Research Paper Volume 11, Issue 8 pp 2327—2342

Cooperative impact of thiazolidinedione and fatty acid synthase on human osteogenesis

Ching-Yun Chen 1, 2, *, , Kuo-Yun Tseng 3, *, , Zhe-Hong Wong 4, , Ya-Ping Chen 5, , Ting-Yu Chen 5, , Hsuan-Ying Chen 5, , Zih-Ying Chen 5, , Feng-Huei Lin 1, 2, , Hung-Ming Wu 5, 6, 7, , Shankung Lin 5, 8, ,

  • 1 Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taiwan, Republic of China
  • 2 Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Taiwan, Republic of China
  • 3 Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Taiwan, Republic of China
  • 4 Department of Orthopedics, National Taiwan University Hospital, Hsin-chu Branch, Taiwan, Republic of China
  • 5 Inflammation Research and Drug Development Center, Taiwan, Republic of China
  • 6 Department of Neurology, Changhua Christian Hospital, Taiwan, Republic of China
  • 7 Graduate Institute of Acupuncture Science, China Medical University, Taiwan, Republic of China
  • 8 Graduate Institute of Biomedical Sciences, China Medical University, Taiwan, Republic of China
* Equal contribution

received: December 21, 2018 ; accepted: April 10, 2019 ; published: April 20, 2019 ;

https://doi.org/10.18632/aging.101916
How to Cite

Copyright: Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

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.

Abbreviations

ZNF521: Zinc finger factor 521; bmMSC: Bone marrow mesenchymal stem cell; TZD: Thiazolidinedione; FASN: Fatty acid synthase; CPC: Cetylpyridinium chloride; GSK3β: Glycogen synthase kinase 3β; RT-qPCR: Real-time quantitative polymerase chain reaction; OC: Osteocalcin; OP: Osteopontin; SEM: Scanning electron microscopy; ALP: Alkaline phosphatase; RUNX2: Runt-related transcription factor 2; PPARγ: Peroxisome proliferator-activated receptor γ.