Home Blog of Signal Transduction Neuronal Signaling Beta Amyloid LY450139 Inhibited Ti-Particle-Induced Bone Dissolution via Suppressing Notch and NF-κB Signaling Pathways

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LY450139 Inhibited Ti-Particle-Induced Bone Dissolution via Suppressing Notch and NF-κB Signaling Pathways

Aseptic loosening of the prosthesis caused by wear-particle-induced osteolysis is a long-term complication and one of the most common reasons for the failure of joint implants. The primary cause of aseptic loosening of the prosthesis is overactive bone resorption caused by wear-particle-activated osteoclasts in both direct and indirect ways. Therefore, drugs that can inhibit differentiation and bone resorption of osteoclasts need investigation as a potential therapeutic strategy to prevent and treat peri-prosthetic osteolysis and thereby prolong the service life of the prosthesis. This study has verified the potential inhibitory effect of LY450139 on inflammatory osteolysis induced by titanium particles in a mice skull model. In addition, we found that LY450139 inhibited receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis, bone resorption, and podosomal actin belt formation in a dose-dependent manner without evidence of cytotoxicity in vitro. In addition, LY450139 significantly decreased the expression of osteoclast-specific markers, including TRAP, CTSK, V-ATPase d2, CTR, DC-STAMP, NFATc1, and the downstream target gene Hes1 in Notch signaling pathway. Further investigation of the molecular mechanism demonstrated that LY450139 inhibited the formation of osteoclasts via inhibition of the NF-κB and Notch signaling pathways. In summary, LY450139 inhibited the formation of RANKL-mediated osteoclasts via NF-κB and Notch signaling and inhibited Ti particle-induced inflammatory osteolysis in vivo. LY450139 is a potential targeted drug for the treatment of peri-prosthetic osteolysis and other osteolytic disease associated with overactive osteoclasts.

 

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In simpler terms, the study found that the drug LY450139 has the potential to prevent the failure of joint implants caused by aseptic loosening. Aseptic loosening is a common long-term complication in joint implants and occurs when there is overactive bone resorption caused by wear particles. The study found that LY450139 can inhibit the formation of osteoclasts, which are cells responsible for breaking down bone, and thereby prevent the overactive resorption of bone. This was tested in a mice skull model and found to be effective in decreasing the expression of markers that indicate osteoclast activity. The study also showed that LY450139 works by inhibiting the NF-κB and Notch signaling pathways, which play a role in the formation of osteoclasts. These findings suggest that LY450139 may be a promising drug for the treatment of peri-prosthetic osteolysis and other osteolytic diseases associated with overactive osteoclasts.

Related Products

Cat.No. Product Name Information
S1594 Semagacestat (LY450139) Semagacestat (LY450139) is a γ-secretase blocker for Aβ42, Aβ40 and Aβ38 with IC50 of 10.9 nM, 12.1 nM and 12.0 nM, also inhibits Notch signaling with IC50 of 14.1 nM in H4 human glioma cell. Phase 3.

Related Targets

Beta Amyloid Secretase Notch