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.

Molecular mechanism of a novel root-end filling material containing zirconium oxide on the osteogenic/odontogenic differentiation of human osteosarcoma MG-63 cells

“…The MAPK signaling pathway mediates various physiological processes, including cell growth, development, proliferation, differentiation, aging, and death. Studies have shown that the MAPK signaling pathway promotes osteoblast proliferation, differentiation, and delayed apoptosis through various pathways ( Luo et al, 2005 ; Greenblatt et al, 2022 ). In the NRFM-Zr group, there were 7 genes involved in this pathway, while the MTA group had 4 genes ( Table 6 ).…”

Unlocking the Therapeutic Potential of Irisin: Harnessing Its Function in Degenerative Disorders and Tissue Regeneration

“…In the realm of load-induced bone formation, the integrin-based adhesion complex holds significant importance and is ubiquitously expressed across all types of bone cells [ 41 , 42 ]. However, since integrins lack inherent enzymatic activity, the transmission of signals through focal adhesion hinges upon associated molecules that trigger downstream signaling events such as intracellular calcium release, tyrosine kinase and MAP kinase activation [ 43 , 44 ]. The Focal adhesion kinase (FAK) family, comprising of FAK and proline-rich tyrosine kinase 2 (PYK2), represents significant tyrosine kinases activated upon integrin engagement, responsible for the regulation of osteoclast adhesion and bone resorption [ 45 ].…”

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“… 92 , 93 , 94 Another relevant substrate of ERK that is associated with osteoblast formation is the Fos family of subunits of the AP-1 transcriptional complex, comprising FOS, FOSL1, FOSL2, and FOSB. 95 The mechanism of Fos and AP-1 stimulation in osteoblast formation by ERK activation remains unclear; however, FOS proteins via cGMP-mediated ERK are reportedly involved in bone formation by mechanical stimulation. 95 , 96 …”

“… 95 The mechanism of Fos and AP-1 stimulation in osteoblast formation by ERK activation remains unclear; however, FOS proteins via cGMP-mediated ERK are reportedly involved in bone formation by mechanical stimulation. 95 , 96 …”