{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T05:24:04Z","timestamp":1778217844801,"version":"3.51.4"},"reference-count":70,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,9,16]],"date-time":"2024-09-16T00:00:00Z","timestamp":1726444800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioeng. Biotechnol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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 \u03bcCT imaging. Biomechanical testing evaluated tissue rigidity. A hydrogel-based delivery system for PTH and siRNAs targeting SIK2\/SIK3 was developed and tested.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>YKL-05-099 enhances fracture repair, supporting selective SIK inhibitors\u2019 development for clinical use. Hydrogel-based siRNA delivery offers targeted localized treatment at fracture sites.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fbioe.2024.1450611","type":"journal-article","created":{"date-parts":[[2024,9,16]],"date-time":"2024-09-16T08:53:57Z","timestamp":1726476837000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Stimulation of fracture mineralization by salt-inducible kinase inhibitors"],"prefix":"10.3389","volume":"12","author":[{"given":"Kaveh","family":"Momenzadeh","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Yeritsyan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammadreza","family":"Abbasian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadim","family":"Kheir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip","family":"Hanna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jialiang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pere","family":"Dosta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Garyfallia","family":"Papaioannou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Goldfarb","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng-Chia","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eliz","family":"Amar-Lewis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michaela","family":"Nicole Prado Larrea","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edith","family":"Martinez Lozano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed","family":"Yousef","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Wixted","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc","family":"Wein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalie","family":"Artzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ara","family":"Nazarian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,9,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1186\/1471-2474-14-42","article-title":"Tibia shaft fractures: costly burden of nonunions","volume":"14","author":"Antonova","year":"2013","journal-title":"BMC Musculoskelet. 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