TGFβ1 Suppressed Matrix Mineralization of Osteoblasts Differentiation by Regulating SMURF1–C/EBPβ–DKK1 Axis
Transforming growth factor β1 (TGFβ1) is a major mediator in the modulation of osteoblast differentiation. However, the underlying molecular mechanism is still not fully understood. Here, we show that TGFβ1 has a dual stage-dependent role in osteoblast differentiation; TGFβ1 induced matrix maturatio...
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MDPI AG
2020-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/24/9771 |
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| author | Bora Nam Hyosun Park Young Lim Lee Younseo Oh Jinsung Park So Yeon Kim Subin Weon Sung Hoon Choi Jae-Hyuk Yang Sungsin Jo Tae-Hwan Kim |
| author_facet | Bora Nam Hyosun Park Young Lim Lee Younseo Oh Jinsung Park So Yeon Kim Subin Weon Sung Hoon Choi Jae-Hyuk Yang Sungsin Jo Tae-Hwan Kim |
| author_sort | Bora Nam |
| collection | DOAJ |
| description | Transforming growth factor β1 (TGFβ1) is a major mediator in the modulation of osteoblast differentiation. However, the underlying molecular mechanism is still not fully understood. Here, we show that TGFβ1 has a dual stage-dependent role in osteoblast differentiation; TGFβ1 induced matrix maturation but inhibited matrix mineralization. We discovered the underlying mechanism of the TGFβ1 inhibitory role in mineralization using human osteoprogenitors. In particular, the matrix mineralization-related genes of osteoblasts such as osteocalcin (OCN), Dickkopf 1 (DKK1), and CCAAT/enhancer-binding protein beta (C/EBPβ) were dramatically suppressed by TGFβ1 treatment. The suppressive effects of TGFβ1 were reversed with anti-TGFβ1 treatment. Mechanically, TGFβ1 decreased protein levels of C/EBPβ without changing mRNA levels and reduced both mRNA and protein levels of DKK1. The degradation of the C/EBPβ protein by TGFβ1 was dependent on the ubiquitin–proteasome pathway. TGFβ1 degraded the C/EBPβ protein by inducing the expression of the E3 ubiquitin ligase Smad ubiquitin regulatory factor 1 (SMURF1) at the transcript level, thereby reducing the C/EBPβ-DKK1 regulatory mechanism. Collectively, our findings suggest that TGFβ1 suppressed the matrix mineralization of osteoblast differentiation by regulating the SMURF1-C/EBPβ-DKK1 axis. |
| first_indexed | 2024-03-10T13:52:58Z |
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| id | doaj.art-3877f0fcac7d45a2a618b0d84799894d |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T13:52:58Z |
| publishDate | 2020-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-3877f0fcac7d45a2a618b0d84799894d2023-11-21T01:56:32ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-12-012124977110.3390/ijms21249771TGFβ1 Suppressed Matrix Mineralization of Osteoblasts Differentiation by Regulating SMURF1–C/EBPβ–DKK1 AxisBora Nam0Hyosun Park1Young Lim Lee2Younseo Oh3Jinsung Park4So Yeon Kim5Subin Weon6Sung Hoon Choi7Jae-Hyuk Yang8Sungsin Jo9Tae-Hwan Kim10Institute for Rheumatology Research, Hanyang University, Seoul 04763, KoreaInstitute for Rheumatology Research, Hanyang University, Seoul 04763, KoreaInstitute for Rheumatology Research, Hanyang University, Seoul 04763, KoreaInstitute for Rheumatology Research, Hanyang University, Seoul 04763, KoreaInstitute for Rheumatology Research, Hanyang University, Seoul 04763, KoreaInstitute for Rheumatology Research, Hanyang University, Seoul 04763, KoreaInstitute for Rheumatology Research, Hanyang University, Seoul 04763, KoreaDepartment of Orthopedic Surgery, Hanyang University Seoul Hospital, Seoul 04763, KoreaDepartment of Orthopedic Surgery, Hanyang University Guri Hospital, Guri 11923, KoreaInstitute for Rheumatology Research, Hanyang University, Seoul 04763, KoreaInstitute for Rheumatology Research, Hanyang University, Seoul 04763, KoreaTransforming growth factor β1 (TGFβ1) is a major mediator in the modulation of osteoblast differentiation. However, the underlying molecular mechanism is still not fully understood. Here, we show that TGFβ1 has a dual stage-dependent role in osteoblast differentiation; TGFβ1 induced matrix maturation but inhibited matrix mineralization. We discovered the underlying mechanism of the TGFβ1 inhibitory role in mineralization using human osteoprogenitors. In particular, the matrix mineralization-related genes of osteoblasts such as osteocalcin (OCN), Dickkopf 1 (DKK1), and CCAAT/enhancer-binding protein beta (C/EBPβ) were dramatically suppressed by TGFβ1 treatment. The suppressive effects of TGFβ1 were reversed with anti-TGFβ1 treatment. Mechanically, TGFβ1 decreased protein levels of C/EBPβ without changing mRNA levels and reduced both mRNA and protein levels of DKK1. The degradation of the C/EBPβ protein by TGFβ1 was dependent on the ubiquitin–proteasome pathway. TGFβ1 degraded the C/EBPβ protein by inducing the expression of the E3 ubiquitin ligase Smad ubiquitin regulatory factor 1 (SMURF1) at the transcript level, thereby reducing the C/EBPβ-DKK1 regulatory mechanism. Collectively, our findings suggest that TGFβ1 suppressed the matrix mineralization of osteoblast differentiation by regulating the SMURF1-C/EBPβ-DKK1 axis.https://www.mdpi.com/1422-0067/21/24/9771osteoblast differentiationmineralizationTGFβ1SMURF1C/EBPβDKK1 |
| spellingShingle | Bora Nam Hyosun Park Young Lim Lee Younseo Oh Jinsung Park So Yeon Kim Subin Weon Sung Hoon Choi Jae-Hyuk Yang Sungsin Jo Tae-Hwan Kim TGFβ1 Suppressed Matrix Mineralization of Osteoblasts Differentiation by Regulating SMURF1–C/EBPβ–DKK1 Axis International Journal of Molecular Sciences osteoblast differentiation mineralization TGFβ1 SMURF1 C/EBPβ DKK1 |
| title | TGFβ1 Suppressed Matrix Mineralization of Osteoblasts Differentiation by Regulating SMURF1–C/EBPβ–DKK1 Axis |
| title_full | TGFβ1 Suppressed Matrix Mineralization of Osteoblasts Differentiation by Regulating SMURF1–C/EBPβ–DKK1 Axis |
| title_fullStr | TGFβ1 Suppressed Matrix Mineralization of Osteoblasts Differentiation by Regulating SMURF1–C/EBPβ–DKK1 Axis |
| title_full_unstemmed | TGFβ1 Suppressed Matrix Mineralization of Osteoblasts Differentiation by Regulating SMURF1–C/EBPβ–DKK1 Axis |
| title_short | TGFβ1 Suppressed Matrix Mineralization of Osteoblasts Differentiation by Regulating SMURF1–C/EBPβ–DKK1 Axis |
| title_sort | tgfβ1 suppressed matrix mineralization of osteoblasts differentiation by regulating smurf1 c ebpβ dkk1 axis |
| topic | osteoblast differentiation mineralization TGFβ1 SMURF1 C/EBPβ DKK1 |
| url | https://www.mdpi.com/1422-0067/21/24/9771 |
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