Abstract

Multiple regulatory mechanisms control osteoblast differentiation and function to ensure unperturbed skeletal formation and remodeling. In this study we identify histone lysine-specific demethylase 1(LSD1/KDM1A) as a key epigenetic regulator of osteoblast differentiation. Knockdown of LSD1 promoted osteoblast differentiation of human mesenchymal stem cells (hMSCs) in vitro and mice lacking LSD1 in mesenchymal cells displayed increased bone mass secondary to accelerated osteoblast differentiation. Mechanistic in vitro studies revealed that LSD1 epigenetically regulates the expression of WNT7B and BMP2. LSD1 deficiency resulted in increased BMP2 and WNT7B expression in osteoblasts and enhanced bone formation, while downregulation of WNT7B- and BMP2-related signaling using genetic mouse model or small-molecule inhibitors attenuated bone phenotype in vivo. Furthermore, the LSD1 inhibitor tranylcypromine (TCP) could increase bone mass in mice. These data identify LSD1 as a novel regulator of osteoblast activity and suggest LSD1 inhibition as a potential therapeutic target for treatment of osteoporosis.

Details

Title
Histone demethylase LSD1 regulates bone mass by controlling WNT7B and BMP2 signaling in osteoblasts
Author
Sun, Jun 1 ; Ermann, Joerg 2   VIAFID ORCID Logo  ; Niu, Ningning 1 ; Yan, Guang 1 ; Yang, Yang 1 ; Shi, Yujiang 3 ; Zou, Weiguo 1   VIAFID ORCID Logo 

1  State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China 
2  Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 
3  Newborn Medicine Division, Boston Children’s Hospital and Department of Cell Biology, Harvard Medical School, Boston, MA, USA 
Pages
1-12
Publication year
2018
Publication date
Apr 2018
Publisher
Springer Nature B.V.
ISSN
20954700
e-ISSN
20956231
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41413-018-0015-x
ProQuest document ID
2030839647
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.