S-nitrosoglutathione reductase-dependent PPARγ denitrosylation participates in MSC-derived adipogenesis and osteogenesis

Yenong Cao, Samirah A. Gomes, Erika B. Rangel, Ellena C. Paulino, Tatiana L. Fonseca, Jinliang Li, Marilia B. Teixeira, Cecilia H. Gouveia, Antonio C. Bianco, Michael S Kapiloff, Wayne E Balkan, Joshua Hare

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Abstract

Bone marrow-derived mesenchymal stem cells (MSCs) are a common precursor of both adipocytes and osteoblasts. While it is appreciated that PPARγ regulates the balance between adipogenesis and osteogenesis, the roles of additional regulators of this process remain controversial. Here, we show that MSCs isolated from mice lacking S-nitrosoglutathione reductase, a denitrosylase that regulates protein S-nitrosylation, exhibited decreased adipogenesis and increased osteoblastogenesis compared with WT MSCs. Consistent with this cellular phenotype, S-nitrosoglutathione reductase-deficient mice were smaller, with reduced fat mass and increased bone formation that was accompanied by elevated bone resorption. WT and S-nitrosoglutathione reductase-deficient MSCs exhibited equivalent PPARγ expression; however, S-nitrosylation of PPARγ was elevated in S-nitrosoglutathione reductase-deficient MSCs, diminishing binding to its downstream target fatty acid-binding protein 4 (FABP4). We further identified Cys 139 of PPARγ as an S-nitrosylation site and demonstrated that S-nitrosylation of PPARγ inhibits its transcriptional activity, suggesting a feedback regulation of PPARγ transcriptional activity by NO-mediated S-nitrosylation. Together, these results reveal that S-nitrosoglutathione reductase-dependent modification of PPARγ alters the balance between adipocyte and osteoblast differentiation and provides checkpoint regulation of the lineage bifurcation of these 2 lineages. Moreover, these findings provide pathophysiological and therapeutic insights regarding MSC participation in adipogenesis and osteogenesis.

Original languageEnglish (US)
Pages (from-to)1679-1691
Number of pages13
JournalJournal of Clinical Investigation
Volume125
Issue number4
DOIs
StatePublished - Apr 1 2015

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glutathione-independent formaldehyde dehydrogenase
Adipogenesis
Peroxisome Proliferator-Activated Receptors
Mesenchymal Stromal Cells
Osteogenesis
Mouse Adh5 protein
Osteoblasts
Adipocytes
Fatty Acid-Binding Proteins
Protein S
Bone Resorption
Bone Marrow

ASJC Scopus subject areas

  • Medicine(all)

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S-nitrosoglutathione reductase-dependent PPARγ denitrosylation participates in MSC-derived adipogenesis and osteogenesis. / Cao, Yenong; Gomes, Samirah A.; Rangel, Erika B.; Paulino, Ellena C.; Fonseca, Tatiana L.; Li, Jinliang; Teixeira, Marilia B.; Gouveia, Cecilia H.; Bianco, Antonio C.; Kapiloff, Michael S; Balkan, Wayne E; Hare, Joshua.

In: Journal of Clinical Investigation, Vol. 125, No. 4, 01.04.2015, p. 1679-1691.

Research output: Contribution to journalArticle

Cao, Y, Gomes, SA, Rangel, EB, Paulino, EC, Fonseca, TL, Li, J, Teixeira, MB, Gouveia, CH, Bianco, AC, Kapiloff, MS, Balkan, WE & Hare, J 2015, 'S-nitrosoglutathione reductase-dependent PPARγ denitrosylation participates in MSC-derived adipogenesis and osteogenesis', Journal of Clinical Investigation, vol. 125, no. 4, pp. 1679-1691. https://doi.org/10.1172/JCI73780
Cao, Yenong ; Gomes, Samirah A. ; Rangel, Erika B. ; Paulino, Ellena C. ; Fonseca, Tatiana L. ; Li, Jinliang ; Teixeira, Marilia B. ; Gouveia, Cecilia H. ; Bianco, Antonio C. ; Kapiloff, Michael S ; Balkan, Wayne E ; Hare, Joshua. / S-nitrosoglutathione reductase-dependent PPARγ denitrosylation participates in MSC-derived adipogenesis and osteogenesis. In: Journal of Clinical Investigation. 2015 ; Vol. 125, No. 4. pp. 1679-1691.
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AU - Cao, Yenong

AU - Gomes, Samirah A.

AU - Rangel, Erika B.

AU - Paulino, Ellena C.

AU - Fonseca, Tatiana L.

AU - Li, Jinliang

AU - Teixeira, Marilia B.

AU - Gouveia, Cecilia H.

AU - Bianco, Antonio C.

AU - Kapiloff, Michael S

AU - Balkan, Wayne E

AU - Hare, Joshua

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AB - Bone marrow-derived mesenchymal stem cells (MSCs) are a common precursor of both adipocytes and osteoblasts. While it is appreciated that PPARγ regulates the balance between adipogenesis and osteogenesis, the roles of additional regulators of this process remain controversial. Here, we show that MSCs isolated from mice lacking S-nitrosoglutathione reductase, a denitrosylase that regulates protein S-nitrosylation, exhibited decreased adipogenesis and increased osteoblastogenesis compared with WT MSCs. Consistent with this cellular phenotype, S-nitrosoglutathione reductase-deficient mice were smaller, with reduced fat mass and increased bone formation that was accompanied by elevated bone resorption. WT and S-nitrosoglutathione reductase-deficient MSCs exhibited equivalent PPARγ expression; however, S-nitrosylation of PPARγ was elevated in S-nitrosoglutathione reductase-deficient MSCs, diminishing binding to its downstream target fatty acid-binding protein 4 (FABP4). We further identified Cys 139 of PPARγ as an S-nitrosylation site and demonstrated that S-nitrosylation of PPARγ inhibits its transcriptional activity, suggesting a feedback regulation of PPARγ transcriptional activity by NO-mediated S-nitrosylation. Together, these results reveal that S-nitrosoglutathione reductase-dependent modification of PPARγ alters the balance between adipocyte and osteoblast differentiation and provides checkpoint regulation of the lineage bifurcation of these 2 lineages. Moreover, these findings provide pathophysiological and therapeutic insights regarding MSC participation in adipogenesis and osteogenesis.

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