Keratan sulfate (KS) proteoglycan side chains are abundant in the human cartilage matrix, but these chains have been said to be absent in murine skeletal tissues. We previously showed that KS suppresses cartilage damage and ameliorates inflammation in mice arthritis model. Because mice deficient of N-acetylglucosamine 6-O-sulfotransferase-1 (GlcNAc6ST-1) (KS biosynthesis enzyme) are now available, we decided to do further examinations. We examined, in culture, the difference between GlcNAc6ST-1(-/-) and wild-type (WT) mice for interleukin (IL)-1 alpha-induced glycosaminoglycan (GAG) release from the articular cartilage. Arthritis was induced by intravenous administration of an anti-type II collagen antibody cocktail and subsequent intraperitoneal injection of lipopolysaccharide. We examined the differences in arthritis seventies in the two genotypes. After intraperitoneal KS administration in phosphate-buffered saline (PBS) or PBS alone, we evaluated the potential of KS in ameliorating arthritis and protecting against cartilage damage in deficient mice. GAG release induced by IL-1 alpha in the explants, and severity of arthritis were greater in GlcNAc6ST-1(-/-) mice than their WT littermates. Intraperitoneal KS administration effectively suppressed arthritis induction in GIcNAc6ST-1(-/-) mice. Thus, GlcNAc6ST-1(-/-) mice cartilage is more fragile than WT mice cartilage, and exogenous KS can suppress arthritis induction in GIcNAc6ST-1(-/-) mice. Vestigial KS chain or altered glycosylation in articular cartilage in GIcNAcEST-1(-/-) mice may be protective against arthritis and associated cartilage damage as well as cartilage damage in culture. KS may offer therapeutic opportunities for chondroprotection and suppression of joint damage in inflammatory arthritis and may become a therapeutic agent for treating rheumatoid arthritis. (C) 2011 Elsevier Inc. All rights reserved.