TY - JOUR
T1 - Vps35 loss promotes hyperresorptive osteoclastogenesis and osteoporosis via sustained RANKL signaling
AU - Xia, Wen Fang
AU - Tang, Fu Lei
AU - Xiong, Lei
AU - Xiong, Shan
AU - Jung, Ji Ung
AU - Lee, Dae Hoon
AU - Li, Xing Sheng
AU - Feng, Xu
AU - Mei, Lin
AU - Xiong, Wen Cheng
PY - 2013/3
Y1 - 2013/3
N2 - 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.
AB - 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.
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U2 - 10.1083/jcb.201207154
DO - 10.1083/jcb.201207154
M3 - Article
C2 - 23509071
AN - SCOPUS:84876329723
SN - 0021-9525
VL - 200
SP - 821
EP - 837
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 6
ER -