PMID- 25486498 OWN - NLM STAT- MEDLINE DCOM- 20151001 LR - 20220309 IS - 1876-7737 (Electronic) IS - 1874-3919 (Linking) VI - 114 DP - 2015 Jan 30 TI - Quantitative proteomics reveals ELP2 as a regulator to the inhibitory effect of TNF-alpha on osteoblast differentiation. PG - 234-46 LID - S1874-3919(14)00507-7 [pii] LID - 10.1016/j.jprot.2014.11.002 [doi] AB - TNF-alpha, one of the most potent pro-inflammatory cytokines, plays a critical role in inhibition of osteoblast differentiation and bone regeneration in persistent inflammatory microenvironment. To explore the mechanism, quantitative proteomics based on iTRAQ and MRM was employed. The results showed 6 proteins involved in BMP-2 induced osteoblast differentiation inhibition by TNF-alpha: Periostin, Protein S100-A4, ATPase inhibitor, Cytochrome b5, SERCA3, and ELP2. The altered proteins were involved in molecular transport, tissue development, energy metabolism, and inflammation. One specific protein, ELP2 (STAT3-interacting protein 1, StIP1) up-regulated in the inhibition of osteoblast differentiation by TNF-alpha was verified to play a critical role in STAT3 pathway. Overexpression or knockdown of ELP2 in C2C12 and MC3T3-E1 cells affected osteoblast differentiation inhibition induced by TNF-alpha. These results highlight the function of ELP2 in inflammatory microenvironment, ELP2 up-regulation and STAT3 pathway activation may down-regulate BMPR2, then BMP-2 was blocked and osteoblast differentiation inhibited. The protein-expression profile revealed here should offer at least partly new clues to understand the mechanism of osteoblast differentiation inhibition by inflammation. BIOLOGICAL SIGNIFICANCE: Persistent inflammation is always associated with osteogenesis and affects this balance to reduce bone mass including traumatic open bone fracture, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), but the cellular mechanisms are not fully elucidated. Tumor necrosis factor-alpha (TNF-alpha) is one of the most potent pro-inflammatory cytokines and is known to be a catabolic factor in these inflammatory reaction of diseases. We show for the first time using proteomics methods that in inflammatory microenvironment, osteoblast differentiation will be inhibited by TNF-alpha induced ELP2 up-regulation and STAT3 pathway activation. Our results are significant since they point to targeting ELP2 activity as a novel therapeutic option to limit the inhibition of osteoblast differentiation by inflammatory microenvironment. CI - Copyright (c) 2014 Elsevier B.V. All rights reserved. FAU - Xu, Chang-Peng AU - Xu CP AD - Guangzhou Institute of Traumatic Surgery, The Fourth Affiliated Hospital of Medical College, Jinan University, Guangzhou, Guangdong, People's Republic of China; Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China. FAU - Li, Xue AU - Li X AD - Department of Orthopaedics, Foshan Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Foshan, Guangdong, People's Republic of China; Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China. FAU - Hu, Yan-Jun AU - Hu YJ AD - Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China. FAU - Cui, Zhuang AU - Cui Z AD - Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China. FAU - Wang, Lei AU - Wang L AD - Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China. FAU - Liang, Liang AU - Liang L AD - Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China. FAU - Zhou, Yi-Lin AU - Zhou YL AD - Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China. FAU - Yang, Ya-Jun AU - Yang YJ AD - Department of Pharmacology, Guangdong Medical College, Zhanjiang, Guangdong, People's Republic of China. FAU - Yu, Bin AU - Yu B AD - Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China. Electronic address: hospitalnanfang@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20141206 PL - Netherlands TA - J Proteomics JT - Journal of proteomics JID - 101475056 RN - 0 (Elp2 protein, mouse) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Tumor Necrosis Factor-alpha) SB - IM MH - Amino Acid Sequence MH - Animals MH - Cell Differentiation/*drug effects MH - Cells, Cultured MH - Cellular Microenvironment MH - Down-Regulation/drug effects MH - Inflammation/metabolism/pathology MH - Intracellular Signaling Peptides and Proteins/chemistry/metabolism/*physiology MH - Mice MH - Molecular Sequence Data MH - Osteoblasts/*drug effects/physiology MH - Protein Interaction Mapping MH - Proteomics/methods MH - Tumor Necrosis Factor-alpha/*pharmacology OTO - NOTNLM OT - ELP2 OT - MRM OT - Osteoblast differentiation OT - Quantitative proteomics OT - TNF-alpha OT - iTRAQ EDAT- 2014/12/09 06:00 MHDA- 2015/10/02 06:00 CRDT- 2014/12/09 06:00 PHST- 2014/05/04 00:00 [received] PHST- 2014/10/11 00:00 [revised] PHST- 2014/11/04 00:00 [accepted] PHST- 2014/12/09 06:00 [entrez] PHST- 2014/12/09 06:00 [pubmed] PHST- 2015/10/02 06:00 [medline] AID - S1874-3919(14)00507-7 [pii] AID - 10.1016/j.jprot.2014.11.002 [doi] PST - ppublish SO - J Proteomics. 2015 Jan 30;114:234-46. doi: 10.1016/j.jprot.2014.11.002. Epub 2014 Dec 6.