The angiogenesis inhibitor protease-activated kringles 1–5 reduces the severity of murine collagen-induced arthritis

Abstract

CIA = collagen-induced arthritis; K1-5 = protease-activated kringles 1-5; PBS = phosphate-buffered saline; RA = rheumatoid arthritis; TNF = tumour necrosis factor; VEGF = vascular endothelial growth factor. Arthritis Research and TherapyVol 5 No 1 Sumariwalla et al. Research articleThe angiogenesis inhibitor protease-activated kringles 1-5 reduces the severity of murine collagen-induced arthritis (Print ISSN 1478-6354; Online ISSN 1478-6362). This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any non-commercial purpose, provided this notice is preserved along with the article's original URL. AbstractDuring rheumatoid arthritis there is enlargement and increased cellularity of the synovial lining of joints, before invasion by the synovium of the underlying cartilage and bone. This increased tissue mass requires a network of blood vessels to supply nutrients and oxygen. Disruption of synovial angiogenesis is thus a desirable aim of antiarthritic therapies. Protease-activated kringles 1-5 (K1-5) is an angiogenesis inhibitor related to angiostatin. In common with angiostatin, K1-5 contains the first four kringle domains of plasminogen, but also encompasses the kringle 5 domain, which confers enhanced antiangiogenic activity when compared with angiostatin. The purpose of the present study was to assess the effect on murine arthritis of K1-5. Arthritis was induced in DBA/1 mice by a single injection of bovine collagen. Treatment with K1-5 was commenced on the day of arthritis onset and continued for 10 days, until the end of the experiment. Daily intraperitoneal administration of K1-5 (2 mg/kg body weight) significantly reduced both paw swelling and clinical score (a composite index of the number of arthritic limbs and the severity of disease). The clinical efficacy of this treatment was reflected by a reduction in joint inflammation and destruction, as assessed histologically. These data suggest that antiangiogenic therapies, which block formation of new blood vessels and hence reduce synovial expansion, might be effective in treating rheumatoid arthritis.

Celastrol Inhibits Lipopolysaccharide-Stimulated Rheumatoid Fibroblast-Like Synoviocyte Invasion through Suppression of TLR4/NF-κB-Mediated Matrix Metalloproteinase-9 Expression

“…The severity of arthritis was clinically evaluated using a four point scale by direct observation of all four limbs of each animal, based on the swelling of ankle and wrist joints and small interphalangeal joints as follows [26]: 0, no redness and swelling (normal joint); 1, redness and swelling in one digit or interphalangeal joint; 2, redness and swelling of more than one digit or interphalangeal joint, or mild redness and swelling of ankle or wrist joints; 3, moderate redness and swelling of ankle or wrist joints, but able to bend and walk; 4, severe redness and swelling and deformation of ankle or wrist joints, and inability to bend and walk. All four legs are scored, so the highest possible articular index (AI) was 16.…”

Targeting VEGF and Its Receptors for the Treatment of Osteoarthritis and Associated Pain

“…In an RA model, K1-5 decreased disease severity, reducing inflammation and joint destruction. (179) Use of a soluble Tie-2 receptor (ExTek), which binds to angiopoietin-1 (Ang-1) and inhibits interaction with Tie-2 receptor on endothelial cells, led to a reduction of RA progression in an animal model. (180) Endothelial Tie-2 signaling is a critical component of angiogenic remodeling, vascular maturation, and vascular stabilization.…”

Endothelial Cells in Inflammation and Angiogenesis

“…Angiostatin gene transfer abrogated murine collagen-induced arthritis (CIA) [95]. Protease-activated kringles 1-5 (k1-5), an angiogenesis inhibitor related to angiostatin, reduced the severity of CIAs in mice [96]. The cartilage-derived angiogenesis inhibitor chondromodulin-1 suppressed antigen-induced arthritis [72].…”