Targeted mast cell silencing protects against joint destruction and angiogenesis in experimental arthritis in mice

Abstract

Induction of arthritis with autoantibodies against glucose-6-phosphate isomerase (GPI) is entirely independent of T cells and B cells but is strictly dependent on the presence of mast cells. Here, we used this disease model to analyze whether exclusive intraarticular mast cell reconstitution is sufficient for disease induction and whether targeted mast cell silencing can prevent neoangiogenesis and joint destruction, 2 hallmarks of rheumatoid arthritis. Ankle swelling and clinical index scores were determined after injection of either K/BxN mouse-derived serum or control serum in wild-type Kit(+)/Kit(+) mice, congenic mast cell-deficient Kit(W)/Kit(W-v) mice, or mast cell-deficient Kit(W)/Kit(W-v) mice reconstituted with mast cells, either by intraperitoneal or selective intraarticular injection. Angiogenesis was quantified in vivo by measuring activated alphavbeta3 integrin using (18)F-galacto-RGD and positron emission tomography. In addition, staining of joint tissue with hematoxylin and eosin, Giemsa, beta3, and alpha-actin was performed. The effect of mast cell stabilization by treatment with cromolyn or salbutamol was investigated in C57BL/6 or BALB/c mice. Comparing wild-type mice, mast cell-deficient Kit(W)/Kit(W-v) mice, and mast cell-reconstituted Kit(W)/Kit(W-v) mice, we first showed that intraarticular and intraperitoneal mast cell engraftment fully restores susceptibility to antibody-induced arthritis, angiogenesis, and alphavbeta3 integrin activation. Importantly, selective mast cell silencing with either salbutamol or cromolyn prevented alphavbeta3 integrin activation, angiogenesis, and joint destruction. Mast cell engraftment fully restores susceptibility to alphavbeta3 integrin activation, angiogenesis, and joint destruction in GPI antibody-induced arthritis. Importantly, selective mast cell stabilization prevents alphavbeta3 integrin activation, angiogenesis, and joint destruction.