PERK controls bone homeostasis through the regulation of osteoclast differentiation and function

Cell Death Dis. 2020 Oct 13;11(10):847. doi: 10.1038/s41419-020-03046-z.


Osteoclasts are multinucleated giant cells with the ability to degrade bone tissue, and are closely related to abnormal bone metabolic diseases. Endoplasmic reticulum (ER) is an organelle responsible for protein modification, quality control, and transportation. The accumulation of unfolded or misfolded proteins in ER cavity induces ER stress. Double-stranded RNA-dependent protein kinase-like ER kinase (PERK) is an ER stress-sensing protein, which is ubiquitous in eukaryotic cells. Systemic PERK knockout mice show severe bone loss, suggesting that PERK is of great significance for maintaining the normal growth and development of bone tissue, but the role of PERK in osteoclastogenesis is still unclear. In this study, we found that PERK was significantly activated during RANKL-induced osteoclast differentiation; knockdown of PERK by siRNA and inhibition of PERK by GSK2606414, respectively, had significant negative regulatory effects on the formation and bone resorption of osteoclasts. PERK inhibitor GSK2606414 down-regulated the mRNA levels and protein expression of osteoclast differentiation marker genes, and inhibited RANKL-induced activation of Mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways. Treatment with PERK inhibitor GSK2606414 in ovariectomized mouse model significantly suppressed bone loss and osteoclast formation. Thapsigargin activated ER stress to enhance autophagy, while GSK2606414 had a significant inhibitory effect on autophagy flux and autophagosome formation. Antioxidant N-acetylcysteine (NAC) could inhibit the expression of PERK phosphorylation, osteoclast-related proteins and autophagy-related proteins, but the use of PERK activator CCT020312 can reverse inhibition effect of NAC. Our findings demonstrate a key role for PERK in osteoclast differentiation and suggest its therapeutic potential.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Animals
  • Bone and Bones / cytology*
  • Bone and Bones / drug effects
  • Bone and Bones / metabolism
  • Cell Differentiation / physiology
  • Down-Regulation / drug effects
  • Endoplasmic Reticulum Stress / drug effects
  • Female
  • Homeostasis
  • Humans
  • Indoles / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Osteoclasts / cytology*
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism
  • RANK Ligand / antagonists & inhibitors
  • RANK Ligand / metabolism
  • Random Allocation
  • Thapsigargin / pharmacology
  • eIF-2 Kinase / antagonists & inhibitors
  • eIF-2 Kinase / metabolism*


  • 7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo(2,3-d)pyrimidin-4-amine
  • Indoles
  • RANK Ligand
  • TNFSF11 protein, human
  • Tnfsf11 protein, mouse
  • Thapsigargin
  • EIF2AK3 protein, human
  • PERK kinase
  • eIF-2 Kinase
  • Adenine