Journal Article

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

Lu, Guoyuan, Gong, Lifeng, Tang, Weigang, Xu, Wei

2024

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Angiology / Antibodies / Bisphosphonates / Blood circulation disorders / Blood Transfusion Medicine / Calcification / Calcification (ectopic) / Calcium / Cardiac Surgery / Cardiology / Cbfa-1 protein / Cell and molecular therapy for cardiovascular disorders / Cell differentiation / Cell Differentiation - drug effects / Cells, Cultured / Core Binding Factor Alpha 1 Subunit - metabolism / Development and progression / Diphosphonates / Enzymes / Experiments / Farnesol / Farnesyl pyrophosphate synthase / Geranyltranstransferase - antagonists & inhibitors / Geranyltranstransferase - metabolism / Glycerophosphates - pharmacology / Health aspects / Humans / Internal Medicine / Medicine / Medicine & Public Health / Mevalonate pathway / Muscle cells / Muscle, Smooth, Vascular - drug effects / Muscle, Smooth, Vascular - enzymology / Muscle, Smooth, Vascular - metabolism / Muscle, Smooth, Vascular - pathology / Myocytes, Smooth Muscle - drug effects / Myocytes, Smooth Muscle - enzymology / Myocytes, Smooth Muscle - metabolism / Myocytes, Smooth Muscle - pathology / Nitrogen / Nitrogen-containing bisphosphonate / OPG / Osteoblasts / Osteogenesis - drug effects / Osteopontin - metabolism / Osteoprotegerin / Osteoprotegerin - metabolism / Physiological aspects / Protein expression / Proteins / RANK Ligand - metabolism / RANKL / Smooth muscle / Software / TRANCE protein / Vascular calcification / Vascular Calcification - drug therapy / Vascular Calcification - enzymology / Vascular Calcification - metabolism / Vascular Calcification - pathology / Vascular smooth muscle / Vascular smooth muscle cells / Western blotting / β-Glycerophosphoric acid