한빛사 논문
Seoyeon Bok1,8, Dong Yeon Shin1,2,8, Alisha R. Yallowitz1, Mark Eiseman1, Michelle Cung1, Ren Xu3, Na Li3, Jun Sun1, Alfred L. Williams4, John E. Scott4, Bing Su5,6, Jae-Hyuck Shim7 & Matthew B. Greenblatt1,*
1Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA. 2Research Center, LegoChem BioSciences, INC., Daejeon 34302, South Korea. 3State Key Laboratory of Cellular Stress Biology, School of Medicine, Xiamen University, 361102 Xiamen, Fujian, China. 4Department of Pharmaceutical Sciences, Biomanufacturing Research Institute and Technology Enterprise (BRITE), North Carolina Central University, Durham, NC 27707, USA. 5Department of Immunology and Microbiology, and the Minister of Education Key Laboratory of Cell Death and Differentiation, Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, 200025 Shanghai, China. 6Yale Institute for Immune Metabolism, Shanghai JiaoTong University School of Medicine, 200025 Shanghai, China. 7Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
8These authors contributed equally: Seoyeon Bok, Dong Yeon Shin
*Corresponding author
Abstract
Neurofibromatosis type I (NF1) is characterized by prominent skeletal manifestations caused by NF1 loss. While inhibitors of the ERK activating kinases MEK1/2 are promising as a means to treat NF1, the broad blockade of the ERK pathway produced by this strategy is potentially associated with therapy limiting toxicities. Here, we have sought targets offering a more narrow inhibition of ERK activation downstream of NF1 loss in the skeleton, finding that MEKK2 is a novel component of a noncanonical ERK pathway in osteoblasts that mediates aberrant ERK activation after NF1 loss. Accordingly, despite mice with conditional deletion of Nf1 in mature osteoblasts (Nf1fl/fl;Dmp1-Cre) and Mekk2−/− each displaying skeletal defects, Nf1fl/fl;Mekk2−/−;Dmp1-Cre mice show an amelioration of NF1-associated phenotypes. We also provide proof-of-principle that FDA-approved inhibitors with activity against MEKK2 can ameliorate NF1 skeletal pathology. Thus, MEKK2 functions as a MAP3K in the ERK pathway in osteoblasts, offering a potential new therapeutic strategy for the treatment of NF1.
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