Modulation of osteoblastogenesis by NRF2: NRF2 activation suppresses osteogenic differentiation and enhances mineralization in human bone marrow-derived mesenchymal stromal cells
Modulation of osteoblastogenesis by NRF2: NRF2 activation suppresses osteogenic differentiation and enhances mineralization in human bone marrow-derived mesenchymal stromal cells
Mesenchymal stromal stem cells (MSCs) or skeletal stem cells (SSCs) play a major role in tissue repair due to their robust ability to differentiate into osteoblasts, chondrocytes, and adipocytes. Complex cell signaling cascades tightly regulate this differentiation. In osteogenic differentiation, Runt-related transcription factor 2 (RUNX2) and ALP activity are essential. Furthermore, during the latter stages of osteogenic differentiation, mineral formation mediated by the osteoblast occurs with the secretion of a collagenous extracellular matrix and calcium deposition. Activation of nuclear factor erythroid 2-related factor 2 (NRF2), an important transcription factor against oxidative stress, inhibits osteogenic differentiation and mineralization via modulation of RUNX2 function; however, the exact role of NRF2 in osteoblastogenesis remains unclear. Here, we demonstrate that NRF2 activation in human bone marrow-derived stromal cells (HBMSCs) suppressed osteogenic differentiation. NRF2 activation increased the expression of STRO-1 and KITLG (stem cell markers), indicating NRF2 protects HBMSCs stemness against osteogenic differentiation. In contrast, NRF2 activation enhanced mineralization, which is typically linked to osteogenic differentiation. We determined that these divergent results were due in part to the modulation of cellular calcium flux genes by NRF2 activation. The current findings demonstrate a dual role for NRF2 as a HBMSC maintenance factor as well as a central factor in mineralization, with implications therein for elucidation of bone formation and cellular Ca2+ kinetics, dystrophic calcification and, potentially, application in the modulation of bone formation.
Onoki, Takahiro
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Kanczler, Janos
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Rawlings, Andrew
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Smith, Melanie
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Kim, Yang-Hee
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Hashimoto, Ko
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Aizawa, Toshimi
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Oreffo, Richard
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4 September 2024
Onoki, Takahiro
bd12620b-2047-4642-a02d-81c5daa4131a
Kanczler, Janos
eb8db9ff-a038-475f-9030-48eef2b0559c
Rawlings, Andrew
f7d578ff-a012-4f84-b91f-097736b1f483
Smith, Melanie
cadd4fbd-c18f-469f-a44b-1c51d546059d
Kim, Yang-Hee
de0d641b-c2cb-4e73-9ae2-e20d33689f5d
Hashimoto, Ko
19b8f3be-d539-4579-a6cb-936ed0243b27
Aizawa, Toshimi
083391a3-01be-4966-9580-83fc18013363
Oreffo, Richard
ff9fff72-6855-4d0f-bfb2-311d0e8f3778
Onoki, Takahiro, Kanczler, Janos, Rawlings, Andrew, Smith, Melanie, Kim, Yang-Hee, Hashimoto, Ko, Aizawa, Toshimi and Oreffo, Richard
(2024)
Modulation of osteoblastogenesis by NRF2: NRF2 activation suppresses osteogenic differentiation and enhances mineralization in human bone marrow-derived mesenchymal stromal cells.
The FASEB Journal, 38 (17), [e23892].
(doi:10.1096/fj.202400602R).
Abstract
Mesenchymal stromal stem cells (MSCs) or skeletal stem cells (SSCs) play a major role in tissue repair due to their robust ability to differentiate into osteoblasts, chondrocytes, and adipocytes. Complex cell signaling cascades tightly regulate this differentiation. In osteogenic differentiation, Runt-related transcription factor 2 (RUNX2) and ALP activity are essential. Furthermore, during the latter stages of osteogenic differentiation, mineral formation mediated by the osteoblast occurs with the secretion of a collagenous extracellular matrix and calcium deposition. Activation of nuclear factor erythroid 2-related factor 2 (NRF2), an important transcription factor against oxidative stress, inhibits osteogenic differentiation and mineralization via modulation of RUNX2 function; however, the exact role of NRF2 in osteoblastogenesis remains unclear. Here, we demonstrate that NRF2 activation in human bone marrow-derived stromal cells (HBMSCs) suppressed osteogenic differentiation. NRF2 activation increased the expression of STRO-1 and KITLG (stem cell markers), indicating NRF2 protects HBMSCs stemness against osteogenic differentiation. In contrast, NRF2 activation enhanced mineralization, which is typically linked to osteogenic differentiation. We determined that these divergent results were due in part to the modulation of cellular calcium flux genes by NRF2 activation. The current findings demonstrate a dual role for NRF2 as a HBMSC maintenance factor as well as a central factor in mineralization, with implications therein for elucidation of bone formation and cellular Ca2+ kinetics, dystrophic calcification and, potentially, application in the modulation of bone formation.
Text
The FASEB Journal - 2024 - Onoki - Modulation of osteoblastogenesis by NRF2 NRF2 activation suppresses osteogenic
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Accepted/In Press date: 5 August 2024
e-pub ahead of print date: 4 September 2024
Published date: 4 September 2024
Identifiers
Local EPrints ID: 493548
URI: http://eprints.soton.ac.uk/id/eprint/493548
ISSN: 0892-6638
PURE UUID: 4123187e-9374-4830-b6fd-0066deb263eb
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Date deposited: 05 Sep 2024 17:16
Last modified: 06 Sep 2024 02:02
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Contributors
Author:
Takahiro Onoki
Author:
Janos Kanczler
Author:
Andrew Rawlings
Author:
Melanie Smith
Author:
Ko Hashimoto
Author:
Toshimi Aizawa
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