Background BGP-15, a small synthetic hydroxylamine derivative is a member of a new class of insulin-sensitizing medications also known as chaperone-inducers. Beside its beneficial effects on glycemic control and insulin sensitivity in patients with Type 2 diabetes, BGP-15 is known to induce heat shock protein Hsp72 and heat shock transcription factor HSF1, which protect cells from thermal or oxidative stress and may be involved in joint inflammation.
Objectives Our objective was to evaluate the in vivo effects of BGP-15 on collagen-induced arthritis (CIA) in DBA/1 mice as well as its in vitro effects on immune cells.
Methods Arthritis was induced by intradermal injection of bovine type II collagen (bCII) and incomplete Freund’s adjuvant (CFA) in male DBA/1 mice. BGP-15 (100mg/kg) was administered either one week prior to the first immunization (prophylactic experiment, n:14 in both groups) or upon the appearance of symptoms (therapeutic experiment, n:12 in both groups) in drinking water. Arthritis incidence and severity was assessed for 28 days following the second immunization (boost) with bCII and CFA on day 21. Histological evaluation was carried out on hind paws using Osteomeasure® software. Anticollagen antibodies were measured by enzyme-linked immunosorbent assay. The cellular composition of the draining lymph nodes was measured by flow cytometry. The cellular composition of synovitis was measured on histological sections using cell-specific antibodies by Histoquest® software. In vitro cytokine measurements were carried out on dendritic cells and macrophages differentiated from murine bone marrow macrophages. Mitochondrial reactive oxygen species production was evaluated by rhodamine 123 staining of LPS-stimulated RAW264.7 murine macrophages.
Results BGP-15 significantly reduced the incidence of CIA by 28% and also reduced both paw swelling (p≤0.01) and grip strength (p≤0.05) in the prophylactic experiment. In the therapeutic experiment BGP-15 significantly attenuated both paw swelling (p≤0.01) and grip strength (p≤0.05). Histological evaluation of the hind paws demonstrated reduced area of inflammation (p≤0.05), area of erosion (p≤0.01) and number of osteoclasts (p≤0.05) in the BGP-15 treated group when compared to the control group. No significant differences were revealed between anticollagen antibody levels or in the distribution of T-cells, B-cells, dendritic cells and monocyte/macrophages harvested from draining lymph nodes. Similarly we found no difference in the cellular composition of synovitis between the control and the treated group, suggesting an effect predominantly involving the innate immune system. Indeed BGP-15, at high doses (<1mM) inhibited the LPS-induced production of IL-12, IL-6 and TNF in bone-marrow derived dendritic cells and macrophages and we could demonstrate a strong inhibitory effect (cc. 50μM) on LPS (1μg/ml) induced mitochondrial ROS production in RAW264.7 murine macrophages.
Conclusions Our results demonstrate that the novel chaperone-inducer BGP-15 has a profound prophylactic and therapeutic effect on autoimmune arthritis, mainly due to an effect on the effector phase, particularly via the inhibition of mitochondrial ROS production.
Disclosure of Interest None Declared
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