Novel thiazolidinedione analog reduces a negative impact on bone and mesenchymal stem cell properties in obese mice compared to classical thiazolidinediones.

Autor:	Benova A; Laboratory of Molecular Physiology of Bone, Institute of Physiology of the Czech Academy of Sciences, Prague 142 20, Czech Republic; Faculty of Science, Charles University, Prague, Czech Republic., Ferencakova M; Laboratory of Molecular Physiology of Bone, Institute of Physiology of the Czech Academy of Sciences, Prague 142 20, Czech Republic., Bardova K; Laboratory of Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences, Prague 142 20, Czech Republic., Funda J; Laboratory of Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences, Prague 142 20, Czech Republic., Prochazka J; Czech Centre for Phenogenomics & Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic., Spoutil F; Czech Centre for Phenogenomics & Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic., Cajka T; Laboratory of Translational Metabolism, Institute of Physiology of the Czech Academy of Sciences, Prague 142 20, Czech Republic., Dzubanova M; Laboratory of Molecular Physiology of Bone, Institute of Physiology of the Czech Academy of Sciences, Prague 142 20, Czech Republic; Faculty of Science, Charles University, Prague, Czech Republic., Balcaen T; Biomechanics lab, Institute of Mechanics, Materials, and Civil Engineering, UCLouvain, Louvain-la-Neuve, Belgium; Pole of Morphology, Institute for Experimental and Clinical Research, UCLouvain, Brussels, Belgium; Department of Chemistry, Molecular Design and Synthesis, KU Leuven, Leuven, Belgium., Kerckhofs G; Biomechanics lab, Institute of Mechanics, Materials, and Civil Engineering, UCLouvain, Louvain-la-Neuve, Belgium; Department of Materials Engineering, KU Leuven, Belgium; Prometheus, Division of Skeletal Tissue Engineering, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; Pole of Morphology, Institute for Experimental and Clinical Research, UCLouvain, Brussels, Belgium., Willekens W; FIBEr, KU Leuven, Leuven, Belgium., van Lenthe GH; Department of Mechanical Engineering, KU Leuven, Leuven, Belgium., Alquicer G; Laboratory of Molecular Physiology of Bone, Institute of Physiology of the Czech Academy of Sciences, Prague 142 20, Czech Republic., Pecinova A; Laboratory of Bioenergetics, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic., Mracek T; Laboratory of Bioenergetics, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic., Horakova O; Laboratory of Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences, Prague 142 20, Czech Republic., Rossmeisl M; Laboratory of Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences, Prague 142 20, Czech Republic., Kopecky J; Laboratory of Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences, Prague 142 20, Czech Republic., Tencerova M; Laboratory of Molecular Physiology of Bone, Institute of Physiology of the Czech Academy of Sciences, Prague 142 20, Czech Republic. Electronic address: michaela.tencerova@fgu.cas.cz.
Jazyk:	angličtina
Zdroj:	Molecular metabolism [Mol Metab] 2022 Nov; Vol. 65, pp. 101598. Date of Electronic Publication: 2022 Sep 11.
DOI:	10.1016/j.molmet.2022.101598
Abstrakt:	Objective: The use of thiazolidinediones (TZDs) as insulin sensitizers has been shown to have side effects including increased accumulation of bone marrow adipocytes (BMAds) associated with a higher fracture risk and bone loss. A novel TZD analog MSDC-0602K with low affinity to PPARγ has been developed to reduce adverse effects of TZD therapy. However, the effect of MSDC-0602K on bone phenotype and bone marrow mesenchymal stem cells (BM-MSCs) in relation to obesity has not been intensively studied yet. Methods: Here, we investigated whether 8-week treatment with MSDC-0602K has a less detrimental effect on bone loss and BM-MSC properties in obese mice in comparison to first generation of TZDs, pioglitazone. Bone parameters (bone microstructure, bone marrow adiposity, bone strength) were examined by μCT and 3-point bending test. Primary BM-MSCs were isolated and measured for osteoblast and adipocyte differentiation. Cellular senescence, bioenergetic profiling, nutrient consumption and insulin signaling were also determined. Results: The findings demonstrate that MSDC-0602K improved bone parameters along with increased proportion of smaller BMAds in tibia of obese mice when compared to pioglitazone. Further, primary BM-MSCs isolated from treated mice and human BM-MSCs revealed decreased adipocyte and higher osteoblast differentiation accompanied with less inflammatory and senescent phenotype induced by MSDC-0602K vs. pioglitazone. These changes were further reflected by increased glycolytic activity differently affecting glutamine and glucose cellular metabolism in MSDC-0602K-treated cells compared to pioglitazone, associated with higher osteogenesis. Conclusion: Our study provides novel insights into the action of MSDC-0602K in obese mice, characterized by the absence of detrimental effects on bone quality and BM-MSC metabolism when compared to classical TZDs and thus suggesting a potential therapeutical use of MSDC-0602K in both metabolic and bone diseases. (Copyright © 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
Databáze:	MEDLINE
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