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Palovarotene inhibits connective tissue progenitor cell proliferation in a rat model of combat-related heterotopic ossification.
- Source :
-
Journal of orthopaedic research : official publication of the Orthopaedic Research Society [J Orthop Res] 2018 Apr; Vol. 36 (4), pp. 1135-1144. Date of Electronic Publication: 2017 Nov 16. - Publication Year :
- 2018
-
Abstract
- Heterotopic ossification (HO) develops in the extremities of wounded service members and is common in the setting of high-energy penetrating injuries and blast-related amputations. No safe and effective prophylaxis modality has been identified for this patient population. Palovarotene has been shown to reduce bone formation in traumatic and genetic models of HO. The purpose of this study was to determine the effects of Palovarotene on inflammation, progenitor cell proliferation, and gene expression following a blast-related amputation in a rodent model (n = 72 animals), as well as the ability of Raman spectroscopy to detect early HO before radiographic changes are present. Treatment with Palovarotene was found to dampen the systemic inflammatory response including the cytokines IL-6 (p = 0.01), TNF-α (p = 0.001), and IFN-γ (p = 0.03) as well as the local inflammatory response via a 76% reduction in the cellular infiltration at post-operative day (POD)-7 (p = 0.03). Palovarotene decreased osteogenic connective tissue progenitor (CTP-O) colonies by as much as 98% both in vitro (p = 0.04) and in vivo (p = 0.01). Palovarotene treated animals exhibited significantly decreased expression of osteo- and chondrogenic genes by POD-7, including BMP4 (p = 0.02). Finally, Raman spectroscopy was able to detect differences between the two groups by POD-1 (p < 0.001). These results indicate that Palovarotene inhibits traumatic HO formation through multiple inter-related mechanisms including anti-inflammatory, anti-proliferative, and gene expression modulation. Further, that Raman spectroscopy is able to detect markers of early HO formation before it becomes radiographically evident, which could facilitate earlier diagnosis and treatment. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1135-1144, 2018.<br /> (© 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)
- Subjects :
- Animals
Blast Injuries complications
Cell Proliferation drug effects
Chondrogenesis drug effects
Drug Evaluation, Preclinical
Gene Expression drug effects
Male
Ossification, Heterotopic etiology
Pyrazoles pharmacology
Rats, Sprague-Dawley
Spectrum Analysis, Raman
Stilbenes pharmacology
Systemic Inflammatory Response Syndrome prevention & control
War-Related Injuries complications
Multipotent Stem Cells drug effects
Ossification, Heterotopic prevention & control
Osteogenesis drug effects
Pyrazoles therapeutic use
Stilbenes therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1554-527X
- Volume :
- 36
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of orthopaedic research : official publication of the Orthopaedic Research Society
- Publication Type :
- Academic Journal
- Accession number :
- 28960501
- Full Text :
- https://doi.org/10.1002/jor.23747