose of SC-3 (50 µg/kg) delivered in a shear-thinning hydrogel matched multi-dose efficacy, addressing adherence challenges. This study identifies two distinct sclerostin-derived peptides: SC-1, a safe dual-action (anabolic and anti-catabolic) peptide for osteoporosis, and SC-3 for OA, with hydrogel-enabled sustained release enhancing its therapeutic potential.

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来源期刊

Biomedicine & Pharmacotherapy 医学-药学

CiteScore

11.90

自引率

2.70%

发文量

1621

审稿时长

48 days

期刊介绍： Biomedicine & Pharmacotherapy stands as a multidisciplinary journal, presenting a spectrum of original research reports, reviews, and communications in the realms of clinical and basic medicine, as well as pharmacology. The journal spans various fields, including Cancer, Nutriceutics, Neurodegenerative, Cardiac, and Infectious Diseases.