Vps35 loss promotes hyperresorptive osteoclastogenesis and osteoporosis via sustained RANKL signaling

Wen Fang Xia, Fulei Tang, Lei Xiong, Shan Xiong, Ji Ung Jung, Dae Hoon Lee, Xing Sheng Li, Xu Feng, Lin Mei, Wencheng Xiong

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Receptor activator of NF-κB (RANK) plays a critical role in osteoclastogenesis, an essential process for the initiation of bone remodeling to maintain healthy bone mass and structure. Although the signaling and function of RANK have been investigated extensively, much less is known about the negative regulatory mechanisms of its signaling. We demonstrate in this paper that RANK trafficking, signaling, and function are regulated by VPS35, a major component of the retromer essential for selective endosome to Golgi retrieval of membrane proteins. VPS35 loss of function altered RANK ligand (RANKL)-induced RANK distribution, enhanced RANKL sensitivity, sustained RANKL signaling, and increased hyperrresorptive osteoclast (OC) formation. Hemizygous deletion of the Vps35 gene in mice promoted hyperresorptive osteoclastogenesis, decreased bone formation, and caused a subsequent osteoporotic deficit, including decreased trabecular bone volumes and reduced trabe- cular thickness and density in long bones. These results indicate that VPS35 critically deregulates RANK signaling, thus restraining increased formation of hyperresorptive OCs and preventing osteoporotic deficits.

Original languageEnglish (US)
Pages (from-to)821-837
Number of pages17
JournalJournal of Cell Biology
Volume200
Issue number6
DOIs
StatePublished - Mar 1 2013

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RANK Ligand
Osteogenesis
Osteoporosis
Bone and Bones
Bone Remodeling
Endosomes
Gene Deletion
Osteoclasts
Membrane Proteins

ASJC Scopus subject areas

  • Cell Biology

Cite this

Vps35 loss promotes hyperresorptive osteoclastogenesis and osteoporosis via sustained RANKL signaling. / Xia, Wen Fang; Tang, Fulei; Xiong, Lei; Xiong, Shan; Jung, Ji Ung; Lee, Dae Hoon; Li, Xing Sheng; Feng, Xu; Mei, Lin; Xiong, Wencheng.

In: Journal of Cell Biology, Vol. 200, No. 6, 01.03.2013, p. 821-837.

Research output: Contribution to journalArticle

Xia, WF, Tang, F, Xiong, L, Xiong, S, Jung, JU, Lee, DH, Li, XS, Feng, X, Mei, L & Xiong, W 2013, 'Vps35 loss promotes hyperresorptive osteoclastogenesis and osteoporosis via sustained RANKL signaling', Journal of Cell Biology, vol. 200, no. 6, pp. 821-837. https://doi.org/10.1083/jcb.201207154
Xia, Wen Fang ; Tang, Fulei ; Xiong, Lei ; Xiong, Shan ; Jung, Ji Ung ; Lee, Dae Hoon ; Li, Xing Sheng ; Feng, Xu ; Mei, Lin ; Xiong, Wencheng. / Vps35 loss promotes hyperresorptive osteoclastogenesis and osteoporosis via sustained RANKL signaling. In: Journal of Cell Biology. 2013 ; Vol. 200, No. 6. pp. 821-837.
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