Abstract
Mitogen-activated protein kinases (MAPKs) are a family of protein kinases that function as key signal transducers of a wide spectrum of extracellular stimuli, including growth factors and pro-inflammatory cytokines. Dysregulation of the extracellular signal-regulated kinase (ERK) MAPK pathway is associated with human skeletal abnormalities including Noonan syndrome, neurofibromatosis type 1, and cardiofaciocutaneous syndrome. Here, we demonstrate that ERK activation in osteoprogenitors is required for bone formation during skeletal development and homeostasis. Deletion of Mek1 and Mek2, kinases upstream of ERK MAPK, in osteoprogenitors (Mek1OsxMek2−/−), resulted in severe osteopenia and cleidocranial dysplasia (CCD), similar to that seen in humans and mice with impaired RUNX2 function. Additionally, tamoxifen-induced deletion of Mek1 and Mek2 in osteoprogenitors in adult mice (Mek1Osx-ERTMek2−/−) significantly reduced bone mass. Mechanistically, this corresponded to decreased activation of osteoblast master regulators, including RUNX2, ATF4, and β-catenin. Finally, we identified potential regulators of osteoblast differentiation in the ERK MAPK pathway using unbiased phospho-mass spectrometry. These observations demonstrate essential roles of ERK activation in osteogenesis and bone formation.
Highlights
Homeostasis in the skeletal system is maintained by coupling between bone-forming osteoblasts and bone-resorbing osteoclasts through a process of continual remodeling
We examined the kinetics of extracellular signal-regulated kinase (ERK) phosphorylation during osteoblast differentiation in vitro (Figure 1B)
Phosphorylation levels of ERK peaked at Day 12 of osteogenic culture and gradually decreased during later differentiation stages, demonstrating that ERK is highly activated in mature osteoblasts
Summary
Homeostasis in the skeletal system is maintained by coupling between bone-forming osteoblasts and bone-resorbing osteoclasts through a process of continual remodeling. Regulation of the anabolic component of this homeostasis occurs through the controlled hierarchical differentiation of skeletal stem cells, osteoprogenitors, and mature osteoblasts [1]. A number of critical signaling pathways, such as transforming growth factor-beta (TGFβ)/bone morphogenic protein (BMP) signaling, wingless-type MMTV integration site (WNT) signaling, and fibroblast growth factors (FGFs), regulate the lineage commitment of skeletal stem cells to osteoprogenitors and subsequent maturation of osteoprogenitors to osteoblasts [2]. MAPKs are dynamically regulated by accessory proteins, such as scaffolds and phosphatases. This complexity allows MAPK pathways to serve diverse tissue-specific functions including skeletal development and homeostasis [3,4,5,6,7]
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