Avagacestat抑制破骨细胞形成及溶骨功能改善骨关节炎骨破坏

doi:10.13591/j.cnki.kqyx.2022.09.002

Abstract

Abstract: Objective To explore the effect of gamma secretase inhibitor (Avagacestat) on inhibiting osteoclast formation and bone resorption to suppress the progress of osteoarthritis. Methods Bone marrow cavity macrophages (BMMs) of 6 weeks old C57 mice were extracted and induced for culture. IC₅₀ of Avagacestat on macrophages induced by M-CSF and RANKL was calculated by CCK8. Osteoclast formation test and function test were conducted to determine the inhibition of Avagacestat on osteoclast by setting 3 groups with drug concentration of 0, 120, 240 nmol/L and osteoclast progress-associated genes such as TRAP, C-fos, Cath-K were checked through RT-PCR in 3 groups. Then osteoarthritis mouse model was constructed by injecting LPS into the Articulatio genus. Bone resorption was examined by 3D bone reconstruction, and distribution of osteoclast was detected through HE staining and TRAP staining. Results At 24 h, 48 h and 96 h, the IC₅₀ of Avagacestat on osteoclasts were 493, 426 and 405 nmol/L, respectively. The cell TRAP and bone resorption test respectively certified that Avagacestat could inhibit the formation of osteoclast and bone resorption, and the inhibition of 240 nmol/L was significantly higher than that of 120 nmol/L. RT-PCR results also indicated that the expression of osteolysis-associated genes TRAP, C-fos, Cath-K was significantly inhibited after the addition of Avagacestat, and with the increasing concentration of Avagacestat, expression of these genes significantly declined. 3D bone reconstruction and TRAP staining showed that the number of osteoclasts increased significantly and osteolysis was enhanced in LPS-induced osteoarthritis model. Avagacestat significantly inhibited the number of osteoclasts, showing bone mineral density and bone trabecular number increasing but osteoclast number decreasing after Avagacestat added, statistically significant. Conclusion Avagacestat can inhibit the proliferation of osteoclasts and the expression of osteolytic genes and resorption in osteoarthritis, so it has the potential to be used as a drug for arthritis treatment.

Key words: Avagacestat, osteoarthritis, osteoclast, bone resorption

CLC Number:

R782.6

HE Jiajia, ZHANG Ping, ZHOU Weina, JIANG Hongbing. Avagacestat inhibits osteoclast formation and attenuates bone destruction in osteoarthritis[J]. Stomatology, 2022, 42(9): 774-780.

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Avagacestat inhibits osteoclast formation and attenuates bone destruction in osteoarthritis

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