Tm4sf19 deficiency inhibits osteoclast multinucleation and prevents bone loss

Sujin Park, Jin Sun Heo, Seiya Mizuno, Minwoo Kim, Haein An, Eunji Hong, Min Gi Kang, Junil Kim, Rebecca Yun, Hyeyeon Park, Eun Hye Noh, Min Jung Lee, Kwiyeom Yoon, Pyunggang Kim, Minjung Son, Kyoungwha Pang, Jihee Lee, Jinah Park, Akira Ooshima, Tae Jin KimJe Yeon Park, Kyung Min Yang, Seung Jae Myung, Hyun Bae, Kyung Mi Lee, John Letterio, Seok Hee Park, Satoru Takahashi, Seong Jin Kim

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Multinucleation is a hallmark of osteoclast formation and has a unique ability to resorb bone matrix. During osteoclast differentiation, the cytoskeleton reorganization results in the generation of actin belts and eventual bone resorption. Tetraspanins are involved in adhesion, migration and fusion in various cells. However, its function in osteoclast is still unclear. In this study, we identified Tm4sf19, a member of the tetraspanin family, as a regulator of osteoclast function. Materials and methods: We investigate the effect of Tm4sf19 deficiency on osteoclast differentiation using bone marrow-derived macrophages obtained from wild type (WT), Tm4sf19 knockout (KO) and Tm4sf19 LELΔ mice lacking the large extracellular loop (LEL). We analyzed bone mass of young and aged WT, KO and LELΔ mice by μCT analysis. The effects of Tm4sf19 LEL-Fc fusion protein were accessed in osteoclast differentiation and osteoporosis animal model. Results: We found that deficiency of Tm4sf19 inhibited osteoclast function and LEL of Tm4sf19 was responsible for its function in osteoclasts in vitro. KO and LELΔ mice exhibited higher trabecular bone mass compared to WT mice. We found that Tm4sf19 interacts with integrin αvβ3 through LEL, and that this binding is important for cytoskeletal rearrangements in osteoclast by regulating signaling downstream of integrin αvβ3. Treatment with LEL-Fc fusion protein inhibited osteoclast function in vitro and administration of LEL-Fc prevented bone loss in an osteoporosis mouse model in vivo. Conclusion: We suggest that Tm4sf19 regulates osteoclast function and that LEL-Fc may be a promising drug to target bone destructive diseases caused by osteoclast hyper-differentiation.

Original languageEnglish
Article number155746
JournalMetabolism: Clinical and Experimental
Volume151
DOIs
Publication statusPublished - 2024 Feb

Bibliographical note

Publisher Copyright:
© 2023 The Authors

Keywords

  • Bone
  • Integrin αvβ3
  • Osteoclast
  • Osteoporosis
  • Tm4sf19

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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