@article{06dfc0b7aef841d587b7fbebc30edb32,
title = "Legumain Regulates Differentiation Fate of Human Bone Marrow Stromal Cells and Is Altered in Postmenopausal Osteoporosis",
abstract = "Secreted factors are a key component of stem cell niche and their dysregulation compromises stem cell function. Legumain is a secreted cysteine protease involved in diverse biological processes. Here, we demonstrate that legumain regulates lineage commitment of human bone marrow stromal cells and that its expression level and cellular localization are altered in postmenopausal osteoporotic patients. As shown by genetic and pharmacological manipulation, legumain inhibited osteoblast (OB) differentiation and in vivo bone formation through degradation of the bone matrix protein fibronectin. In addition, genetic ablation or pharmacological inhibition of legumain activity led to precocious OB differentiation and increased vertebral mineralization in zebrafish. Finally, we show that localized increased expression of legumain in bone marrow adipocytes was inversely correlated with adjacent trabecular bone mass in a cohort of patients with postmenopausal osteoporosis. Our data suggest that altered proteolytic activity of legumain in the bone microenvironment contributes to decreased bone mass in postmenopausal osteoporosis.",
keywords = "adipocyte, bone marrow stromal cells, differentiation, extracellular matrix, fibronectin, legumain, mesenchymal stem cell, osteoblast, osteoporosis, proliferation",
author = "Abbas Jafari and Diyako Qanie and Andersen, {Thomas L.} and Yuxi Zhang and Li Chen and Benno Postert and Stuart Parsons and Nicholas Ditzel and Sundeep Khosla and Johansen, {Harald Thidemann} and Per Kj{\ae}rsgaard-Andersen and Delaisse, {Jean Marie} and Abdallah, {Basem M.} and Daniel Hesselson and Rigmor Solberg and Moustapha Kassem",
note = "Funding Information: We would like to thank Dr. Henrik Daa Schr?der, Department of Pathology, University of Southern Denmark, for providing bone sections for initial evaluation of legumain expression and help with staining interpretation and Dr. Charles Edward Frary for collecting human bone marrow samples. The SD-134 legumain inhibitor was kindly provided by Dr. Matt Bogyo, Stanford University, California, USA. The excellent technical assistance of Bianca J?rgensen, Vivianne Joosten, Lone Christiansen, Hilde Nilsen, Kaja Rau Laursen, and Birgit MacDonald is highly appreciated. D.Q. received a fellowship from the Ministry of Higher Education, Kurdistan Regional Government (KRG). The project received support from the Nordisk Research Committee, Novo Nordisk Foundation (projects 10309 and 16284), the Lundbeck Foundation (R77-A7208), and the Region of Southern Denmark, University of Oslo and Anders Jahres Foundation for the Promotion of Science (to R.S.), and NHRMC, and NIH AG027065 (to S.K.).",
year = "2017",
month = feb,
day = "14",
doi = "10.1016/j.stemcr.2017.01.003",
language = "English (US)",
volume = "8",
pages = "373--386",
journal = "Stem Cell Reports",
issn = "2213-6711",
publisher = "Cell Press",
number = "2",
}