Transcriptional regulation of cyclophilin D by BMP/Smad signaling and its role in osteogenic differentiation

Elife. 2022 May 30:11:e75023. doi: 10.7554/eLife.75023.


Cyclophilin D (CypD) promotes opening of the mitochondrial permeability transition pore (MPTP) which plays a key role in both cell physiology and pathology. It is, therefore, beneficial for cells to tightly regulate CypD and MPTP but little is known about such regulation. We have reported before that CypD is downregulated and MPTP deactivated during differentiation in various tissues. Herein, we identify BMP/Smad signaling, a major driver of differentiation, as a transcriptional regulator of the CypD gene, Ppif. Using osteogenic induction of mesenchymal lineage cells as a BMP/Smad activation-dependent differentiation model, we show that CypD is in fact transcriptionally repressed during this process. The importance of such CypD downregulation is evidenced by the negative effect of CypD 'rescue' via gain-of-function on osteogenesis both in vitro and in a mouse model. In sum, we characterized BMP/Smad signaling as a regulator of CypD expression and elucidated the role of CypD downregulation during cell differentiation.

Keywords: BMP/Smad; bone; cyclophilin D; human; mitochondria; mouse; osteoprogenitor; permeability transition; regenerative medicine; stem cells.

MeSH terms

  • Animals
  • Bone Morphogenetic Proteins* / genetics
  • Bone Morphogenetic Proteins* / metabolism
  • Cell Differentiation / genetics
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism
  • Mitochondrial Permeability Transition Pore* / metabolism
  • Osteogenesis* / physiology
  • Peptidyl-Prolyl Isomerase F* / genetics
  • Peptidyl-Prolyl Isomerase F* / metabolism
  • Signal Transduction
  • Smad Proteins* / genetics
  • Smad Proteins* / metabolism


  • Bone Morphogenetic Proteins
  • Peptidyl-Prolyl Isomerase F
  • Mitochondrial Permeability Transition Pore
  • Smad Proteins