title: Gliotoxin potentiates osteoblast differentiation by inhibiting nuclear factor-κB signaling.
abstract: The differentiation of pluripotent mesenchymal stem cells to mature osteoblasts is crucial for the maintenance of the adult skeleton. In rheumatic arthritis, osteoblast differentiation is impaired by the overproduction of cytokine tumor necrosis factor (TNF)‑α. It has been demonstrated that TNF-α is able to inhibit osteoblast differentiation through the activation of nuclear factor (NF)-κB signaling. As a result of the critical role of TNF-α and NF-κB in the pathogenesis of bone-loss associated diseases, these factors are regarded as key targets for the development of therapeutic agents. In the current study, the role of the NF-κB inhibitor gliotoxin (GTX) in the regulation of osteoblast differentiation was evaluated. The non-toxic GTX doses were determined to be ≤ 3 µg/ml. It was revealed that GTX was able to block TNF-α-induced inhibition of osteoblast differentiation, as indicated by alkaline phosphatase (ALP) activity and ALP staining assays, as well as the expression levels of osteoblast-associated genes Col I, Ocn, Bsp, Runx2, Osx and ATF4. Additionally, it was identified that gliotoxin directly promoted bone morphogenetic protein-2-induced osteoblast differentiation. GTX was found to inhibit the accumulation of NF-κB protein p65 in the nucleus and reduce NF-κB transcriptional activity, suggesting that GTX potentiated osteoblast differentiation via the suppression of NF-κB signaling.
authors: The Third Department of Orthopaedics, Wuhu Second People's Hospital, Wuhu, Anhui 241000, P.R. China.
authors: Guangye
authors: G
authors: Wang
authors: The Third Department of Orthopaedics, Wuhu Second People's Hospital, Wuhu, Anhui 241000, P.R. China.
authors: Xiaohai
authors: X
authors: Zhang
authors: Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Centre, Shanghai 201399, P.R. China.
authors: Baoqing
authors: B
authors: Yu
authors: Department of Orthopedics, Nanjing General Hospital of Nanjing Military Command Region, Nanjing, Jiangsu 210002, P.R. China.
authors: Ke
authors: K
authors: Ren
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005912:Gliotoxin / Q000494:pharmacology*; D058574:Integrin-Binding Sialoprotein / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000470:Alkaloids; C081452:Atf4 protein, mouse; D024042:Collagen Type I; D050659:Core Binding Factor Alpha 1 Subunit; C546872:Ibsp protein, mouse; D058574:Integrin-Binding Sialoprotein; D016328:NF-kappa B; C493716:Runx2 protein, mouse; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D015675:Osteocalcin; D051701:Activating Transcription Factor 4; D005912:Gliotoxin; D000469:Alkaline Phosphatase