盐诱导激酶抑制剂对骨折矿化的刺激作用。

Stimulation of fracture mineralization by salt-inducible kinase inhibitors.

作者信息

Momenzadeh Kaveh, Yeritsyan Diana, Abbasian Mohammadreza, Kheir Nadim, Hanna Philip, Wang Jialiang, Dosta Pere, Papaioannou Garyfallia, Goldfarb Sarah, Tang Cheng-Chia, Amar-Lewis Eliz, Nicole Prado Larrea Michaela, Martinez Lozano Edith, Yousef Mohamed, Wixted John, Wein Marc, Artzi Natalie, Nazarian Ara

机构信息

Musculoskeletal Translational Innovation Initiative, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.

The Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, United States.

出版信息

Front Bioeng Biotechnol. 2024 Sep 16;12:1450611. doi: 10.3389/fbioe.2024.1450611. eCollection 2024.

DOI:10.3389/fbioe.2024.1450611

PMID:39359266

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11445660/

Abstract

INTRODUCTION

Over 6.8 million fractures occur annually in the US, with 10% experiencing delayed- or non-union. Anabolic therapeutics like PTH analogs stimulate fracture repair, and small molecule salt inducible kinase (SIK) inhibitors mimic PTH action. This study tests whether the SIK inhibitor YKL-05-099 accelerates fracture callus osteogenesis.

METHODS

126 female mice underwent femoral shaft pinning and midshaft fracture, receiving daily injections of PBS, YKL-05-099, or PTH. Callus tissues were analyzed via RT-qPCR, histology, single-cell RNA-seq, and μCT imaging. Biomechanical testing evaluated tissue rigidity. A hydrogel-based delivery system for PTH and siRNAs targeting SIK2/SIK3 was developed and tested.

RESULTS

YKL-05-099 and PTH-treated mice showed higher mineralized callus volume fraction and improved structural rigidity. RNA-seq indicated YKL-05-099 increased osteoblast subsets and reduced chondrocyte precursors. Hydrogel-released siRNAs maintained target knockdown, accelerating callus mineralization.

DISCUSSION

YKL-05-099 enhances fracture repair, supporting selective SIK inhibitors' development for clinical use. Hydrogel-based siRNA delivery offers targeted localized treatment at fracture sites.

摘要

引言

在美国，每年发生超过680万例骨折，其中10%会出现延迟愈合或不愈合。甲状旁腺激素（PTH）类似物等促合成疗法可刺激骨折修复，小分子盐诱导激酶（SIK）抑制剂可模拟PTH的作用。本研究旨在测试SIK抑制剂YKL-05-099是否能加速骨折痂的骨生成。

方法

126只雌性小鼠接受股骨干穿针和骨干骨折手术，每天注射磷酸盐缓冲液（PBS）、YKL-05-099或PTH。通过逆转录定量聚合酶链反应（RT-qPCR）、组织学、单细胞RNA测序和微计算机断层扫描（μCT）成像分析骨痂组织。生物力学测试评估组织刚度。开发并测试了一种基于水凝胶的PTH和靶向SIK2/SIK3的小干扰RNA（siRNA）递送系统。