Treatment With Anti-γ-Glutamyl Transpeptidase Antibody Attenuates Osteolysis in Collagen-Induced Arthritis Mice

Abstract

The effectiveness of a new antibody treatment on arthritis-associated osteolysis was studied by using CIA mice. GGT, a newly identified bone-resorbing factor, was upregulated in arthritic joints. We generated monoclonal antibodies against GGT and injected them into CIA mice. Mice treated with antibodies showed a reduction in osteoclast number and bone erosion.Introduction: ␥-Glutamyl transpeptidase (GGT) acts as a bone-resorbing factor that stimulates osteoclast formation. GGT expression has been detected in active lymphocytes that accumulate at inflammation sites, such as rheumatoid arthritis (RA). We hypothesize that GGT is an effective target for suppression of arthritisrelated osteoclastogenesis and joint destruction. Here, we describe the therapeutic effect of neutralizing antibodies against GGT on joint destruction using a collagen-induced arthritis (CIA) mouse model. Materials and Methods: GGT expression in the synovium of RA patients and CIA mice was determined by immunohistochemistry and RT-PCR. Monoclonal antibodies were generated against recombinant human GGT (GGT-mAbs) using BALB/c mice. Antibody treatment was performed by intraperitoneal injections of GGT-mAbs into CIA mice. Effects of antibody treatment on arthritis and bone erosion were evaluated by incidence score, arthritis score, and histopathological observations. The role of GGT in osteoclast development was examined by using the established osteoclastogenic culture system. Results: GGT expression was significantly upregulated in inflamed synovium. Immunohistochemistry revealed that GGT was present in lymphocytes, plasma cells, and macrophages, as well as capillaries. Injection of GGT-mAbs significantly decreased the number of osteoclasts and attenuated the severity of joint destruction in CIA mice. In vitro examination showed that GGT enhanced RANKL-dependent osteoclast formation. GGT stimulated the expression of RANKL in osteoblasts and its receptor RANK in osteoclast precursors, respectively. Conclusions: This study indicates that inflamed synovial tissue-derived GGT acts as a risk factor for joint destruction and that the antibody-mediated inhibition of GGT significantly decreases osteoclast number and bone erosion in CIA mice. GGT antagonists might be novel therapeutic agents for attenuating joint destruction in RA patients.

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“…The injection itself caused tissue damage in the upper portion of periodontal tissue. Therefore, we used a cotton roll applicator saturated with stimulator to evoke tissue responses in rat periodontal tissue 10,36,37 . This method is useful because it avoids the tissue destruction caused by the application method itself.…”

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“…Ishizuka et al (2007) found that neutralizing antibodies against GGT had a therapeutic effect on joint destruction in collagen-induced arthritis in mice. Increased GGT activity was observed in serum and also in the synovial fluid of affected joints in patients with RA (Rambabu et al , 1990) and also in joints of AA-animals (Ponist et al , 2010).…”

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“…GGT expression has been detected in active lymphocytes that accumulate at the inflammation region, as observed in RA. Ishizuka et al (2007) found that neutralizing antibodies against GGT had a therapeutic effect on joint destruction in collagen-induced arthritis in mice. Elevated expression and activity of GGT in joint tissue is a good marker for synovial inflammation and bone resorption.…”