Cooperative impact of thiazolidinedione and fatty acid synthase on human osteogenesis

• Published in: Aging (Albany, NY.) NY.), 2019-04, Vol.11 (8), p.2327-2342
• Main Authors: Chen, Ching-Yun, Tseng, Kuo-Yun, Wong, Zhe-Hong, Chen, Ya-Ping, Chen, Ting-Yu, Chen, Hsuan-Ying, Chen, Zih-Ying, Lin, Feng-Huei, Wu, Hung-Ming, Lin, Shankung
• Format: Article
• Language: English
• Subjects: Adipocytes - cytology; Adipocytes - drug effects; Adipocytes - metabolism; Adipogenesis - drug effects; Bone Marrow Cells - cytology; Bone Marrow Cells - drug effects; Bone Marrow Cells - metabolism; Cell Line; DNA-Binding Proteins - metabolism; Fatty Acid Synthases - genetics; Fatty Acid Synthases - metabolism; Gene Knockdown Techniques; Humans; Male; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - drug effects; Mesenchymal Stem Cells - metabolism; Middle Aged; Osteoblasts - cytology; Osteoblasts - drug effects; Osteoblasts - metabolism; Osteogenesis - drug effects; Research Paper; Thiazolidinediones - pharmacology
• ISSN: 1945-4589; 1945-4589
• DOI: 10.18632/aging.101916

Previous, we found that the small molecules capable of inhibiting the expression and the pro-adipogenic activity of ZNF521 might improve the osteogenic performance of aging human bone marrow MSCs (bmMSCs), and that fatty acid synthase (FASN) was a critical effector of ZNF521's pro-adipogenic activity. Here, by characterizing the netoglitazone (MCC-555), one of the thiazolidinediones known as adipogenic enhancers, as an inhibitor of ZNF521 expression, we found that MCC-555 indeed also harbored pro-osteoblastic effect. Investigation revealed that MCC-555 might function as a GSK3β inhibitor to promote osteoblastogenesis and bone formation. Importantly, combination of MCC-555 with FASN knockdown, but not with GW9662 (a PPARγ2 antagonist), blocked the pro-adipogenic but retained the pro-osteoblastic effect of MCC-555. Using a 3-dimentional culture system, we showed that MCC-555 facilitated the FASN-knockdown of aging human bmMSCs to form cell clusters in scaffolds, and to promote osteoblastic differentiation and biomineralization in cell clusters. These data indicated that MCC-555 promoted bmMSCs to produce bone-like tissues. Our data narrate a thiazolidinedione-based novel strategy to improve the osteogenic performance of aging bmMSCs to support the application of autologous aging bmMSCs in cell therapy and in producing bone-like tissues for repairing bone injury in the elderly.