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The multi-kinase inhibitor dasatinib suppresses autoinflammation and increases bone density in a mouse model for
1Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Japan.
Abstract:
Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disease that presents with bone destruction and pain. Although genetic studies have identified signalling pathways involving CRMO, molecularly targeted drugs remain unavailable. We used an animal model of CRMO as an in vivo screening system for candidate therapeutic agents. A gain-of-function mutation in Fgr, a member of Src family kinases (SFKs), causes peripheral paw inflammation and reduced bone mineral density (BMD) in Ali18 mice. The SFK inhibitor dasatinib was selected for administration to Ali18 mice daily for 2 weeks. Local inflammation and BMD were assessed by clinical scoring and computed tomography, respectively. Pilot studies in a small number of animals showed that dasatinib administration effectively suppressed the early phase of autoinflammation in Ali18 mice. Serial oral gavage of dasatinib to a group of Ali18 mice confirmed significant suppression of paw swelling with no side effects. Histological analysis revealed that abnormal proliferative bone marrow cells and inflammatory infiltration into the skin in the affected area were clearly reduced in the animals with dasatinib administration. Further, trabecular BMD in Ali18 long bones was restored to levels similar to that found in wild type mice. Our results indicate that autoinflammation and related-bone phenotypes were completely suppressed by the dasatinib kinase inhibitor in CRMO model animals. Thus, it is strongly suggested that dasatinib can be used for clinical treatments of CRMO with the combination of molecular diagnosis of the FGR locus. SIGNIFICANCE OF THE STUDY: Autoinflammation and related-bone phenotypes were effectively suppressed by the kinase inhibitor dasatinib in CRMO model animals. In combination with molecular analysis of the FGR locus, dasatinib is a strong candidate for the clinical treatments of CRMO. We propose that the animal model employed in this study can be used to screen this and other potential drugs for CRMO.
Insights
Dasatinib, a kinase inhibitor, effectively treated a mouse model of Chronic Recurrent Multifocal Osteomyelitis (CRMO). This study suggests dasatinib could be a viable treatment for CRMO patients with FGR gene mutations.
Area of Science:
- Immunology
- Bone Biology
- Pharmacology
Background:
- Chronic Recurrent Multifocal Osteomyelitis (CRMO) is an autoinflammatory bone disease with no targeted therapies.
- Genetic studies implicate signaling pathways, but molecularly targeted drugs are lacking.
Purpose of the Study:
- To evaluate dasatinib, a Src family kinase (SFK) inhibitor, as a potential therapeutic agent for CRMO using an established animal model.
- To investigate the efficacy of dasatinib in suppressing inflammation and restoring bone mineral density in CRMO.
Main Methods:
- Utilized an Ali18 mouse model with a gain-of-function mutation in Fgr, a SFK, mimicking CRMO.
- Administered dasatinib daily for two weeks to assess its impact on paw inflammation and bone mineral density (BMD).
- Evaluated outcomes through clinical scoring, computed tomography, and histological analysis.
Main Results:
- Dasatinib significantly suppressed early-phase autoinflammation and paw swelling in Ali18 mice without observed side effects.
- Histological analysis showed reduced abnormal bone marrow cells and inflammatory infiltration in dasatinib-treated mice.
- Trabecular BMD in long bones of treated mice was restored to levels comparable to wild-type controls.
Conclusions:
- Dasatinib effectively suppressed autoinflammation and bone phenotypes in a CRMO animal model.
- Dasatinib is a strong candidate for clinical CRMO treatment, particularly when combined with molecular diagnosis of the FGR locus.
- The employed animal model is suitable for screening dasatinib and other potential CRMO therapeutics.
