Control of the Osteoblast Lineage by Mitogen-Activated Protein Kinase Signaling

Abstract

Purpose of the review This review will provide a timely assessment of MAP kinase actions in bone development and homeostasis with particular emphasis on transcriptional control of the osteoblast lineage Recent findings ERK and p38 MAP kinases function as transducers of signals initiated by the extracellular matrix, mechanical loading, TGF-β, BMPs and FGF2. MAPK signals may also affect and/or interact with other important pathways such as WNT and HIPPO. ERK and p38 MAP kinase pathways phosphorylate specific osteogenic transcription factors including RUNX2, Osterix, ATF4 and DLX5. For RUNX2, phosphorylation at specific serine residues initiates epigenetic changes in chromatin necessary for decondensation and increased transcription. MAPK also suppresses marrow adipogenesis by phosphorylating and inhibiting PPARγ, which may explain the well-known relationship between reduced skeletal loading and marrow fat accumulation. Summary MAPKs transduce signals from the extracellular environment to the nucleus allowing bone cells to respond to changes in hormonal/growth factor signaling and mechanical loading thereby optimizing bone structure to meet physiological and mechanical needs of the body.

Effect of Nano-Montmorillonite on Osteoblast Differentiation, Mineral Density, and Osteoclast Differentiation in Bone Formation

“…Mitogen-activated protein kinase (MAPK) signaling is important for the regulation of osteoblast differentiation and maturation [44]. In Figure 7D, we evaluated the effects of the NM diet on the activation of MAPK signaling, including the expression levels of p-p38, p-JNK, and p-ERK for the regulation of osteoblast differentiation.…”

RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1

“…Although RUNX2 is a substrate for both p38 and pERK1/2, pERK1/2 can activate RUNX2 on average six times more efficiently than p38 ( Ge et al, 2012 ). In addition, ERK1/2 binding to RUNX2 through MAPK D site has greater affinity than p38 binding and more sensitive to osteoblast differentiation during calvaria explant or primary osteoblast culture ( Franceschi and Ge, 2017 ; Ge et al, 2012 ). The importance of pERK1/2 regulation of RUNX2 during osteogenesis is shown in this study by the reversal of the craniosynostotic phenotype in Rab23 -/- mice.…”

Betulin Promotes Differentiation of Human Osteoblasts In Vitro and Exerts an Osteoinductive Effect on the hFOB 1.19 Cell Line Through Activation of JNK, ERK1/2, and mTOR Kinases

“…Since osteogenesis is mediated among others by JNK, ERK1/2, and p38 signaling pathways [8], we evaluated the activation of these kinases in order to elucidate the mechanism by which BET acts on osteoblasts. Considering the osteoblast differentiation, ERK has been reported to regulate the process by regulating the activity of RUNX2 [52].…”

“…Considering the osteoblast differentiation, ERK has been reported to regulate the process by regulating the activity of RUNX2 [52]. It was described that numerous bone-active factors, including fibroblast growth factor (FGF), insulin-like growth factors (IGFs), or estrogen, induce ERK signaling in osteoblasts [8,53]. The p38 signaling in turn is activated by TGF-β and bone morphogenetic proteins (BMPs), and controls RUNX2 activity as well.…”

“…RUNX2 is considered to be the master transcription factor, as it regulates the expression of genes linked with osteoblast maturation such as ALPL (alkaline phosphatase, ALP), Col1A1 (collagen α1 type I, COL1), SPP1 (osteopontin, OPN), IBSP (bone sialoprotein II, BSPII), and BGLAP (osteocalcin, OCN) [7]. Different signaling systems regulate bone formation, but mitogen-activated kinase (MAPK) and mammalian target of rapamycin (mTOR) pathways play a key role in this process, as they affect osteoblast differentiation [8,9]. MAP kinases, i.e., extracellular signal-regulated kinases (ERK1/2) and p38, have been identified as regulators of RUNX2 activation [10,11], while c-Jun N-terminal protein kinases (JNKs) regulate the expression of activating transcription factor 4 (ATF4) and are required for late-stage osteoblast differentiation [12].…”