Inhibition of inflammatory bone erosion by constitutively active STAT-6 through blockade of JNK and NF-kappaB activation

Teruhisa Hirayama, Simon Dai, Sabiha Abbas, Yasuhiro Yamanaka, Yousef Abu-Amer
Arthritis and Rheumatism 2005, 52 (9): 2719-29

OBJECTIVE: NF-kappaB and JNK signaling pathways play key roles in the pathogenesis of inflammatory arthritis. Both factors are also activated in response to osteoclastogenic factors, such as RANKL and tumor necrosis factor alpha. Inflammatory arthritis and bone erosion subside in the presence of antiinflammatory cytokines such as interleukin-4 (IL-4). We have previously shown that IL-4 inhibits osteoclastogenesis in vitro through inhibition of NF-kappaB and JNK activation in a STAT-6-dependent manner. This study was undertaken to investigate the potential of constitutively active STAT-6 to arrest the activation of NF-kappaB and JNK and to subsequently ameliorate the bone erosion associated with inflammatory arthritis in mice.

METHODS: Inflammatory arthritis was induced in wild-type and STAT-6-null mice by intraperitoneal injection of arthritis-eliciting serum derived from K/BxN mice. Bone erosion was assessed in the joints by histologic and immunostaining techniques. Cell-permeable Tat-STAT-6 fusion proteins were administered intraperitoneally. Cells were isolated from bone marrow and from joints for the JNK assay, the DNA-binding assays (electrophoretic mobility shift assays), and for in vitro osteoclastogenesis.

RESULTS: Activation of NF-kappaB and JNK in vivo was increased in extracts of cells retrieved from the joints of arthritic mice. Cell-permeable, constitutively active STAT-6 (i.e., STAT-6-VT) was effective in blocking NF-kappaB and JNK activation in RANKL-treated osteoclast progenitors. More importantly, STAT-6-VT protein significantly inhibited the in vivo activation of NF-kappaB and JNK, attenuated osteoclast recruitment in the inflamed joints, and decreased bone destruction.

CONCLUSION: Our findings indicate that the administration of STAT-6-VT presents a novel approach to the alleviation of bone erosion in inflammatory arthritis.

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