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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. CONCLUSION: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.

SUBMITTER: Zhou Q

PROVIDER: S-EPMC3149728 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Vascular endothelial growth factor C attenuates joint damage in chronic inflammatory arthritis by accelerating local lymphatic drainage in mice.

Zhou Quan Q Guo Ruolin R Wood Ronald R Boyce Brendan F BF Liang Qianqian Q Wang Yong-Jun YJ Schwarz Edward M EM Xing Lianping L

Arthritis and rheumatism 20110801 8

<h4>Objective</h4>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.<h4>Methods</h4>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 injec ...[more]

PMID: 21538325

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Project description:Osteoarthritis (OA) is a chronic degenerative joint disease characterized by the breakdown of articular cartilage, subchondral bone remodeling, and inflammation of the synovium. In this study, we investigated whether Fang-Ji-Huang-Qi-Tang (FJHQT) decoction improved the joint structure of OA or delayed the process of knee joint degeneration in OA mice by promoting lymphatic drain function. The mice were randomly divided into four groups, the sham group, the PBS group, the FJHQT-treated group, and the Mobic-treated group. The mice in each group were tested for lymphatic draining function at 4, 6, 8, and 10 weeks postsurgery (WPS), then sacrificed (N?=?10/group). Using a near-infrared indocyanine green (NIR-ICG) lymphatic imaging system, we found that the lymphatic drain function was significantly reduced in the PBS group compared with the sham group. After treatment with the FJHQT decoction, the lymphatic draining function improved at 4 wps and 6 wps. The results of the analysis indicated a strong correlation between lymphatic draining function (ICG clearance) and the degree of joint structural damage (OARSI score). By Alcian blue/orange G (ABOG) staining of the paraffin sections, the FJHQT-treated group exhibited less cartilage destruction and lower OARSI scores. Moreover, the result of immunohistochemical staining (IHC) shows that FJHQT decoction increased the content of type II collagen in knee joints of OA mice at 4 wps and 6 wps. By the double immunofluorescence staining of podoplanin and smooth muscle actin in the paraffin sections, the capillaries and mature lymphatics in the FJHQT group increased at 4 wps. In conclusion, the FJHQT decoction can increase lymphatic vessel number, promote joint lymphatic draining function, and postpone knee osteoarthritis pathologic progression in the early stage of a collagen-induced mouse model. Therefore, the application of sufficient lymphatic drainage in the knee joint may be a new treatment method for knee joint osteoarthritis (KOA).

Dataset Information

Vascular endothelial growth factor C attenuates joint damage in chronic inflammatory arthritis by accelerating local lymphatic drainage in mice.

Publications

Vascular endothelial growth factor C attenuates joint damage in chronic inflammatory arthritis by accelerating local lymphatic drainage in mice.

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