Treatment with anti-gamma-glutamyl transpeptidase antibody attenuates osteolysis in collagen-induced arthritis mice.

Applied Cell Biotechnologies, Yokohama, Kanagawa, Japan.
Journal of Bone and Mineral Research (Impact Factor: 6.83). 01/2008; 22(12):1933-42. DOI: 10.1359/jbmr.070726
Source: PubMed


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.
Gamma-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 arthritis-related 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.
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.
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.
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.

Download full-text


Available from: Miutsumi Miyauchi, Oct 21, 2014
  • Source
    • "The activity of GGT is considered a reliable biochemical marker of oxidative stress as it is sensitive to immunomodulating effects of yeast polysaccharides (Bauerova et al., 2006). 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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Oxygen metabolism has an important role in the pathogenesis of rheumatoid arthritis. A certain correlation was observed between oxidative stress, arthritis and the immune system. Reactive oxygen species produced in the course of cellular oxidative phosphorylation and by activated phagocytic cells during oxidative burst, exceed the physiological buffering capacity and result in oxidative stress. The excessive production of ROS can damage protein, lipids, nucleic acids, and matrix components. Patients with rheumatoid arthritis have an altered antioxidant defense capacity barrier. In the present study the effect of substances with antioxidative properties, i.e. pinosylvin and carnosine, was determined in monotherapy for the treatment of adjuvant arthritis (AA). Moreover carnosine was evaluated in combination therapy with methotrexate. Rats with AA were administered first pinosylvin (30 mg/kg body mass daily per os), second carnosine (150 mg/kg body mass daily per os) in monotherapy for a period of 28 days. Further, rats with AA were administered methotrexate (0.3 mg/kg body mass 2-times weekly per os), and a combination of methotrexate+carnosine, with the carnosine dose being the same as in the previous experiment. Parameters, i.e. changes in hind paw volume and arthritic score were determined in rats as indicators of destructive arthritis-associated clinical changes. Plasmatic levels of TBARS and lag time of Fe(2+)-induced lipid peroxidation (tau-FeLP) in plasma and brain were specified as markers of oxidation. Plasmatic level of CRP and activity of γ-glutamyltransferase (GGT) in spleen and joint were used as inflammation markers. In comparison to pinosylvin, administration of carnosine monotherapy led to a significant decrease in the majority of the parameters studied. In the combination treatment with methotrexate+carnosine most parameters monitored were improved more remarkably than by methotrexate alone. Carnosine can increase the disease-modifying effect of methotrexate treatment in rat AA.
    Interdisciplinary toxicology 06/2012; 5(2):84-91. DOI:10.2478/v10102-012-0015-4
  • [Show abstract] [Hide abstract]
    ABSTRACT: We present three applications of adaptive λ-tracking that show the suitability of this control method for industrial process control problems. The λ-tracker is a simple design/low complexity adaptive controller that is universal in the sense, that no process model or plant tests are required for the controller design. Furthermore, the controller exhibits remarkable robustness properties. We briefly review the theory of adaptive λ-tracking, and discuss advantages and shortcomings of this method
    American Control Conference, 1997. Proceedings of the 1997; 07/1997

  • Nippon Saikingaku Zasshi 01/2009; 63(2-4):387-90. DOI:10.3412/jsb.63.387
Show more