The MEK5/ERK5 mitogen-activated protein kinase cascade is an effector pathway of bone-sustaining bisphosphonates that
Christian Adam1, Lucia Glück1, Regina Ebert2
1Department of Dermatology, University Hospital Würzburg, Germany.
Abstract:
Bisphosphonates play an important role in the treatment of metabolic bone diseases such as osteoporosis. In addition to their anti-resorptive activity by triggering osteoclast apoptosis, nitrogen-containing bisphosphonates (N-BP) may also influence osteogenic differentiation, which might rely on their capacity to inhibit the mevalonate pathway. In vascular endothelial cells inhibition of this pathway by cholesterol-lowering statins activates the MEK5/ERK5 mitogen-activated protein kinase cascade, which plays an important role in cellular differentiation, apoptosis or inflammatory processes. Here we evaluated whether N-BP may also target the MEK5/ERK5 pathway and analysed the consequences of ERK5 activation on osteogenic differentiation. We show that N-BP dose-dependently activate ERK5 in primary human endothelial cells and osteoblasts. The mechanism likely involves farnesyl pyrophosphate synthase inhibition and subsequent functional inhibition of the small GTPase Cdc42 since siRNA-mediated knockdown of both genes could reproduce N-BP-induced ERK5 activation. ERK5 activation resulted in regulation of several bone-relevant genes and was required for calcification and osteogenic differentiation of bone marrow-derived mesenchymal stems cells as evident by the lack of alkaline phosphatase induction and alizarin-red S staining observed upon ERK5 knockdown or upon differentiation initiation in presence of a pharmacological ERK5 inhibitor. Our data provide evidence that N-BP activate the MEK5/ERK5 cascade and reveal an essential role of ERK5 in osteogenic differentiation and mineralization of skeletal precursors.
Insights
Nitrogen-containing bisphosphonates (N-BP) activate the MEK5/ERK5 pathway in bone cells. This activation is crucial for osteogenic differentiation and mineralization of skeletal precursors, impacting bone disease treatments.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Bisphosphonates are key treatments for metabolic bone diseases like osteoporosis.
- Nitrogen-containing bisphosphonates (N-BP) exhibit anti-resorptive activity and may influence osteogenic differentiation via mevalonate pathway inhibition.
- Inhibition of the mevalonate pathway in endothelial cells by statins activates the MEK5/ERK5 cascade, influencing cellular processes.
Purpose of the Study:
- To investigate if N-BP target the MEK5/ERK5 pathway.
- To analyze the consequences of ERK5 activation on osteogenic differentiation.
Main Methods:
- Treatment of primary human endothelial cells and osteoblasts with N-BP.
- siRNA-mediated knockdown of farnesyl pyrophosphate synthase and Cdc42.
- Assessment of ERK5 activation and its role in osteogenic differentiation using gene expression analysis, alkaline phosphatase induction, and alizarin-red S staining.
- Inhibition of ERK5 using a pharmacological inhibitor.
Main Results:
- N-BP dose-dependently activated ERK5 in endothelial cells and osteoblasts.
- N-BP-induced ERK5 activation likely involves farnesyl pyrophosphate synthase inhibition and Cdc42 functional inhibition.
- ERK5 activation regulated bone-relevant genes and was essential for the calcification and osteogenic differentiation of mesenchymal stem cells.
- Knockdown or inhibition of ERK5 abolished alkaline phosphatase induction and alizarin-red S staining during differentiation.
Conclusions:
- N-BP activate the MEK5/ERK5 signaling cascade.
- ERK5 plays an essential role in the osteogenic differentiation and mineralization of skeletal precursors.
- These findings offer new insights into the mechanisms of bisphosphonates in bone metabolism.
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