焦磷酸法尼酯
破骨细胞
成骨细胞
基因敲除
甲戊酸途径
化学
小干扰RNA
双膦酸盐
细胞生物学
活力测定
法尼基二磷酸合酶
细胞
生物化学
生物
医学
骨质疏松症
内科学
体外
转染
酶
ATP合酶
细胞凋亡
生物合成
基因
作者
Yuwei Wang,Alexandra Panasiuk,David W. Grainger
摘要
Farnesyl pyrophosphate synthase (FPPS), an enzyme in the mevalonate pathway, is the inhibition target of alendronate, a potent FDA-approved nitrogen-containing bisphosphonate (N-BP) drug, at the molecular level. Alendronate not only inhibits osteoclasts but also has been reported to positively affect osteoblasts. This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures. Primary murine bone marrow cell-induced osteoclasts and the preosteoblast MC3T3-E1 cell line were used to assess effects of anti-FPPS siRNA compared with alendronate. Results show that both FPPS mRNA message and protein knockdown in serum-based culture is correlated with reduced osteoclast viability. FPPS siRNA is more potent than 10 μM alendronate, but less potent than 50 μM alendronate on reducing osteoclast viability. Despite FPPS knockdown, no significant changes were observed in osteoblast proliferation. FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition. However, compared with 50 μM alendronate dosing, FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation. Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization. Overall, results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast-mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways.
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