RT Journal Article
SR Electronic
T1 Transcriptional regulation of cyclophilin D by BMP/SMAD signaling and its role in osteogenic differentiation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.11.01.466735
DO 10.1101/2021.11.01.466735
A1 Sautchuk, Rubens
A1 Kalicharan, Brianna H
A1 Escalera-Rivera, Katherine
A1 Jonason, Jennifer H
A1 Porter, George A
A1 Awad, Hani
A1 Eliseev, Roman A
YR 2021
UL http://biorxiv.org/content/early/2021/11/02/2021.11.01.466735.abstract
AB 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 repressor of the CypD gene, Ppif. Using osteogenic induction of mesenchymal lineage cells as a model of BMP/Smad-dependent differentiation, 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 vivo. In sum, we characterized BMP/Smad signaling as a regulator of CypD expression and elucidated the role of CypD downregulation during cell differentiation.Competing Interest StatementThe authors have declared no competing interest.AAV2adeno associated virus serotype 2Alk Palkaline phosphataseArareaARalizarin redATPadenosine triphosphateBMbone marrowBMPbone morphogenic proteinBMSCbone marrow stromal (a.k.a. mesenchymal stem) cellBV/TVbone over total volumecaCypDconstitutively active CypDCalcein AMcalcein acetoxymethylChIPchromatin immunoprecipitationCross-Seccross-sectionalCtcortical areaCVcrystal violetCypDcyclophilin DD+Mdistal + middleDIOdouble-floxed inverted orientationEVempty vectorf/ffloxed/floxedGOFgain-of-functionIMMinner mitochondrial membraneiPSCinduced pluripotent stem cellK166Qsubstitution of lysine at position 166 for glutamineKOknock-outLOFloss-of-functionLucluciferaseMOImoment of inertiaMPTPmitochondrial permeability transition poreM+Pmiddle + proximalNnumberOBosteoblastOxPhosoxidation phosphorylation respirationROSreactive oxygen speciesSBEsmad binding elementSpspaceTbtrabecularTFtranscription factorTg/0hemizygous transgeneThthicknessTRAPtartrate-resistant acid phosphataseVDAC1voltage-dependent anion channel 1Δψmmitochondrial membrane potential