Frontiers in Bioengineering and Biotechnology (Sep 2024)
Stimulation of fracture mineralization by salt-inducible kinase inhibitors
- Kaveh Momenzadeh,
- Diana Yeritsyan,
- Mohammadreza Abbasian,
- Nadim Kheir,
- Philip Hanna,
- Jialiang Wang,
- Pere Dosta,
- Pere Dosta,
- Pere Dosta,
- Garyfallia Papaioannou,
- Sarah Goldfarb,
- Cheng-Chia Tang,
- Eliz Amar-Lewis,
- Eliz Amar-Lewis,
- Eliz Amar-Lewis,
- Michaela Nicole Prado Larrea,
- Michaela Nicole Prado Larrea,
- Edith Martinez Lozano,
- Mohamed Yousef,
- John Wixted,
- Marc Wein,
- Natalie Artzi,
- Natalie Artzi,
- Natalie Artzi,
- Ara Nazarian,
- Ara Nazarian,
- Ara Nazarian
Affiliations
- Kaveh Momenzadeh
- Musculoskeletal Translational Innovation Initiative, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
- Diana Yeritsyan
- Musculoskeletal Translational Innovation Initiative, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
- Mohammadreza Abbasian
- Musculoskeletal Translational Innovation Initiative, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
- Nadim Kheir
- Musculoskeletal Translational Innovation Initiative, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
- Philip Hanna
- Musculoskeletal Translational Innovation Initiative, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
- Jialiang Wang
- The Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, United States
- Pere Dosta
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
- Pere Dosta
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, United States
- Pere Dosta
- Wyss Institute for Biologically-Inspired Engineering, Harvard University, Boston, MA, United States
- Garyfallia Papaioannou
- Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- Sarah Goldfarb
- Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- Cheng-Chia Tang
- Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- Eliz Amar-Lewis
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
- Eliz Amar-Lewis
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, United States
- Eliz Amar-Lewis
- Wyss Institute for Biologically-Inspired Engineering, Harvard University, Boston, MA, United States
- Michaela Nicole Prado Larrea
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
- Michaela Nicole Prado Larrea
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, United States
- Edith Martinez Lozano
- Musculoskeletal Translational Innovation Initiative, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
- Mohamed Yousef
- Musculoskeletal Translational Innovation Initiative, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
- John Wixted
- Musculoskeletal Translational Innovation Initiative, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
- Marc Wein
- Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- Natalie Artzi
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
- Natalie Artzi
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, United States
- Natalie Artzi
- Wyss Institute for Biologically-Inspired Engineering, Harvard University, Boston, MA, United States
- Ara Nazarian
- Musculoskeletal Translational Innovation Initiative, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
- Ara Nazarian
- Department of Mechanical Engineering, Boston University, Boston, MA, United States
- Ara Nazarian
- Department of Orthopaedic Surgery, Yerevan State Medical University, Yerevan, Armenia
- DOI
- https://doi.org/10.3389/fbioe.2024.1450611
- Journal volume & issue
-
Vol. 12
Abstract
IntroductionOver 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.Methods126 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.ResultsYKL-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.DiscussionYKL-05-099 enhances fracture repair, supporting selective SIK inhibitors’ development for clinical use. Hydrogel-based siRNA delivery offers targeted localized treatment at fracture sites.
Keywords
