Stimulation of fracture mineralization by salt-inducible kinase inhibitors
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fbioe-12-1450611.pdf
Description
Published version
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3.24 MB
Format
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Checksum (MD5)
f9111e34ac61f7e5fe3cdbaae99e4d3a
Author(s)
Momenzadeh, Kaveh
Yeritsyan, Diana
Abbasian, Mohammadreza
Kheir, Nadim
Hanna, Philip
Wang, Jialiang
Dosta, Pere
Papaioannou, Garyfallia
Goldfarb, Sarah
Tang, Cheng-Chia
Date Issued
September 15, 2024
Journal
Frontiers in Bioengineering and Biotechnology
Publisher
Frontiers Media SA
Citation
Momenzadeh K, Yeritsyan D, Abbasian M, Kheir N, Hanna P, Wang J, Dosta P, Papaioannou G, Goldfarb S, Tang C-C, Amar-Lewis E, Nicole Prado Larrea M, Martinez Lozano E, Yousef M, Wixted J, Wein M, Artzi N and Nazarian A (2024) Stimulation of fracture mineralization by salt-inducible kinase inhibitors. Front. Bioeng. Biotechnol. 12:1450611.
Version
Final published version
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.
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DOI of Published Version
https://doi.org/10.3389/fbioe.2024.1450611
