Role of Anti-Fractalkine Antibody in Suppression of Joint Destruction by Inhibiting Migration of Osteoclast Precursors to the Synovium in Experimental Arthritis.

Abstract

OBJECTIVE:

To elucidate the role of the fractalkine (FKN)/CX3 CR1 pathway in joint destruction in rheumatoid arthritis.

METHODS:

We examined the effect of treatment with anti-mouse FKN (anti-mFKN) monoclonal antibody (mAb) on joint destruction and the migration of osteoclast precursors (OCPs) into the joint, using the collagen-induced arthritis (CIA) model. DBA/1 mice were immunized with bovine type II collagen to induce arthritis, and then treated with anti-mFKN mAb. Disease severity was monitored by arthritis score, and joint destruction was evaluated by soft x-ray and histologic analyses. Plasma levels of joint destruction markers were assessed by enzyme-linked immunosorbent assay. FKN expression on endothelial cells was detected by immunohistochemistry. Bone marrow-derived OCPs were labeled with fluorescein and transferred to mice with CIA, and the migration of the OCPs to the joints was then analyzed.

RESULTS:

Both prophylactic and therapeutic treatment with anti-mFKN mAb significantly decreased the arthritis and soft x-ray scores. Plasma levels of cartilage oligomeric matrix protein and matrix metalloproteinase 3 decreased after treatment with anti-mFKN mAb. Histologic analysis revealed that anti-mFKN mAb inhibited synovitis, pannus formation, and cartilage destruction, as well as suppressed bone damage, with a marked reduction in the number of tartrate-resistant acid phosphatase-positive osteoclasts. Anti-mFKN mAb strongly inhibited the migration of bone marrow-derived OCPs into the affected synovium.

CONCLUSION:

Anti-mFKN mAb notably ameliorates arthritis and joint destruction in the CIA model, as well as inhibits migration of OCPs into the synovium. These results suggest that inhibition of the FKN/CX3 CR1 pathway could be a novel strategy for treatment of both synovitis and joint destruction in rheumatoid arthritis.

• Authors: Kana Hoshino-Negishi, Masayoshi Ohkuro, Tomoya Nakatani, Yoshikazu Kuboi, Miyuki Nishimura, Yoko Ida, Jungo Kakuta, Akiko Hamaguchi, Minoru Kumai, Tsutomu Kamisako, Fumihiro Sugiyama, Wataru Ikeda, Naoto Ishii, Nobuyuki Yasuda, Toshio Imai
• Journal: Arthritis & rheumatology (Hoboken, N.J.) (Arthritis Rheumatol) Vol. 71 Issue 2 Pg. 222-231 (02 2019) ISSN: 2326-5205 [Electronic] United States
• PMID: 30079992 (Publication Type: Journal Article)
• Copyright: 2018, American College of Rheumatology.

Chemical References

• Antibodies, Monoclonal
• CX3C Chemokine Receptor 1
• Cartilage Oligomeric Matrix Protein
• Chemokine CX3CL1
• Comp protein, mouse
• Cx3cl1 protein, mouse
• Cx3cr1 protein, mouse
• Tartrate-Resistant Acid Phosphatase
• Matrix Metalloproteinase 3
• Mmp3 protein, mouse

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Arthritis, Experimental (immunology)
• Arthritis, Rheumatoid (immunology)
• CX3C Chemokine Receptor 1 (immunology)
• Cartilage Oligomeric Matrix Protein (drug effects, metabolism)
• Cartilage, Articular (drug effects, immunology, pathology)
• Cell Movement (drug effects)
• Chemokine CX3CL1 (antagonists & inhibitors, immunology)
• Matrix Metalloproteinase 3 (drug effects, metabolism)
• Mice
• Mice, Inbred DBA
• Osteoclasts (drug effects, metabolism)
• Stem Cells (drug effects)
• Synovial Membrane (drug effects, immunology, pathology)
• Synovitis (pathology)
• Tartrate-Resistant Acid Phosphatase (metabolism)