Transcriptional regulation of Cyclophilin D by BMP/SMAD signaling and its role in osteogenic differentiation
- University of Rochester, United States
Abstract
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files (Raw data file)
Article and author information
Author details
Rubens Sautchuk Jr
Funding
National Institute of Dental and Craniofacial Research (R90-DE022529)
- Rubens Sautchuk Jr
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R21 AR070928)
- Jennifer H Jonason
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR070613)
- Hani A Awad
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R21 AR070928)
- Roman A Eliseev
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR072601)
- Roman A Eliseev
National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30 AR069655)
- Rubens Sautchuk Jr
- Brianna H Kalicharan
- Katherine Escalera-Rivera
- Jennifer H Jonason
- Hani A Awad
- Roman A Eliseev
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocol (#2012-043) of the University of Rochester. All surgery was performed under anesthesia, and every effort was made to minimize suffering.
Copyright
© 2022, Sautchuk et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Transcriptional regulation of Cyclophilin D by BMP/SMAD signaling and its role in osteogenic differentiation
eLife 11:e75023.
https://doi.org/10.7554/eLife.75023
