PMID- 29137952 OWN - NLM STAT- MEDLINE DCOM- 20190422 LR - 20221017 IS - 1525-2191 (Electronic) IS - 0002-9440 (Print) IS - 0002-9440 (Linking) VI - 188 IP - 2 DP - 2018 Feb TI - Neural EGFL-Like 1 Regulates Cartilage Maturation through Runt-Related Transcription Factor 3-Mediated Indian Hedgehog Signaling. PG - 392-403 LID - S0002-9440(17)30767-8 [pii] LID - 10.1016/j.ajpath.2017.09.020 [doi] AB - The pro-chondrogenic function of runt-related transcription factor 2 (Runx2) was previously considered to be dependent on direct binding with the promoter of Indian hedgehog (Ihh)-the major regulator of chondrocyte differentiation, proliferation, and maturation. The authors' previous studies identified neural EGFL like 1 (Nell-1) as a Runx2-responsive growth factor for chondrogenic differentiation and maturation. In this study, it was further revealed that the pro-chondrogenic activities of Nell-1 also rely on Ihh signaling, by showing: i) Nell-1 significantly elevated Ihh signal transduction; ii) Nell-1 deficiency markedly reduced Ihh activation in chondrocytes; and iii) Nell-1-stimulated chondrogenesis was significantly reduced by the specific hedgehog inhibitor cyclopamine. Importantly, the authors demonstrated that Nell-1-responsive Ihh signaling and chondrogenic differentiation extended to Runx2(-/-) models in vitro and in vivo. In Runx2(-/-) chondrocytes, Nell-1 stimulated the expression and signal transduction of Runx3, another transcription factor required for complete chondrogenic differentiation and maturation. Furthermore, knocking down Runx3 in Runx2(-/-) chondrocytes abolished Nell-1's stimulation of Ihh-associated molecule expression, which validates Runx3 as a major mediator of Nell-1-stimulated Ihh activation. For the first time, the Runx2-->Nell-1-->Runx3-->Ihh signaling cascade during chondrogenic differentiation and maturation has been identified as an alternative, but critical, pathway for Runx2 to function as a pro-chondrogenic molecule via Nell-1. CI - Copyright (c) 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. FAU - Li, Chenshuang AU - Li C AD - Section of Orthodontics, Division of Growth and Development, School of Dentistry, University of California, Los Angeles, California; Department of Orthodontics, Peking University, School and Hospital of Stomatology, Beijing, People's Republic of China. FAU - Zheng, Zhong AU - Zheng Z AD - Section of Orthodontics, Division of Growth and Development, School of Dentistry, University of California, Los Angeles, California. FAU - Jiang, Jie AU - Jiang J AD - UCLA Division of Plastic and Reconstructive Surgery and Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, University of California, Los Angeles, California. FAU - Jiang, Wenlu AU - Jiang W AD - Section of Orthodontics, Division of Growth and Development, School of Dentistry, University of California, Los Angeles, California; State Key Laboratory of Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, People's Republic of China. FAU - Lee, Kevin AU - Lee K AD - Section of Orthodontics, Division of Growth and Development, School of Dentistry, University of California, Los Angeles, California. FAU - Berthiaume, Emily A AU - Berthiaume EA AD - David Geffen School of Medicine at UCLA, University of California, Los Angeles, California. FAU - Chen, Eric C AU - Chen EC AD - Section of Orthodontics, Division of Growth and Development, School of Dentistry, University of California, Los Angeles, California. FAU - Culiat, Cymbeline T AU - Culiat CT AD - Oak Ridge National Laboratory, Oak Ridge, Tennessee. FAU - Zhou, Yan-Heng AU - Zhou YH AD - Department of Orthodontics, Peking University, School and Hospital of Stomatology, Beijing, People's Republic of China. FAU - Zhang, Xinli AU - Zhang X AD - Section of Orthodontics, Division of Growth and Development, School of Dentistry, University of California, Los Angeles, California. FAU - Ting, Kang AU - Ting K AD - Section of Orthodontics, Division of Growth and Development, School of Dentistry, University of California, Los Angeles, California; UCLA Division of Plastic and Reconstructive Surgery and Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, University of California, Los Angeles, California. Electronic address: kting@dentistry.ucla.edu. FAU - Soo, Chia AU - Soo C AD - UCLA Division of Plastic and Reconstructive Surgery and Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, University of California, Los Angeles, California. Electronic address: bsoo@ucla.edu. LA - eng GR - R01 AR061399/AR/NIAMS NIH HHS/United States GR - R01 AR066782/AR/NIAMS NIH HHS/United States GR - R01 AR068835/AR/NIAMS NIH HHS/United States GR - UL1 TR000124/TR/NCATS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20171111 PL - United States TA - Am J Pathol JT - The American journal of pathology JID - 0370502 RN - 0 (Calcium-Binding Proteins) RN - 0 (Core Binding Factor Alpha 1 Subunit) RN - 0 (Core Binding Factor Alpha 3 Subunit) RN - 0 (Glycoproteins) RN - 0 (Hedgehog Proteins) RN - 0 (Nell1 protein, mouse) RN - 0 (Runx2 protein, mouse) RN - 0 (Runx3 protein, mouse) RN - 0 (ihh protein, mouse) SB - IM MH - Animals MH - Calcium-Binding Proteins/*physiology MH - Cartilage/cytology/physiology MH - Cell Differentiation/physiology MH - Cells, Cultured MH - Chondrocytes/cytology/*physiology MH - Chondrogenesis/physiology MH - Core Binding Factor Alpha 1 Subunit/deficiency/*physiology MH - Core Binding Factor Alpha 3 Subunit/physiology MH - Glycoproteins/*physiology MH - Hedgehog Proteins/*physiology MH - Mice, Knockout MH - Signal Transduction/physiology PMC - PMC5785559 EDAT- 2017/11/16 06:00 MHDA- 2019/04/23 06:00 PMCR- 2019/02/01 CRDT- 2017/11/16 06:00 PHST- 2017/07/25 00:00 [received] PHST- 2017/09/02 00:00 [revised] PHST- 2017/09/26 00:00 [accepted] PHST- 2017/11/16 06:00 [pubmed] PHST- 2019/04/23 06:00 [medline] PHST- 2017/11/16 06:00 [entrez] PHST- 2019/02/01 00:00 [pmc-release] AID - S0002-9440(17)30767-8 [pii] AID - 10.1016/j.ajpath.2017.09.020 [doi] PST - ppublish SO - Am J Pathol. 2018 Feb;188(2):392-403. doi: 10.1016/j.ajpath.2017.09.020. Epub 2017 Nov 11.