title: All-trans retinoic acid shifts rosiglitazone-induced adipogenic differentiation to osteogenic differentiation in mouse embryonic fibroblasts.
abstract: Rosiglitazone (RSG) is a potent drug used in the treatment of insulin resistance; however, it is associated with marked skeletal toxicity. RSG-induced osteoporosis may contribute to the promotion of adipogenic differentiation at the expense of osteogenic differentiation in bone marrow stromal cells. The aim of this study was to investigate whether RSG-induced bone toxicity can be reversed by combined treatment with all-trans retinoic acid (ATRA). We examined different osteogenic markers in mouse embryonic fibroblasts (MEFs) following treatment with RSG, ATRA, or RSG and ATRA in combination. We examined the effects of RSG and/or ATRA on ectopic bone formation, and dissected the possible molecular mechanisms underlying this process. We found that ATRA or RSG both induced alkaline phosphatase (ALP) activity in the MEFs, and that the ATRA-induced ALP activity was enhanced by RSG and vice versa. However, only the combination of RSG and ATRA increased the expression of osteopontin and osteocalcin, promoted matrix mineralization, and induced ectopic ossification in MEFs. Mechanistically, we found that the osteogenic differentiation induced by the combination of RSG and ATRA may be mediated partly by suppressing RSG-induced adipogenic differentiation and activating bone morphogenetic protein (BMP)/Smad signaling. On the whole, our findings demonstrate that RSG in combination with ATRA promotes the commitment of MEFs to the osteoblast lineage. Thus, the combination of these two agents may prove to be a promising and novel therapeutic regimen for insulin resistance without skeletal toxicity. It may also be a better strategy with which to prevent RSG-induced osteoporosis.
authors: Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, Sichuan 400016, P.R. China.
authors: Ying
authors: Y
authors: Shao
authors: Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, Sichuan 400016, P.R. China.
authors: Qian-Zhao
authors: QZ
authors: Chen
authors: Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, Sichuan 400016, P.R. China.
authors: Yu-Hua
authors: YH
authors: Zeng
authors: Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, Sichuan 400016, P.R. China.
authors: Yang
authors: Y
authors: Li
authors: Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, Sichuan 400016, P.R. China.
authors: Wen-Yan
authors: WY
authors: Ren
authors: Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, Sichuan 400016, P.R. China.
authors: Lin-Yun
authors: LY
authors: Zhou
authors: Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, Sichuan 400016, P.R. China.
authors: Rong-Xin
authors: RX
authors: Liu
authors: Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, Sichuan 400016, P.R. China.
authors: Ke
authors: K
authors: Wu
authors: Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, Sichuan 400016, P.R. China.
authors: Jun-Qing
authors: JQ
authors: Yang
authors: Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing, Sichuan 400016, P.R. China.
authors: Zhong-Liang
authors: ZL
authors: Deng
authors: Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, Sichuan 400016, P.R. China.
authors: Yu
authors: Y
authors: Yu
authors: Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, Sichuan 400016, P.R. China.
authors: Wen-Juan
authors: WJ
authors: Sun
authors: Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, Sichuan 400016, P.R. China.
authors: Bai-Cheng
authors: BC
authors: He
mesh_terms: D050156:Adipogenesis / Q000187:drug effects* / Q000235:genetics; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D051379:Mice; D010012:Osteogenesis / Q000187:drug effects* / Q000235:genetics; D047495:PPAR gamma / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D047488:Retinoid X Receptors / Q000378:metabolism; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; D047495:PPAR gamma; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D051785:Smad Proteins; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D014212:Tretinoin; D000469:Alkaline Phosphatase