The Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase Pathway in Osteoblasts

Abstract

Extracellular signal-regulated kinases (ERKs) are evolutionarily ancient signal transducers of the mitogen-activated protein kinase (MAPK) family that have long been linked to the regulation of osteoblast differentiation and bone formation. Here, we review the physiological functions, biochemistry, upstream activators, and downstream substrates of the ERK pathway. ERK is activated in skeletal progenitors and regulates osteoblast differentiation and skeletal mineralization, with ERK serving as a key regulator of Runt-related transcription factor 2, a critical transcription factor for osteoblast differentiation. However, new evidence highlights context-dependent changes in ERK MAPK pathway wiring and function, indicating a broader set of physiological roles associated with changes in ERK pathway components or substrates. Consistent with this importance, several human skeletal dysplasias are associated with dysregulation of the ERK MAPK pathway, including neurofibromatosis type 1 and Noonan syndrome. The continually broadening array of drugs targeting the ERK pathway for the treatment of cancer and other disorders makes it increasingly important to understand how interference with this pathway impacts bone metabolism, highlighting the importance of mouse studies to model the role of the ERK MAPK pathway in bone formation.

Keywords: Bone and bones; Extracellular signal-regulated MAP kinases; Mitogen-activated protein kinases; Osteoblasts.

Fig. 1

A diagram of extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling pathways in osteoblasts. Noteworthy inhibitors, including both clinical drugs and tool compounds, are indicated. NF1, neurofibromatosis type 1; GDP, guanosine diphosphate; GTP, guanosine triphosphate; MAP3K, mitogen-activated protein kinase kinase kinase; MAP2K, mitogen-activated protein kinase kinase; MEKK2, mitogen-activated protein kinase kinase kinase 2; MLK3, mixed-lineage kinase 3; MEK, mitogen-activated protein kinase kinase; CREB, cAMP response element-binding protein; RSK2, p90 ribosomal S6 kinase; Runx2, Runt-related transcription factor 2.