title: Vascular endothelial growth factor C attenuates joint damage in chronic inflammatory arthritis by accelerating local lymphatic drainage in mice.
abstract: OBJECTIVE
  To investigate whether the enhancement of joint lymphangiogenesis by injection of vascular endothelial growth factor C (VEGF-C) adeno-associated virus (AAV) into the affected joints has therapeutic efficacy in chronic inflammatory arthritis in mice.
  
  
  METHODS
  Tumor necrosis factor-transgenic (TNF-Tg) mice were used as a model of chronic inflammatory arthritis. Human VEGF-C was cloned into an AAV expression vector to generate AAV-VEGF-C. The joints of TNF-Tg mice were injected with AAV-VEGF-C or AAV-luciferase (AAV-Luc) as a control. During the 4 months following injection, magnetic resonance imaging of the joints and lymphatic imaging were performed to assess changes in synovial volume and lymph flow from the joint tissues to local draining lymph nodes. Joint inflammation, bone erosion, and cartilage loss were examined by histologic analyses. Lymphatic vessel formation was assessed using immunohistochemistry.
  
  
  RESULTS
  Intraarticular administration of AAV-VEGF-C virus significantly attenuated the increase in synovial volume and increased lymphatic vessel number in the joint sections, as compared with that in control AAV-Luc-injected joints, during the 4-month period. This was accompanied by a reduction in the area of inflammation, bone erosion, cartilage loss, and osteoclast numbers. Lymph flow from the joints to local draining lymph nodes was slower in TNF-Tg mice than in wild-type littermates, and was significantly improved with AAV-VEGF-C treatment.
  
  
  CONCLUSIONS
  Intraarticular injection of AAV-VEGF-C increased lymphangiogenesis and improved lymphatic drainage from the inflamed joints of mice, resulting in attenuation of joint tissue damage. Thus, improvement of joint lymphatic function by local administration of lymphatic growth factors represents a new therapeutic approach for chronic inflammatory arthritis.
authors.affiliation: Longhua Hospital and Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhou
authors.forename: Ruolin
authors.initials: R
authors.lastname: Guo
authors.forename: Ronald
authors.initials: R
authors.lastname: Wood
authors.forename: Brendan F
authors.initials: BF
authors.lastname: Boyce
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Liang
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Wang
authors.forename: Edward M
authors.initials: EM
authors.lastname: Schwarz
authors.forename: Lianping
authors.initials: L
authors.lastname: Xing
mesh_terms: D000818:Animals; D001168:Arthritis / Q000473:pathology / Q000628:therapy*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D007596:Joints / Q000378:metabolism / Q000473:pathology*; D042601:Lymphatic Vessels / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D042582:Vascular Endothelial Growth Factor C; C467483:vascular endothelial growth factor C, mouse