TY - JOUR
T1 - LIS1 regulates osteoclastogenesis through modulation of M-SCF and RANKL signaling pathways and CDC42
AU - Ye, Shiqiao
AU - Fujiwara, Toshifumi
AU - Zhou, Jian
AU - Varughese, Kottayil I.
AU - Zhao, Haibo
N1 - Funding Information:
The authors would like to thank Dr. O Reiner (The Weizmann Institute of Science, Rehovot, Israel) for providing LIS1 antibody and Andrea Harris for Flow Cytometry. UAMS Flow Cytometry Core Facility is supported in part by the Center for Microbial Pathogenesis and Host Inflammatory Responses grant P20GM103625 through the NIH National Institute of General Medical Sciences Centers of Biomedical Research Excellence. Erin Hogan is grateful for her support in microscopes. The work was supported by grants from National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS, AR062012 and AR068509) and National Institute of Aging (NIA, P01 AG13918).
Publisher Copyright:
© Ivyspring International Publisher.
PY - 2016/11/25
Y1 - 2016/11/25
N2 - We have previously reported that depletion of LIS1, a key regulator of microtubules and cytoplasmic dynein motor complex, in osteoclast precursor cells by shRNAs attenuates osteoclastogenesis in vitro. However, the underlying mechanisms remain unclear. In this study, we show that conditional deletion of LIS1 in osteoclast progenitors in mice led to increased bone mass and decreased osteoclast number on trabecular bone. In vitro mechanistic studies revealed that loss of LIS1 had little effects on cell cycle progression but accelerated apoptosis of osteoclast precursor cells. Furthermore, deletion of LIS1 prevented prolonged activation of ERK by M-CSF and aberrantly enhanced prolonged JNK activation stimulated by RANKL. Finally, lack of LIS1 abrogated M-CSF and RANKL induced CDC42 activation and retroviral transduction of a constitutively active form of CDC42 partially rescued osteoclastogenesis in LIS1-deficient macrophages. Therefore, these data identify a key role of LIS1 in regulation of cell survival of osteoclast progenitors by modulating M-CSF and RANKL induced signaling pathways and CDC42 activation.
AB - We have previously reported that depletion of LIS1, a key regulator of microtubules and cytoplasmic dynein motor complex, in osteoclast precursor cells by shRNAs attenuates osteoclastogenesis in vitro. However, the underlying mechanisms remain unclear. In this study, we show that conditional deletion of LIS1 in osteoclast progenitors in mice led to increased bone mass and decreased osteoclast number on trabecular bone. In vitro mechanistic studies revealed that loss of LIS1 had little effects on cell cycle progression but accelerated apoptosis of osteoclast precursor cells. Furthermore, deletion of LIS1 prevented prolonged activation of ERK by M-CSF and aberrantly enhanced prolonged JNK activation stimulated by RANKL. Finally, lack of LIS1 abrogated M-CSF and RANKL induced CDC42 activation and retroviral transduction of a constitutively active form of CDC42 partially rescued osteoclastogenesis in LIS1-deficient macrophages. Therefore, these data identify a key role of LIS1 in regulation of cell survival of osteoclast progenitors by modulating M-CSF and RANKL induced signaling pathways and CDC42 activation.
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U2 - 10.7150/ijbs.15583
DO - 10.7150/ijbs.15583
M3 - Article
C2 - 27994513
AN - SCOPUS:84997522717
SN - 1449-2288
VL - 12
SP - 1488
EP - 1499
JO - International Journal of Biological Sciences
JF - International Journal of Biological Sciences
IS - 12
ER -