caa a22 4500 605521492 CHVBK 20210128100740.0 cr unu---uuuuu 210128e20150501xx s 000 0 eng 10.1007/s00223-015-9967-7 doi (NATIONALLICENCE)springer-10.1007/s00223-015-9967-7 Ubiquitin E3 Ligase LNX2 is Critical for Osteoclastogenesis In Vitro by Regulating M-CSF/RANKL Signaling and Notch2 [Elektronische Daten] [Jian Zhou, Toshifumi Fujiwara, Shiqiao Ye, Xiaolin Li, Haibo Zhao] The Notch signaling pathway plays a crucial role in skeletal development and homeostasis by regulating the proliferation and differentiation of osteoblasts and osteoclasts. However, the molecular mechanisms modulating the level and activity of Notch receptors in bone cells remain unknown. In this study, we uncovered that LNX2, an E3 ubiquitin ligase and Notch inhibitor Numb binding protein, was up-regulated during osteoclast differentiation. Knocking-down LNX2 expression in bone marrow macrophages by lentivirus-mediated short hairpin RNAs markedly inhibited osteoclast formation. Decreased LNX2 expression attenuated macrophage colony-stimulating factor (M-CSF)-induced ERK and AKT activation and RANKL-stimulated activation of NF-κB and JNK pathways; therefore, accelerated osteoclast apoptosis. Additionally, loss of LNX2 led to an increased accumulation of Numb, which promoted the degradation of Notch and caused a reduction of the expression of the Notch downstream target gene, Hes1. We conclude that LNX2 regulates M-CSF/RANKL and the Notch signaling pathways during osteoclastogenesis. Springer Science+Business Media New York, 2015 LNX2 nationallicence Osteoclast nationallicence Bone resorption nationallicence RANKL nationallicence M-CSF nationallicence Notch nationallicence Numb nationallicence Zhou Jian Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Xuhui District, 200233, Shanghai, People's Republic of China aut Fujiwara Toshifumi Division of Endocrinology and Metabolism, Department of Internal Medicine, Center for Osteoporosis and Bone Metabolic Diseases, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 587, 72205, Little Rock, AR, USA aut Ye Shiqiao Division of Endocrinology and Metabolism, Department of Internal Medicine, Center for Osteoporosis and Bone Metabolic Diseases, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 587, 72205, Little Rock, AR, USA aut Li Xiaolin Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Xuhui District, 200233, Shanghai, People's Republic of China aut Zhao Haibo Division of Endocrinology and Metabolism, Department of Internal Medicine, Center for Osteoporosis and Bone Metabolic Diseases, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 587, 72205, Little Rock, AR, USA aut Calcified Tissue International Springer US; http://www.springer-ny.com 96/5(2015-05-01), 465-475 0171-967X 96:5<465 2015 96 223 https://doi.org/10.1007/s00223-015-9967-7 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00223-015-9967-7 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Zhou Jian Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Xuhui District, 200233, Shanghai, People's Republic of China aut NATIONALLICENCE 700 1- Fujiwara Toshifumi Division of Endocrinology and Metabolism, Department of Internal Medicine, Center for Osteoporosis and Bone Metabolic Diseases, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 587, 72205, Little Rock, AR, USA aut NATIONALLICENCE 700 1- Ye Shiqiao Division of Endocrinology and Metabolism, Department of Internal Medicine, Center for Osteoporosis and Bone Metabolic Diseases, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 587, 72205, Little Rock, AR, USA aut NATIONALLICENCE 700 1- Li Xiaolin Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Xuhui District, 200233, Shanghai, People's Republic of China aut NATIONALLICENCE 700 1- Zhao Haibo Division of Endocrinology and Metabolism, Department of Internal Medicine, Center for Osteoporosis and Bone Metabolic Diseases, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 587, 72205, Little Rock, AR, USA aut NATIONALLICENCE 773 0- Calcified Tissue International Springer US; http://www.springer-ny.com 96/5(2015-05-01), 465-475 0171-967X 96:5<465 2015 96 223