title: Deficiency of sorting nexin 10 prevents bone erosion in collagen-induced mouse arthritis through promoting NFATc1 degradation.
abstract: Periarticular and subchondral bone erosion in rheumatoid arthritis caused by osteoclast differentiation and activation is a critical index for diagnosis, therapy and monitoring of the disease. Sorting nexin (SNX) 10, a member of the SNX family which functions in regulation of endosomal sorting, has been implicated to play an important clinical role in malignant osteopetrosis. Here we studied the roles and precise mechanisms of SNX10 in the bone destruction of collagen-induced arthritis (CIA) mice.
  
  
  
  The role of SNX10 in bone destruction was evaluated by a CIA mice model which was induced in male SNX10(-/-) mice and wild type littermates. The mechanism was explored in osteoclasts induced by receptor activator of nuclear factor κB ligand from bone marrow mononuclear cells of wild type and SNX10(-/-) mice.
  
  
  
  SNX10 knockout prevented bone loss and joint destruction in CIA mice with reduced serum levels of TNF-α, interleukin 1β and anticollagen IgG 2α antibody. SNX10 deficiency did not block osteoclastogenesis, but significantly impaired osteoclast maturation and bone-resorption function by disturbing the formation of actin belt. The production of TRAP, CtsK and MMP9 in SNX10(-/-) osteoclasts was significantly inhibited, and partially restored by SNX10 overexpression. We further demonstrated that the degradation of NFATc1 was accelerated in SNX10(-/-) osteoclasts causing an inhibition of integrin β3-Src-PYK2 signalling.
  
  
  
  Our study discloses a crucial role and novel mechanism for SNX10 in osteoclast function, and provides evidence for SNX10 as a promising novel therapeutic target for suppression of immune inflammation and bone erosion in rheumatoid arthritis.
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: You
authors.affiliation: The Translational Medicine Research Center, Nanjing University of Traditional Chinese Medicine, Nanjing, China.
authors.forename: Weixing
authors.initials: W
authors.lastname: Shen
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Yi-Zhun
authors.initials: YZ
authors.lastname: Zhu
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Peng
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Western Australia, Australia.
authors.forename: Hao-Tian
authors.initials: HT
authors.lastname: Feng
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Shao
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
authors.forename: Cui-Xian
authors.initials: CX
authors.lastname: Li
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Wan-Zhen
authors.initials: WZ
authors.lastname: Li
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Western Australia, Australia.
authors.forename: Jiake
authors.initials: J
authors.lastname: Xu
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Shen
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000150:complications* / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D001862:Bone Resorption / Q000000981:diagnostic imaging / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D039661:Integrin beta3 / Q000502:physiology; D008297:Male; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010010:Osteoclasts / Q000473:pathology / Q000502:physiology; D010012:Osteogenesis / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D058305:Sorting Nexins / Q000172:deficiency / Q000502:physiology*; D013583:Synovial Membrane / Q000473:pathology; D014057:Tomography, X-Ray Computed
chemical_list: D039661:Integrin beta3; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; C000619258:SNX10 protein, mouse; D058305:Sorting Nexins
keywords: Autoimmune Diseases; Rheumatoid Arthritis; Treatment