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

0562691 - FGÚ 2023 RIV NL eng J - Článek v odborném periodiku
Beňová, Andrea - Ferenčáková, Michaela - Bardová, Kristina - Funda, Jiří - Procházka, Jan - Špoutil, František - Čajka, Tomáš - Džubanová, Martina - Balcaen, T. - Kerckhofs, G. - Willekens, W. - van Lenthe, G. H. - Alquicer, Glenda - Pecinová, Alena - Mráček, Tomáš - Horáková, Olga - Rossmeisl, Martin - Kopecký, Jan - Tencerová, Michaela
Novel thiazolidinedione analog reduces a negative impact on bone and mesenchymal stem cell properties in obese mice compared to classical thiazolidinediones.
Molecular Metabolism. Roč. 65, Nov (2022), č. článku 101598. ISSN 2212-8778. E-ISSN 2212-8778
Grant CEP: GA ČR(CZ) GA20-03586S; GA ČR(CZ) GA19-02411S; GA MŠMT(CZ) LX22NPO5104
Grant ostatní: Novo Nordisk Fonden(DK) NNF20SA0066174
Institucionální podpora: RVO:67985823 ; RVO:68378050
Klíčová slova: obesity-induced bone fragility * bone microstructure * bone marrow mesenchymal stem cells * bone marrow adiposity * thiazolidinedione analog MSDC-0602K * pioglitazone
Obor OECD: Physiology (including cytology)
Impakt faktor: 8.1, rok: 2022
Způsob publikování: Open access
https://doi.org/10.1016/j.molmet.2022.101598

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.
Trvalý link: https://hdl.handle.net/11104/0334944