Journal
ELIFE
Volume 11, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.75023
Keywords
cyclophilin D; mitochondria; permeability transition; BMP; Smad; osteoprogenitor; bone; Human; Mouse
Categories
Funding
- National Institute of Dental and Craniofacial Research [R90-DE022529]
- National Institute of Arthritis and Musculoskeletal and Skin Diseases [R21 AR070928, R01 AR072601, R01 AR070613]
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This study identifies BMP/Smad signaling as a transcriptional regulator of CypD expression and reveals the transcriptional repression of CypD during cell differentiation. The downregulation of CypD has a negative effect on osteogenesis.
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.
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