title: Vps35 loss promotes hyperresorptive osteoclastogenesis and osteoporosis via sustained RANKL signaling.
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 hyperresorptive 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 trabecular 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.
authors.affiliation: Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA 30912, USA.
authors.forename: Wen-Fang
authors.initials: WF
authors.lastname: Xia
authors.forename: Fu-Lei
authors.initials: FL
authors.lastname: Tang
authors.forename: Lei
authors.initials: L
authors.lastname: Xiong
authors.forename: Shan
authors.initials: S
authors.lastname: Xiong
authors.forename: Ji-Ung
authors.initials: JU
authors.lastname: Jung
authors.forename: Dae-Hoon
authors.initials: DH
authors.lastname: Lee
authors.forename: Xing-Sheng
authors.initials: XS
authors.lastname: Li
authors.forename: Xu
authors.initials: X
authors.lastname: Feng
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Xiong
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009929:Organ Size; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D010024:Osteoporosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport / Q000235:genetics; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D033921:Vesicular Transport Proteins; C101274:Vps35 protein, mouse