| First Author | Adam C | Year | 2018 |
| Journal | Bone | Volume | 111 |
| Pages | 49-58 | PubMed ID | 29567200 |
| Mgi Jnum | J:266604 | Mgi Id | MGI:6199809 |
| Doi | 10.1016/j.bone.2018.03.020 | Citation | Adam C, et al. (2018) The MEK5/ERK5 mitogen-activated protein kinase cascade is an effector pathway of bone-sustaining bisphosphonates that regulates osteogenic differentiation and mineralization. Bone 111:49-58 |
| abstractText | 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. |
