Dexamethasone Induces Changes in Osteogenic Differentiation of Human Mesenchymal Stromal Cells via SOX9 and PPARG, but Not RUNX2

被引:18
|
作者
Della Bella, Elena [1 ]
Buetti-Dinh, Antoine [2 ,3 ]
Licandro, Ginevra [4 ,5 ]
Ahmad, Paras [1 ]
Basoli, Valentina [1 ]
Alini, Mauro [1 ]
Stoddart, Martin J. [1 ,6 ]
机构
[1] AO Res Inst Davos, CH-7270 Davos, Switzerland
[2] Univ Appl Sci Southern Switzerland SUPSI, Dept Environm Construct & Design DACD, Lab Appl Microbiol LMA, CH-6500 Bellinzona, Switzerland
[3] Swiss Inst Bioinformat, Quartier Sorge Batiment Genopode, CH-1015 Lausanne, Switzerland
[4] Univ Italian Switzerland USI, Dalle Molle Inst Artificial Intelligence IDSIA, CH-6928 Manno, Switzerland
[5] Univ Appl Sci & Art Southern Switzerland SUPSI, CH-6928 Manno, Switzerland
[6] Albert Ludwigs Univ Freiburg, Fac Med, Dept Orthoped & Trauma Surg, Med Ctr, D-79106 Freiburg, Germany
关键词
Osteogenesis; glucocorticoids; transcription factors; MSC; gene expression; approximate Bayesian computation (ABC); GLUCOCORTICOID-RECEPTOR; IN-VITRO; OSTEOBLASTIC DIFFERENTIATION; CHONDROCYTE DIFFERENTIATION; ADIPOGENIC DIFFERENTIATION; BONE; TRANSCRIPTION; SIMULATIONS; METASTASIS; S100A4;
D O I
10.3390/ijms22094785
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Despite the huge body of research on osteogenic differentiation and bone tissue engineering, the translation potential of in vitro results still does not match the effort employed. One reason might be that the protocols used for in vitro research have inherent pitfalls. The synthetic glucocorticoid dexamethasone is commonly used in protocols for trilineage differentiation of human bone marrow mesenchymal stromal cells (hBMSCs). However, in the case of osteogenic commitment, dexamethasone has the main pitfall of inhibiting terminal osteoblast differentiation, and its pro-adipogenic effect is well known. In this work, we aimed to clarify the role of dexamethasone in the osteogenesis of hBMSCs, with a particular focus on off-target differentiation. The results showed that dexamethasone does induce osteogenic differentiation by inhibiting SOX9 expression, but not directly through RUNX2 upregulation as it is commonly thought. Rather, PPARG is concomitantly and strongly upregulated, leading to the formation of adipocyte-like cells within osteogenic cultures. Limiting the exposure to dexamethasone to the first week of differentiation did not affect the mineralization potential. Gene expression levels of RUNX2, SOX9, and PPARG were simulated using approximate Bayesian computation based on a simplified theoretical model, which was able to reproduce the observed experimental trends but with a different range of responses, indicating that other factors should be integrated to fully understand how dexamethasone influences cell fate. In summary, this work provides evidence that current in vitro differentiation protocols based on dexamethasone do not represent a good model, and further research is warranted in this field.
引用
收藏
页数:16
相关论文
共 50 条
  • [11] Pax2 is essential for proliferation and osteogenic differentiation of mouse mesenchymal stem cells via Runx2
    Lu, Mengting
    Guo, Shuyu
    Hong, Fangling
    Zhang, Yuxin
    Yuan, Lichan
    Ma, Changyan
    Ma, Junqing
    [J]. EXPERIMENTAL CELL RESEARCH, 2018, 371 (02) : 342 - 352
  • [12] Expression of SATB2, RUNX2, and SOX9 and possible osteoblastic and chondroblastic differentiation in chondroblastoma
    Toda, Yu
    Yamamoto, Hidetaka
    Iwasaki, Takeshi
    Ishihara, Shin
    Ito, Yoshihiro
    Susuki, Yosuke
    Kawaguchi, Kengo
    Kinoshita, Izumi
    Kiyozawa, Daisuke
    Yamada, Yuichi
    Kohashi, Kenichi
    Kimura, Atsushi
    Fujiwara, Toshifumi
    Setsu, Nokitaka
    Endo, Makoto
    Matsumoto, Yoshihiro
    Nakashima, Yasuharu
    Mawatari, Masaaki
    Oda, Yoshinao
    [J]. PATHOLOGY RESEARCH AND PRACTICE, 2023, 241
  • [13] SOX9 is a potent transcriptional repressor for RUNX2 during skeletogenesis
    Zhou, G
    Munivez, E
    Zheng, Q
    Elgin, F
    Fonseca, P
    Chen, Y
    Sebald, E
    Krakow, D
    Lee, B
    [J]. JOURNAL OF BONE AND MINERAL RESEARCH, 2005, 20 (09) : S6 - S6
  • [14] SOX9 Determines RUNX2 Transactivity by Directing Intracellular Degradation
    Cheng, Aixin
    Genever, Paul G.
    [J]. JOURNAL OF BONE AND MINERAL RESEARCH, 2010, 25 (12) : 2404 - 2413
  • [15] Dominance of SOX9 function over RUNX2 during skeletogenesis
    Zhou, Guang
    Zheng, Qiping
    Engin, Feyza
    Munivez, Elda
    Chen, Yuqing
    Sebald, Eiman
    Krakow, Deborah
    Lee, Brendan
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (50) : 19004 - 19009
  • [16] BIMODAL EFFECTS OF DEXAMETHASONE ON OSTEOGENIC DIFFERENTIATION OF MESENCHYMAL STROMAL CELLS
    Rimando, M. G.
    Wu, H.
    Lee, C.
    Kuo, S.
    Lo, Y.
    Liu, Y.
    Lee, O.
    [J]. CYTOTHERAPY, 2016, 18 (06) : S49 - S50
  • [17] Tranilast stimulates endochondral ossification by upregulating SOX9 and RUNX2 promoters
    Hasegawa, Sachi
    Kitoh, Hiroshi
    Ohkawara, Bisei
    Mishima, Kenichi
    Matsushita, Masaki
    Masuda, Akio
    Ishiguro, Naoki
    Ohno, Kinji
    [J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2016, 470 (02) : 356 - 361
  • [18] Hierarchy revealed in the specification of three skeletal fates by Sox9 and Runx2
    Eames, BF
    Sharpe, PT
    Helms, JA
    [J]. DEVELOPMENTAL BIOLOGY, 2004, 274 (01) : 188 - 200
  • [19] Regulation of Runx2 by microRNA-9 and microRNA-10 modulates the osteogenic differentiation of mesenchymal stem cells
    Luo, Hong
    Gao, Hualin
    Liu, Fang
    Qiu, Bing
    [J]. INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, 2017, 39 (04) : 1046 - 1052
  • [20] Vascular endothelial growth factor-C induces osteogenic differentiation of human mesenchymal stem cells through the ERK and RUNX2 pathway
    Murakami, Juri
    Ishii, Masakazu
    Suehiro, Fumio
    Ishihata, Kiyohide
    Nakamura, Norifumi
    Nishimura, Masahiro
    [J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2017, 484 (03) : 710 - 718