Dasatinib, a selective tyrosine kinase inhibitor, prevents joint destruction in rheumatoid arthritis animal model

Abstract

Aim:We aimed to evaluate the preventive role of the tyrosine kinase inhibitor dasatinib in an animal model of rheumatoid arthritis (RA).Methods: DBA/1J mice were injected with bovine type II collagen to induce arthritis (collagen-induced arthritis [CIA]). There were four experimental groups of mice, namely negative control (non-CIA), vehicle-treated CIA, dasatinib-pretreated CIA, and dasatinib-treated CIA. After collagen immunization, arthritis progression in the mice was clinically scored twice weekly for 5 weeks. Flow cytometry was used to evaluate in vitro CD4 + T-cell differentiation and ex vivo mast cell/CD4 + T-cell differentiation.Osteoclast formation was evaluated using tartrate-resistant acid phosphatase (TRAP) staining and by estimating the resorption pit area. Results:We found that the clinical arthritis histological scores were lower in the dasatinib pretreatment group than in the vehicle and dasatinib post-treatment groups.Flow cytometry showed that FcεR1 + cells were downregulated and regulatory T cells were upregulated in splenocytes of the dasatinib pretreatment group compared with those in the vehicle group. Additionally, there was a decline in IL-17 + CD4 + T-cell differentiation and an increase in CD4 + CD24 high Foxp3 + T-cell differentiation with in vitro dasatinib treatment of human CD4 + T cells. The number of TRAP + osteoclasts and the area of the resorption were decreased in the bone marrow cells derived from dasatinib-pretreated mice compared with those derived from vehicle group. Conclusion: Dasatinib protected against arthritis in an animal model of RA by regulating the differentiation of regulatory T cells and IL-17 + CD4 + T cells and inhibiting osteoclastogenesis, indicating the therapeutic potential of dasatinib in the treatment of early RA.

Regorafenib Attenuates Osteoclasts Differentiation by Inhibiting the NF-κB, NFAT, ERK, and p38 Signaling Pathways

“…Extensive research has validated the inhibitory impact of numerous multitargeted tyrosine kinase inhibitors on bone resorption and loss, suggesting potential therapeutic advantages for bone disease management. For example, dasatinib has been shown to forestall joint destruction in models of rheumatoid arthritis by impeding osteoclastogenesis, while also enhancing bone volume in xenograft mice models infused with osteotropic MDA-MB-231 cells by diminishing osteoclast activity . Similarly, the tyrosine kinase inhibitor GNF-2 was observed to inhibit osteoclast differentiation by curtailing RANKL-induced NF-κB signaling, thereby offering protection against inflammation-induced bone destruction .…”

The potential for senotherapy as a novel approach to extend life quality in veterinary medicine

“…The senescent cells displayed impaired chondrogenic differentiation ( 193 ) when compared with a non-senescent cell population, making them potential targets for senotherapeutics. Murine models of rheumatoid arthritis (RA) found that dasatinib was protective against RA by inhibiting osteoclastogenesis through immunomodulatory effects ( 194 ). Additional murine studies have shown that SC interact with synovial cells and that dasatinib and/or quercetin have been effective in ameliorating cartilage damage and pain due to OA, as well as alleviating post-menopausal osteoporosis ( 73 , 75 , 195 , 196 ).…”

Janus kinase inhibitor for multicentric reticulohistiocytosis, a new potential treatment

“…25,26 Moreover, while pan-JAKi will provide maximal efficacy,theycarrythegreatestriskoftoxicityduetobroadpathwaysuppression.Incontrast,selectiveJAKimaydecreaseadverse effects and increase safety and efficacy. 16,27 More and more JAKi…”

“…Moreover, while pan‐JAKi will provide maximal efficacy, they carry the greatest risk of toxicity due to broad pathway suppression. In contrast, selective JAKi may decrease adverse effects and increase safety and efficacy 16,27 . More and more JAKi are currently in development, so it is important to consider the balance between benefits and risks of different agents in the future.…”