Endoplasmic Reticulum Stress Response Mediated by the PERK-eIF2α-ATF4 Pathway Is Involved in Osteoblast Differentiation Induced by BMP2*

To avoid excess accumulation of unfolded proteins in the endoplasmic reticulum (ER), eukaryotic cells have signaling pathways from the ER to the cytosol or nucleus. These processes are collectively termed the ER stress response. Double stranded RNA activated protein kinase (PKR)-like endoplasmic reticulum kinase (PERK) is a major transducer of the ER stress response and directly phosphorylates eIF2α, resulting in translational attenuation. Phosphorylated eIF2α specifically promotes the translation of the transcription factor ATF4. ATF4 plays important roles in osteoblast differentiation and bone formation. Perk−/− mice are reported to exhibit severe osteopenia, and the phenotypes observed in bone tissues are very similar to those of Atf4−/− mice. However, the involvement of the PERK-eIF2α-ATF4 signaling pathway in osteogenesis is unclear. Phosphorylated eIF2α and ATF4 protein levels were attenuated in Perk−/− calvariae, and the gene expression levels of osteocalcin (Ocn) and bone sialoprotein (Bsp), which are targets for ATF4, were also down-regulated. Treatment of wild-type primary osteoblasts with BMP2, which is required for osteoblast differentiation, induced ER stress, leading to an increase in ATF4 protein expression levels. In contrast, the level of ATF4 in Perk−/− osteoblasts was severely diminished. The results indicate that PERK signaling is required for ATF4 activation during osteoblast differentiation. Perk−/− osteoblasts exhibited decreased alkaline phosphatase activities and delayed mineralized nodule formation relative to wild-type cultures. These abnormalities were almost completely restored by the introduction of ATF4 into Perk−/− osteoblasts. Taken together, ER stress occurs during osteoblast differentiation and activates the PERK-eIF2α-ATF4 signaling pathway followed by the promotion of gene expression essential for osteogenesis, such as Ocn and Bsp.

• Publication year

  2010

• Venue

  Journal of Biological Chemistry

• Publication date

  2010-12-06

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/jbc.M110.152900PMID 21135100PMCID 3039352
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• Perk−/− osteoblasts had reduced osteoblast differentiation readouts, including lower alkaline phosphatase activity and delayed mineralized nodule formation, and ATF4 reintroduction nearly completely rescued these defects.

  Confidence 0.94

  imjlk (vdp8mqzes2) extractionmexicorea (qjvnbu8xg3) reviewB (s683577b42) review
• BMP2 treatment increased ER stress and ATF4 protein in wild-type primary osteoblasts, while Perk−/− osteoblasts showed severely diminished ATF4 under the same BMP2 treatment.

  Confidence 0.93

  imjlk (vdp8mqzes2) extractionmexicorea (qjvnbu8xg3) reviewB (s683577b42) review
• Perk−/− calvariae showed attenuated phosphorylated eIF2α and ATF4 with reduced ATF4 target osteoblast gene expression.

  Confidence 0.95

  imjlk (vdp8mqzes2) extractionmexicorea (qjvnbu8xg3) reviewB (s683577b42) review
• ER stress during osteoblast differentiation activates the PERK-eIF2α-ATF4 pathway and raises ATF4, supporting induction of ATF4 target osteoblast genes.

  Confidence 0.92

  imjlk (vdp8mqzes2) extractionmexicorea (qjvnbu8xg3) reviewB (s683577b42) review

• atf4

  transcription factor, osteogenesis regulator

  A transcription factor whose increased protein level is monitored as a downstream output in the osteoblast differentiation context.

  Aliases: ATF4 protein

  imjlk (vdp8mqzes2) extractionmexicorea (qjvnbu8xg3) reviewB (s683577b42) review
• atf4 target osteoblast genes

  gene group, osteoblast markers

  Downstream osteoblast genes measured in this abstract, including Ocn and Bsp, used as readouts of ATF4-associated osteogenic gene expression.

  Aliases: osteocalcin, bone sialoprotein, Ocn, Bsp

  imjlk (vdp8mqzes2) extractionmexicorea (qjvnbu8xg3) reviewB (s683577b42) review
• bmp2

  differentiation inducer, osteogenic cytokine

  A differentiation stimulus used to drive osteoblast differentiation in primary osteoblast cultures in this study.

  Aliases: BMP-2

  imjlk (vdp8mqzes2) extractionmexicorea (qjvnbu8xg3) reviewB (s683577b42) review
• er stress

  cellular condition, signaling trigger

  The condition in which unfolded proteins accumulate in the ER and trigger signaling from the ER to cytosolic/nuclear pathways.

  Aliases: ER stress response

  imjlk (vdp8mqzes2) extractionmexicorea (qjvnbu8xg3) reviewB (s683577b42) review
• osteoblast differentiation

  cellular process, lineage progression

  The process by which precursor cells acquire osteoblast identity and function for bone formation.

  Aliases: osteogenesis

  imjlk (vdp8mqzes2) extractionmexicorea (qjvnbu8xg3) reviewB (s683577b42) review
• osteoblast differentiation readouts

  phenotypic endpoint, functional readout

  Functional or phenotypic indicators of osteoblast maturation used in the experiments.

  Aliases: alkaline phosphatase activity, mineralized nodule formation

  imjlk (vdp8mqzes2) extractionmexicorea (qjvnbu8xg3) reviewB (s683577b42) review
• perk-eif2α-atf4 pathway

  signaling pathway, stress response mechanism

  An ER stress response pathway centered on PERK that leads to eIF2α phosphorylation and ATF4 activity during osteoblast differentiation.

  Aliases: PERK signaling pathway, PERK-eIF2α-ATF4 signaling pathway

  imjlk (vdp8mqzes2) extractionmexicorea (qjvnbu8xg3) reviewB (s683577b42) review
• phosphorylated eif2α

  protein state, signaling state marker

  The phosphorylated state of eIF2α used here as an indicator of PERK pathway activation.

  Aliases: p-eIF2α

  imjlk (vdp8mqzes2) extractionmexicorea (qjvnbu8xg3) reviewB (s683577b42) review

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