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.
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页数:16
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