Suppression of arthritic bone destruction by adenovirus-mediated csk gene transfer to synoviocytes and osteoclasts
Hiroshi Takayanagi, … , Kozo Nakamura, Sakae Tanaka
Hiroshi Takayanagi, … , Kozo Nakamura, Sakae Tanaka
Published July 15, 1999
Citation Information: J Clin Invest. 1999;104(2):137-146. https://doi.org/10.1172/JCI6093.
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Suppression of arthritic bone destruction by adenovirus-mediated csk gene transfer to synoviocytes and osteoclasts

Abstract

Rheumatoid arthritis (RA) is characterized by a chronic inflammation of the synovial joints resulting from hyperplasia of synovial fibroblasts and infiltration of lymphocytes, macrophages, and plasma cells, all of which manifest signs of activation. Recent studies have revealed the essential role of osteoclasts in joint destruction in RA. Src family tyrosine kinases are implicated in various intracellular signaling pathways, including mitogenic response to growth factors in fibroblasts, activation of lymphocytes, and osteoclastic bone resorption. Therefore, inhibiting Src activity can be a good therapeutic strategy to prevent joint inflammation and destruction in RA. We constructed an adenovirus vector carrying the csk gene, which negatively regulates Src family tyrosine kinases. Csk overexpression in cultured rheumatoid synoviocytes remarkably suppressed Src kinase activity and reduced their proliferation rate and IL-6 production. Bone-resorbing activity of osteoclasts was strongly inhibited by Csk overexpression. Furthermore, local injection of the virus into rat ankle joints with adjuvant arthritis not only ameliorated inflammation but suppressed bone destruction. In conclusion, adenovirus-mediated direct transfer of the csk gene is useful in repressing bone destruction and inflammatory reactions, suggesting the involvement of Src family tyrosine kinases in arthritic joint breakdown and demonstrating the feasibility of intervention in the kinases for gene therapy in RA.

Authors

Hiroshi Takayanagi, Takuo Juji, Tsuyoshi Miyazaki, Hideharu Iizuka, Tokiharu Takahashi, Masashi Isshiki, Masato Okada, Yoshiya Tanaka, Yasuko Koshihara, Hiromi Oda, Takahide Kurokawa, Kozo Nakamura, Sakae Tanaka

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Figure 7

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Therapeutic effects of Csk virus injection on rat adjuvant arthritis. Al...
Therapeutic effects of Csk virus injection on rat adjuvant arthritis. All rats were immunized with adjuvant in the right foot-pad (day 0). Viruses were intra-articularly injected into ankles on day 7. Data are shown as mean ± SD. (a) Effects of Csk virus injection into right ankles, as evaluated by arthritis score. The arthritis score of the Csk group (n = 10) was significantly lower than that of the WT (n = 10) and LacZ (n = 10) groups on days 21, 28, and 35 (*P < 0.01 Csk vs. LacZ, Csk vs. WT [day 21]; **P < 0.001 Csk vs. LacZ, Csk vs. WT [days 28 and 35]). (b) Effects of Csk virus injection into right ankles, as evaluated by increase in paw volume. The increase in paw volume of the Csk group was significantly less than that of the WT and LacZ groups on days 14, 21, 28, and 35 (*P < 0.05 Csk vs. WT; #P < 0.01 Csk vs. LacZ [day 21]; **P < 0.01 Csk vs. WT, Csk vs. LacZ [day 14]; ##P < 0.001 Csk vs. WT, Csk vs. LacZ [days 28 and 35]). (c) Effects of Csk virus injection into left ankles, as evaluated by arthritis score. The arthritis score of the Csk group (n = 10) was significantly lower than that of the WT (n = 10) and LacZ (n = 10) groups on days 28 and 35 (*P < 0.05 Csk vs. LacZ; #P < 0.05 Csk vs. WT). (d) Effects of Csk virus injection into left ankles, as evaluated by increase in paw volume. The increase in paw volume of the Csk group was significantly less than that of the WT and LacZ groups (*P < 0.05 Csk vs. WT; #P < 0.05 Csk vs. LacZ). (f) On day 35, the right ankles of WT virus–injected rats showed the radiological findings of severe joint destruction — joint space narrowing, erosion, periarticular osteoporosis, and bone spur formation — compared with a normal rat ankle (e). (g) Radiological examination of Csk virus–injected right ankles showing minimal destructive changes. (j) The radiological score of Csk virus–injected right ankles was significantly decreased in comparison with WT and LacZ groups (*P < 0.001 Csk vs. WT, Csk vs. LacZ). (h) Pathohistological findings of WT virus–injected right ankles. Hyperplasia of synovial membrane occupied the articular spaces of talo-tibial (arrowhead a), talo-calcaneal (arrowhead b), and calcaneo-navicular (arrowhead c) joints. (i) Pathohistological findings of Csk virus–injected right ankles. Synovial hyperplasia and invasion into subchondral bone were markedly suppressed. (k) The pathological score of Csk virus–injected right ankles was significantly decreased in comparison with WT and LacZ groups (*P < 0.001 Csk vs. WT, Csk vs. LacZ).