Lysosomal Ca 2+ Signaling is Essential for Osteoclastogenesis and Bone Remodeling

Munkhsoyol Erkhembaatar, Dong Ryun Gu, Seoung Hoon Lee, Yu Mi Yang, Soonhong Park, Shmuel Muallem, Dong Min Shin, Min Seuk Kim

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Lysosomal Ca 2+ emerges as a critical component of receptor-evoked Ca 2+ signaling and plays a crucial role in many lysosomal and physiological functions. Lysosomal Ca 2+ 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 Ca 2+ signaling in osteoclastogenesis and bone metabolism. In this study, we addressed this knowledge gap by studying the role of lysosomal Ca 2+ signaling in osteoclastogenesis, osteoclast and osteoblast functions, and bone homeostasis in vivo. We manipulated lysosomal Ca 2+ signaling by acute knockdown of TRPML1, deletion of TRPML1 in mice, pharmacological inhibition of lysosomal Ca 2+ influx, and depletion of lysosomal Ca 2+ 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 Ca 2+ 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 Ca 2+ with ML-SA1 similarly abrogated RANKL-induced Ca 2+ 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 Ca 2+ signaling in osteoclast differentiation and mature osteoclast function, which play key roles in bone homeostasis.

Original languageEnglish
Pages (from-to)385-396
Number of pages12
JournalJournal of Bone and Mineral Research
Volume32
Issue number2
DOIs
Publication statusPublished - 2017 Feb 1

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Bone Remodeling
Osteoclasts
Osteogenesis
Bone and Bones
Lysosomes
Osteoblasts
Homeostasis
Mucolipidoses
Lysosomal Storage Diseases
Osteopetrosis
Macrophages
Pharmacology
Mutation
Genes

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

Erkhembaatar, M., Gu, D. R., Lee, S. H., Yang, Y. M., Park, S., Muallem, S., ... Kim, M. S. (2017). Lysosomal Ca 2+ Signaling is Essential for Osteoclastogenesis and Bone Remodeling Journal of Bone and Mineral Research, 32(2), 385-396. https://doi.org/10.1002/jbmr.2986
Erkhembaatar, Munkhsoyol ; Gu, Dong Ryun ; Lee, Seoung Hoon ; Yang, Yu Mi ; Park, Soonhong ; Muallem, Shmuel ; Shin, Dong Min ; Kim, Min Seuk. / Lysosomal Ca 2+ Signaling is Essential for Osteoclastogenesis and Bone Remodeling In: Journal of Bone and Mineral Research. 2017 ; Vol. 32, No. 2. pp. 385-396.
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Erkhembaatar, M, Gu, DR, Lee, SH, Yang, YM, Park, S, Muallem, S, Shin, DM & Kim, MS 2017, ' Lysosomal Ca 2+ Signaling is Essential for Osteoclastogenesis and Bone Remodeling ', Journal of Bone and Mineral Research, vol. 32, no. 2, pp. 385-396. https://doi.org/10.1002/jbmr.2986

Lysosomal Ca 2+ Signaling is Essential for Osteoclastogenesis and Bone Remodeling . / Erkhembaatar, Munkhsoyol; Gu, Dong Ryun; Lee, Seoung Hoon; Yang, Yu Mi; Park, Soonhong; Muallem, Shmuel; Shin, Dong Min; Kim, Min Seuk.

In: Journal of Bone and Mineral Research, Vol. 32, No. 2, 01.02.2017, p. 385-396.

Research output: Contribution to journalArticle

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AU - Lee, Seoung Hoon

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