Biomechanical stimulation of osteoblast gene expression requires phosphorylation of the RUNX2 transcription factor

Li, Yán; Ge, Chunxi; Long, Jason P.; Begun, Dana L.; Rodríguez, José A.; Goldstein, Steven A.; Franceschi, Renny T.

doi:10.1002/jbmr.1574

Cited by 82 publications

(71 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…ERK1/2 binds and phosphorylates RUNX2 on several serine residues including S301 and S319, that are both required for RUNX2-dependent transcription(21). These phosphorylation events are necessary for the response of bone to several important stimuli including ECM synthesis, mechanical loading, FGF2 and BMP treatment(21–23). Similarly, PPARγ undergoes ERK-dependent phosphorylation at S112, resulting in decreased PPARγ transcriptional activity(24).…”

Section: Introductionmentioning

confidence: 99%

Discoidin Receptor 2 Controls Bone Formation and Marrow Adipogenesis

Wang

Zhao

et al. 2016

Journal of Bone and Mineral Research

Self Cite

View full text Add to dashboard Cite

Cell-extracellular matrix interactions play major roles in controlling progenitor cell fate and differentiation. The receptor tyrosine kinase, discoidin receptor 2 (DDR2), is an important mediator of interactions between cells and fibrillar collagens. DDR2 signals through both ERK1/2 and p38 MAP kinase, which stimulate osteoblast differentiation and bone formation. Here we show that DDR2 is critical for skeletal development and differentiation of marrow progenitor cells to osteoblasts while suppressing marrow adipogenesis. Smallie mice (Ddr2slie/slie), which contain a non-functional Ddr2 allele, have multiple skeletal defects. A progressive decrease in tibial trabecular BV/TV was observed when wild type, Ddr2wt/slie and Ddr2slie/slie mice were compared. These changes were associated with reduced trabecular number and thickness and increased trabecular spacing in both males and females, but reduced cortical thickness only in Ddr2slie/slie females. Bone changes were attributed to decreased bone formation rather than increased osteoclast activity. Significantly, marrow fat and adipocyte-specific mRNA expression were significantly elevated in Ddr2slie/slie animals. Additional skeletal defects include widened calvarial sutures and reduced vertebral trabecular bone. To examine the role of DDR2 signaling in cell differentiation, bone marrow stromal cells (BMSCs) were grown under osteogenic and adipogenic conditions. Ddr2slie/slie cells exhibited defective osteoblast differentiation and accelerated adipogenesis. Changes in differentiation were related to activity of RUNX2 and PPARγ, transcription factors that are both controlled by MAPK-dependent phosphorylation. Specifically, the defective osteoblast differentiation in calvarial cells from Ddr2slie/slie mice was associated with reduced ERK/MAP kinase and RUNX2-S319 phosphorylation and could be rescued with a constitutively-active phosphomimetic Runx2 mutant. Also, DDR2 was shown to increase RUNX2-S319 phosphorylation and transcriptional activity while also increasing PPARγ-S112 phosphorylation, but reducing its activity. DDR2 is, therefore, important for maintenance of osteoblast activity and suppression of marrow adipogenesis in vivo and these actions are related to changes in MAPK-dependent RUNX2 and PPARγ phosphorylation.

show abstract

Section: Introductionmentioning

confidence: 99%

Discoidin Receptor 2 Controls Bone Formation and Marrow Adipogenesis

Wang

Zhao

et al. 2016

Journal of Bone and Mineral Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Transmitted via intracellular signaling cascades including MAPK26, PI3K/Akt27, GTPases28, Wnt29 and calcium30 pathways, the signals modulate osteoblastic differentiation by up-regulation of genes such as Runx2, Alp , and Ocn 31. RUNX2 is a master control transcription factor of osteoblastic differentiation and function.…”

Section: Discussionmentioning

confidence: 99%

Magnitude-dependent response of osteoblasts regulated by compressive stress

Shen

Geng

Liu

et al. 2017

Sci Rep

View full text Add to dashboard Cite

The present study aimed to investigate the role of magnitude in adaptive response of osteoblasts exposed to compressive stress. Murine primary osteoblasts and MC3T3-E1 cells were exposed to compressive stress (0, 1, 2, 3, 4, and 5 g/cm2) in 3D culture. Cell viability was evaluated, and expression levels of Runx2, Alp, Ocn, Rankl, and Opg were examined. ALP activity in osteoblasts and TRAP activity in RAW264.7 cells co-cultured with MC3T3-E1 cells were assayed. Results showed that compressive stress within 5.0 g/cm2 did not influence cell viability. Both osteoblastic and osteoblast-regulated osteoclastic differentiation were enhanced at 2 g/cm2. An increase in stress above 2 g/cm2 did not enhance osteoblastic differentiation further but significantly inhibited osteoblast-regualted osteoclastic differentiation. This study suggested that compressive stress regulates osteoblastic and osteoclastic differentiation through osteoblasts in a magnitude-dependent manner.

show abstract

“…Mechanical stimulation of osteoblasts by exposure to fluid flow shear stress rapidly (i.e. within minutes) increases P-ERK-dependent phosphorylation of RUNX2 at Ser 301 and Ser 319 on target gene chromatin and this phosphorylation is necessary for subsequent induction of histone acetylation and transcription(91). It is not currently known if P-ERK also phosphorylates PPARγ on the chromatin of adipocyte genes versus at other nuclear or cytoplasmic sites.…”

Section: Mapks and The Response Of Skeletal Progenitor Cells To Mechamentioning

confidence: 99%

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

Franceschi

2017

Curr Mol Bio Rep

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Biomechanical stimulation of osteoblast gene expression requires phosphorylation of the RUNX2 transcription factor

Cited by 82 publications

References 48 publications

Discoidin Receptor 2 Controls Bone Formation and Marrow Adipogenesis

Discoidin Receptor 2 Controls Bone Formation and Marrow Adipogenesis

Magnitude-dependent response of osteoblasts regulated by compressive stress

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

Contact Info

Product

Resources

About