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Lysosomal Ca2+ Signaling is Essential for Osteoclastogenesis and Bone Remodeling

Authors
 Munkhsoyol Erkhembaatar  ;  Dong Ryun Gu  ;  Seoung Hoon Lee  ;  Yu-Mi Yang  ;  Soonhong Park  ;  Shmuel Muallem  ;  Dong Min Shin  ;  Min Seuk Kim 
Citation
 JOURNAL OF BONE AND MINERAL RESEARCH, Vol.32(2) : 385-396, 2017 
Journal Title
 JOURNAL OF BONE AND MINERAL RESEARCH 
ISSN
 0884-0431 
Issue Date
2017
MeSH
Animals ; Bone Remodeling*/drug effects ; Bone Resorption/pathology ; Calcium Signaling*/drug effects ; Cell Size ; Gene Deletion ; Lysosomes/drug effects ; Lysosomes/metabolism* ; Macrophages/drug effects ; Macrophages/metabolism ; Mice, Inbred C57BL ; Osteoclasts/drug effects ; Osteoclasts/metabolism* ; Osteogenesis*/drug effects ; RANK Ligand/pharmacology ; Tartrate-Resistant Acid Phosphatase/metabolism ; Transient Receptor Potential Channels/deficiency ; Transient Receptor Potential Channels/metabolism
Keywords
BONE REMODELING ; CA2+ SIGNALING ; LYSOSOME ; OSTEOCLASTOGENESIS ; TRPML1
Abstract
Lysosomal Ca2+ emerges as a critical component of receptor-evoked Ca2+ signaling and plays a crucial role in many lysosomal and physiological functions. Lysosomal Ca2+ release is mediated by the transient receptor potential (TRP) family member TRPML1, mutations that cause the lysosomal storage disease mucolipidosis type 4. Lysosomes play a key role in osteoclast function. However, nothing is known about the role of lysosomal Ca2+ signaling in osteoclastogenesis and bone metabolism. In this study, we addressed this knowledge gap by studying the role of lysosomal Ca2+ signaling in osteoclastogenesis, osteoclast and osteoblast functions, and bone homeostasis in vivo. We manipulated lysosomal Ca2+ signaling by acute knockdown of TRPML1, deletion of TRPML1 in mice, pharmacological inhibition of lysosomal Ca2+ influx, and depletion of lysosomal Ca2+ storage using the TRPML agonist ML-SA1. We found that knockdown and deletion of TRPML1, although it did not have an apparent effect on osteoblast differentiation and bone formation, markedly attenuated osteoclast function, RANKL-induced cytosolic Ca2+ oscillations, inhibited activation of NFATc1 and osteoclastogenesis-controlling genes, suppressed the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs), and markedly reduced the differentiation of bone marrow-derived macrophages into osteoclasts. Moreover, deletion of TRPML1 resulted in enlarged lysosomes, inhibition of lysosomal secretion, and attenuated the resorptive activity of mature osteoclasts. Notably, depletion of lysosomal Ca2+ with ML-SA1 similarly abrogated RANKL-induced Ca2+ oscillations and MNC formation. Deletion of TRPML1 in mice reduced the TRAP-positive bone surfaces and impaired bone remodeling, resulting in prominent osteopetrosis. These findings demonstrate the essential role of lysosomal Ca2+ signaling in osteoclast differentiation and mature osteoclast function, which play key roles in bone homeostasis. © 2016 American Society for Bone and Mineral Research.
Full Text
http://onlinelibrary.wiley.com/doi/10.1002/jbmr.2986/abstract
DOI
10.1002/jbmr.2986
Appears in Collections:
2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
Yonsei Authors
Park, Soon Hong(박순홍)
Shin, Dong Min(신동민) ORCID logo https://orcid.org/0000-0001-6042-0435
Yang, Yu Mi(양유미)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/154195
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