Legumain Regulates Differentiation Fate of Human Bone Marrow Stromal Cells and Is Altered in Postmenopausal Osteoporosis.
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.
Department of Cellular and Molecular Medicine, Danish Stem Cell Center (DanStem), University of Copenhagen, 2200 Copenhagen, Denmark; Molecular Endocrinology & Stem Cell Research Unit (KMEB), Department of Endocrinology and Metabolism, Odense University Hospital & University of Southern Denmark, J.B. Winsloewsvej 25, 1st Floor, 5000 Odense C, Denmark.
Abbas
A
Jafari
Molecular Endocrinology & Stem Cell Research Unit (KMEB), Department of Endocrinology and Metabolism, Odense University Hospital & University of Southern Denmark, J.B. Winsloewsvej 25, 1st Floor, 5000 Odense C, Denmark.
Diyako
D
Qanie
Department of Clinical Cell Biology, Vejle/ Lillebaelt Hospital, Institute of Regional Health Research, University of Southern Denmark, 7100, Vejle, Denmark.
Thomas L
TL
Andersen
Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
Yuxi
Y
Zhang
Molecular Endocrinology & Stem Cell Research Unit (KMEB), Department of Endocrinology and Metabolism, Odense University Hospital & University of Southern Denmark, J.B. Winsloewsvej 25, 1st Floor, 5000 Odense C, Denmark.
Li
L
Chen
Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
Benno
B
Postert
Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
Stuart
S
Parsons
Molecular Endocrinology & Stem Cell Research Unit (KMEB), Department of Endocrinology and Metabolism, Odense University Hospital & University of Southern Denmark, J.B. Winsloewsvej 25, 1st Floor, 5000 Odense C, Denmark.
Nicholas
N
Ditzel
Endocrine Research Unit, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Sundeep
S
Khosla
Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, 0363 Oslo, Norway.
Harald Thidemann
HT
Johansen
Department of Orthopaedic Surgery, Vejle/Lillebaelt Hospital, 7100 Vejle, Denmark.
Per
P
Kjærsgaard-Andersen
Department of Clinical Cell Biology, Vejle/ Lillebaelt Hospital, Institute of Regional Health Research, University of Southern Denmark, 7100, Vejle, Denmark.
Jean-Marie
JM
Delaisse
Molecular Endocrinology & Stem Cell Research Unit (KMEB), Department of Endocrinology and Metabolism, Odense University Hospital & University of Southern Denmark, J.B. Winsloewsvej 25, 1st Floor, 5000 Odense C, Denmark; Department of Biological Sciences, College of Science, King Faisal University, Hofuf 6996, Saudi Arabia.
Basem M
BM
Abdallah
Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St Vincent's Clinical School, UNSW Australia, Sydney, NSW 2010, Australia.
Daniel
D
Hesselson
Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, 0363 Oslo, Norway.
Rigmor
R
Solberg
Department of Cellular and Molecular Medicine, Danish Stem Cell Center (DanStem), University of Copenhagen, 2200 Copenhagen, Denmark; Molecular Endocrinology & Stem Cell Research Unit (KMEB), Department of Endocrinology and Metabolism, Odense University Hospital & University of Southern Denmark, J.B. Winsloewsvej 25, 1st Floor, 5000 Odense C, Denmark; Stem Cell Unit, Department of Anatomy, Faculty of Medicine, King Saud University, Riyadh 12372, Saudi Arabia. Electronic address: mkassem@health.sdu.dk.
Moustapha
M
Kassem
D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000818:Animals; D002113:Calcification, Physiologic / Q000235:genetics; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D060833:Cellular Microenvironment; D003546:Cysteine Endopeptidases / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics; D015663:Osteoporosis, Postmenopausal / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D000099240:Asparaginyl Endopeptidase
D003546:Cysteine Endopeptidases; D000099240:Asparaginyl Endopeptidase
adipocyte; bone marrow stromal cells; differentiation; extracellular matrix; fibronectin; legumain; mesenchymal stem cell; osteoblast; osteoporosis; proliferation