Background and Objectives BGP-15, a small synthetic hydroxylamine derivative is a member of a new class of insulin-sensitising 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 in turn are involved in joint inflammation. Moreover, BGP-15 also inhibits poly-ADP-ribose polymerase (PARP) and the phosphorylation of c-JUN N-terminal kinase via Hsp72 overexpression. Therefore it might also play a role in the regulation of inflammatory joint disease. Our objective was to evaluate the in vivo effects of BGP-15 on collagen-induced arthritis (CIA) in DBA/1 mice.
Materials and 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 was administered either one week prior to the first immunisation (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 immunisation (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.
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 anti-collagen antibody levels or in the distribution of T-cells, B-cells, dendritic cells and monocyte/macrophages harvested from draining lymph nodes, suggesting an effect predominantly involving the innate immune system.
Conclusions Our results demonstrate that the novel chaperone-inducer BGP-15 has a profound prophylactic and therapeutic effect on autoimmune arthritis, likely due to an effect on the effector phase.