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.

• Klíčová slova
• Bone marrow adiposity, Bone marrow mesenchymal stem cells, Bone microstructure, Obesity-induced bone fragility, Pioglitazone, Thiazolidinedione analog MSDC-0602K,
• MeSH
• antigen stromálních buněk kostní dřeně metabolismus   farmakologie   MeSH
• glukosa metabolismus   MeSH
• glutamin metabolismus   MeSH
• hypoglykemika farmakologie   MeSH
• inzulin metabolismus   MeSH
• lidé MeSH
• mezenchymální kmenové buňky * metabolismus   MeSH
• myši obézní MeSH
• myši MeSH
• obezita farmakoterapie   metabolismus   MeSH
• pioglitazon metabolismus   farmakologie   MeSH
• PPAR gama metabolismus   MeSH
• spirosloučeniny MeSH
• thiazolidindiony * farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 10-methyl spiro(4.5)dec-6-en-6-carboxylic acid MeSH Prohlížeč
• 2,4-thiazolidinedione MeSH Prohlížeč
• antigen stromálních buněk kostní dřeně MeSH
• glukosa MeSH
• glutamin MeSH
• hypoglykemika MeSH
• inzulin MeSH
• pioglitazon MeSH
• PPAR gama MeSH
• spirosloučeniny MeSH
• thiazolidindiony * MeSH