含氮双膦酸盐通过抑制法呢基焦磷酸合酶诱导骨保护素表达增强和核因子-κB 受体活化因子配体表达抑制，从而抑制血管平滑肌细胞的成骨分化和钙化。

Nitrogen-containing bisphosphonate induces enhancement of OPG expression and inhibition of RANKL expression via inhibition of farnesyl pyrophosphate synthase to inhibit the osteogenic differentiation and calcification in vascular smooth muscle cells.

机构信息

Department of Nephrology, First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, China.

Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.

出版信息

BMC Cardiovasc Disord. 2024 Sep 17;24(1):494. doi: 10.1186/s12872-024-04048-x.

DOI:10.1186/s12872-024-04048-x

PMID:39289624

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11406803/

Abstract

BACKGROUND

Nitrogen-containing bisphosphonate(N-BP)had been found to inhibit the osteogenic differentiation and calcification in vascular smooth muscle cells (VSMCs), but the mechanism is not clear. We intend to verify that N-BP induces enhancement of OPG expression and inhibition of RANKL expression via inhibition of farnesyl pyrophosphate synthase(FPPS) to inhibit the osteogenic differentiation and calcification in VSMCs.

METHODS

β-glycerophosphate (β-GP) was used to induce the osteogenic differentiation and calcification in VSMCs. VSMCs were treated with N-BP or pretreated with downstream products of farnesyl pyrophosphate synthase(FPPS) in mevalonate pathway, such as farnesol (FOH) or geranylgeraniol (GGOH). Alizarin red S staining and determination of calcium content were used to detect calcium deposition.Western Blotting were used to detect expressions of proteins(OPG and RANKL ) and osteogenic marker proteins (Runx2 and OPN).

RESULTS

β-GP induced the osteogenic differentiation and calcification in VSMCs, increased RANKL protein expression and had no significant effect on OPG protein expression. With the treatment of N-BP, the expression of OPG protein was increased and expression of RANKL protein was decreased in VSMCs undergoing osteogenic differentiation and calcification. In addition, N-BP reduced the osteogenic marker proteins (Runx2 and OPN) expression and calcium deposition in VSMCs undergoing osteogenic differentiation and calcification. These effects of N-BP on the osteogenic differentiation and calcification in VSMCs were concentration-dependent, which could be reversed by the downstream products of FPPS, such as FOH or GGOH.

CONCLUSION

N-BP increases OPG expression and decreases RANKL expression via inhibition of FPPS to inhibit the osteogenic differentiation and calcification in VSMCs.

摘要

背景

含氮双膦酸盐（N-BP）已被发现可抑制血管平滑肌细胞（VSMCs）的成骨分化和钙化，但具体机制尚不清楚。我们旨在验证 N-BP 通过抑制法呢基焦磷酸合酶（FPPS）来增加 OPG 表达和降低 RANKL 表达，从而抑制 VSMCs 的成骨分化和钙化。

方法

使用β-甘油磷酸（β-GP）诱导 VSMCs 的成骨分化和钙化。用 N-BP 或法尼基焦磷酸合酶（FPPS）下游产物，如法呢醇（FOH）或香叶基香叶醇（GGOH）预处理 VSMCs。茜素红 S 染色和钙含量测定用于检测钙沉积。Western Blotting 用于检测蛋白（OPG 和 RANKL）和成骨标记蛋白（Runx2 和 OPN）的表达。

结果

β-GP 诱导 VSMCs 成骨分化和钙化，增加 RANKL 蛋白表达，对 OPG 蛋白表达无明显影响。用 N-BP 处理后，成骨分化和钙化的 VSMCs 中 OPG 蛋白表达增加，RANKL 蛋白表达减少。此外，N-BP 降低成骨分化和钙化的 VSMCs 中成骨标记蛋白（Runx2 和 OPN）的表达和钙沉积。N-BP 对 VSMCs 成骨分化和钙化的这些作用呈浓度依赖性，可被 FPPS 的下游产物如 FOH 或 GGOH 逆转。