Biochemical and Biophysical Research Communications
Keratan sulfate suppresses cartilage damage and ameliorates inflammation in an experimental mice arthritis model
Research highlights
► Intraperitoneal administration of keratan sulfate (KS) reduced the intraarticular inflammation and cartilage degradation in mice induced by anti-type II collagen antibody cocktail, an animal model of human arthritis. ► The presence of KS in culture of murine cartilage explants suppressed IL-1-induced aggrecan degradation. ► KS may have important therapeutic potential in the treatment of inflammatory arthritis.
Introduction
Rheumatoid arthritis (RA) is a major musculoskeletal disorder involving joint destruction of articular cartilage and subchondral bone resulting in a negative impact on the quality of life [1]. Articular cartilage is composed of chondrocytes embedded in an extracellular matrix (ECM), which provides the biomechanical factors essential for articular movement, especially those for resisting compressive forces. The two major components of cartilage ECM are type II collagen and proteoglycans. A predominant component of the latter is aggrecan, which is further composed of two types of glycosaminoglycan (GAG) side chains in humans, namely chondroitin sulfate (CS) and keratan sulfate (KS). GAGs contain sulfate residues and are thus negatively charged. This negative charge facilitates water retention in ECM, enabling the cartilage to resist compressive forces.
CS combined with glucosamine salts provides symptomatic relief and chondroprotection [2], [3], [4]. However, whether KS has similar properties during articular cartilage degradation remains unclear. The role of KS side chains in articular cartilage degradation remains to be understood with regard to arthritis [5].
In general, KS side chains of the type found in human cartilage and other mammals are not found in the skeletal tissues of mice and rats [6]. However, human articular cartilage has smaller amounts of KS than CS, and higher rates of KS/CS changes occur in older individuals [7], [8]. Thus, we hypothesized that KS affect changes in articular cartilage characteristics of arthritis and may be chondroprotective in humans based on their longevity compared to rats and mice.
Murine anti-type II collagen antibody-induced arthritis and cartilage organ culture are widely used to study the mechanisms of cartilage degradation associated with inflammatory joint diseases such as RA [9], [10]. In this study, we employed these arthritis models to verify the role of KS in cartilage degradation in arthritis.
Molecular fragments of cartilage are antigenic and can stimulate an arthritic response [11], [12], [13], [14]. Thus, lesser the cartilage breaks down and releases fragments into synovial fluid, lesser is the severity of arthritis in the joint. Based on this, if KS has chondroprotective ability in vitro, this ability may lead to suppressive effects of arthritis in vivo.
Section snippets
Mice
DBA/1J mice, aged 6–7 weeks, were purchased from Japan SLC, Shizuoka, Japan. They were maintained with sterilized food, water, and bedding at the Animal Facility of Nagoya University School of Medicine. All experiments were approved by the Animal Ethics Committee of Nagoya University.
Mouse arthritis models
Arthritis was induced in 20 mice to examine arthritis scores. On day 0, each mouse received intravenous tail vein injection of 2 mg in 200 μ arthritogenic monoclonal antibody cocktail (Iwai Chemicals, Tokyo, Japan)
Suppression of antibody-induced arthritis in DBA/1J mice by KS administration
First, we examined and assessed the effect of exogenous KS on arthritis in DBA/1J mice. Arthritis was induced by intravenous administration of an anti-type II collagen antibody cocktail and subsequently injecting lipopolysaccharide intraperitoneally. These agents were supplemented with 40 μg of intraperitoneal KS in PBS administered daily to evaluate the therapeutic potential of KS.
Arthritis scores increased in a time-dependent manner in mice treated with and without KS after antibody
Discussion
The results of our study demonstrate that KS administration ameliorated arthritis in vivo, and that KS inhibited aggrecan release from cartilage in vitro. Molecular fragments of cartilage are antigenic and can stimulate an arthritic response [11], [12], [13], [14]. Thus, if KS has chondroprotective ability in vitro, this can lead to the suppression of arthritis in vivo. The results of our study collectively suggest that KS plays a suppressive role in arthritis in terms of chondroprotection.
The
Conclusions
Our results collectively suggest that KS plays an important role in suppressing cartilage degradation associated with inflammatory joint diseases, resulting in a suppression of inflammation. Low molecular weight CS suppresses type II collagen-induced arthritis in DBA/1J mice [39], and its oral administration is clinically useful for OA and RA therapy. Phosphate prodrugs derived from N-acetylglucosamine have chondroprotective ability in bovine articular cartilage cultures in vitro [40]. Our
Acknowledgments
This work was supported in part by the 21st Century COE program and Global COE program, MEXT, Japan. The authors wish to thank A. Robin Poole for his comments on this study.
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