Flightless I is a catabolic factor of chondrocytes that promotes hypertrophy and cartilage degeneration in osteoarthritis
Taku Ebata,
Mohamad Alaa Terkawi,
Masanari Hamasaki,
Gen Matsumae,
Tomohiro Onodera,
Mahmoud Khamis Aly,
Shunichi Yokota,
Hend Alhasan,
Tomohiro Shimizu,
Daisuke Takahashi,
Kentaro Homan,
Ken Kadoya,
Norimasa Iwasaki
Affiliations
Taku Ebata
Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nish-7, Kita-ku, Sapporo 060-8638, Japan
Mohamad Alaa Terkawi
Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nish-7, Kita-ku, Sapporo 060-8638, Japan; Corresponding author
Masanari Hamasaki
Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nish-7, Kita-ku, Sapporo 060-8638, Japan
Gen Matsumae
Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nish-7, Kita-ku, Sapporo 060-8638, Japan
Tomohiro Onodera
Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nish-7, Kita-ku, Sapporo 060-8638, Japan; Corresponding author
Mahmoud Khamis Aly
Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nish-7, Kita-ku, Sapporo 060-8638, Japan
Shunichi Yokota
Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nish-7, Kita-ku, Sapporo 060-8638, Japan
Hend Alhasan
Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nish-7, Kita-ku, Sapporo 060-8638, Japan
Tomohiro Shimizu
Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nish-7, Kita-ku, Sapporo 060-8638, Japan
Daisuke Takahashi
Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nish-7, Kita-ku, Sapporo 060-8638, Japan
Kentaro Homan
Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nish-7, Kita-ku, Sapporo 060-8638, Japan
Ken Kadoya
Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nish-7, Kita-ku, Sapporo 060-8638, Japan
Norimasa Iwasaki
Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nish-7, Kita-ku, Sapporo 060-8638, Japan
Summary: Synovial macrophages that are activated by cartilage fragments initiate synovitis, a condition that promotes hypertrophic changes in chondrocytes leading to cartilage degeneration in OA. In this study, we analyzed the molecular response of chondrocytes under condition of this type of stimulation to identify a molecular therapeutic target. Stimulated macrophages promoted hypertrophic changes in chondrocytes resulting in production of matrix-degrading enzymes of cartilage. Among the top-upregulated genes, FliI was found to be released from activated chondrocytes and exerted autocrine/paracrine effects on chondrocytes leading to an increase in expression of catabolic and hypertrophic factors. Silencing FliI in stimulated cells significantly reduced expression of catabolic and hypertrophic factors in cocultured chondrocytes. Our further results demonstrated that the FliI-TLR4-ERK1/2 axis is involved in the hypertrophic signaling of chondrocytes and catabolism of cartilage. Our findings provide a new insight into the pathogenesis of OA and identify a potentially new molecular target for diagnostics and therapeutics.
