title: Lysosomal Ca2+Signaling is Essential for Osteoclastogenesis and Bone Remodeling.
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.
authors: Department of Oral Physiology, and Institute of Biomaterial-Implant, College of Dentistry, Wonkwang University, Iksan, Republic of Korea.|Department of Physiology, School of Pharmacy and Bio-Medicine, Mongolian National University of Medical Science, Ulaanbaatar, Mongolia.
authors: Munkhsoyol
authors: M
authors: Erkhembaatar
authors: Center for Metabolic Function Regulation (CMFR), School of Medicine, Wonkwang University, Iksan, Republic of Korea.|Department of Oral Microbiology and Immunology, College of Dentistry, Wonkwang University, Iksan, Republic of Korea.
authors: Dong Ryun
authors: DR
authors: Gu
authors: Center for Metabolic Function Regulation (CMFR), School of Medicine, Wonkwang University, Iksan, Republic of Korea.|Department of Oral Microbiology and Immunology, College of Dentistry, Wonkwang University, Iksan, Republic of Korea.
authors: Seoung Hoon
authors: SH
authors: Lee
authors: Department of Oral Biology, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, Republic of Korea.
authors: Yu-Mi
authors: YM
authors: Yang
authors: Department of Oral Biology, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, Republic of Korea.
authors: Soonhong
authors: S
authors: Park
authors: Epithelial Signaling and Transport Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors: Shmuel
authors: S
authors: Muallem
authors: Department of Oral Biology, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, Republic of Korea.
authors: Dong Min
authors: DM
authors: Shin
authors: Department of Oral Physiology, and Institute of Biomaterial-Implant, College of Dentistry, Wonkwang University, Iksan, Republic of Korea.
authors: Min Seuk
authors: MS
authors: Kim
mesh_terms: D000818:Animals; D016723:Bone Remodeling / Q000187:drug effects; D001862:Bone Resorption / Q000473:pathology; D020013:Calcium Signaling / Q000187:drug effects; D048429:Cell Size; D017353:Gene Deletion; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects; D053245:RANK Ligand / Q000494:pharmacology; D000071681:Tartrate-Resistant Acid Phosphatase / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000172:deficiency / Q000378:metabolism
chemical_list: C512321:Mcoln1 protein, mouse; D053245:RANK Ligand; D050051:Transient Receptor Potential Channels; D000071681:Tartrate-Resistant Acid Phosphatase
keywords: BONE REMODELING; CA2+ SIGNALING; LYSOSOME; OSTEOCLASTOGENESIS; TRPML1