Bone-Targeting Endogenous Secretory Receptor for Advanced Glycation End Products Rescues Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory synovitis that leads to the destruction of bone and cartilage. The receptor for advanced glycation end products (RAGE) is a multiligand membrane-bound receptor for high-mobility group box-1 (HMGB1) associated with development of RA by inducing production of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1 and IL-6. We developed a bone-targeting therapeutic agent by tagging acidic oligopeptide to a nonmem-brane-bound form of RAGE (endogenous secretory RAGE [esRAGE]) functioning as a decoy receptor. We assessed its tissue distribution and therapeutic effectiveness in a murine model of collagen-induced arthritis (CIA). Acidic oligopeptide-tagged esRAGE (D6-esRAGE) was localized to mineralized region in bone, resulting in the prolonged retention of more than 1 wk. Weekly administration of D6-esRAGE with a dose of 1 mg/kg to RA model mice significantly ameliorated inflammatory arthritis, synovial hyperplasia, cartilage destruction and bone destruction, while untagged esRAGE showed little effectiveness. Moreover, D6-esRAGE reduced plasma levels of proinflammatory cytokines including TNF-α, IL-1 and IL-6, while esRAGE reduced the levels of IL-1 and IL-6 to a lesser extent, suggesting that production of IL-1 and IL-6 reduced along the blockade of HMGB1 receptor downstream signals by D6-esRAGE could be attributed to remission of CIA. These findings indicate that D6-esRAGE enhances drug delivery to bone, leading to rescue of clinical and pathological lesions in murine CIA.

Sialylated Immunoglobulins for the Treatment of Immuno-Inflammatory Diseases

“…D6-esRAGE administered weekly (1 mg/kg) to RA model mice was able to reduce inflammatory arthritis, synovial hyperplasia, cartilage destruction, and bone destruction. D6-esRAGE also reduced plasma levels of proinflammatory cytokines (TNF)-α, IL-1, and IL-6 [64]. Thus, it was shown that D6-esRAGE greatly facilitated drug delivery to bones.…”

HMGB1 in health and disease

“…HMGB1 forms complexes with IL-1α, IL-1β, and LPS to enhance immune and inflammatory responses at the joint (Qin et al, 2014; Wahamaa et al, 2011). Moreover, therapeutic targeting of HMGB1 (e.g., HMGB1 neutralizing antibodies, recombinant A box, recombinant thrombomodulin, soluble RAGE, oxaliplatin, gold salts, and glucocorticoid) inhibits HMGB1 release and activity, which prevents the progression of arthritis in experimental animals (af Klint et al, 2005; Bossaller and Rothe, 2013; Goldstein et al, 2007; Hamada et al, 2008; Ostberg et al, 2010; Ostberg et al, 2008; Takahashi et al, 2013b; Yuan et al, 2008; Zetterstrom et al, 2008). These findings suggest that HMGB1 is an important target in the treatment of rheumatoid arthritis (Andersson and Harris, 2010).…”

Therapies of mucopolysaccharidosis IVA (Morquio A syndrome)

“…Recently, a novel bone-targeting peptide has been attached to an enzyme (alkaline phosphatase) and shown that the tagged enzyme is delivered more specifically to bone than unmodified native enzyme. This tagged enzyme improves the clinical and pathological consequence of systemic bone disease, hypophosphatasia and osteoarthritis [31,32,38]. A clinical trial for hypophosphatasia using this bone-targeting system showed substantial improvement of bone pathology and was clinically effective [33].…”

“…Specific delivery of drugs to avascular cartilage tissue has not yet been attained, although several promising results targeting drugs to bone to treat a range of bone diseases have been demonstrated to be effective both experimentally and clinically [26,31-38,9]. …”