Chondroitin sulfate (CS) was isolated from ray fish cartilage, an industrial waste, after protease digestion, and its structure and neurite outgrowth-promoting (NOP) activity were analyzed to investigate a potential application to nerve regeneration.A disaccharide analysis using chondroitinase ABC revealed that the major unit in the CS preparation was GlcUA-GalNAc(6-O-sulfate) (63%), where GlcUA and GalNAc represent D-glucuronic acid and N-acetyl-D-galactosamine, respectively. Small proportions of other disaccharide units, GlcUA-GalNAc(4-O-sulfate) (25%), GlcUA(2-O-sulfate)-GalNAc(6-O-sulfate) (7%), and GlcUA-GalNAc (5%), were also detected. The average molecular mass of CS was estimated to be 142 kDa by gel-filtration chromatography. The prepration showed NOP activity in vitro, which was eliminated by digestion with chondroitinase ABC, suggesting that a polymeric structure is required for the activity. Antibodies against hepatocyte growth factor (HGF) and its receptor c-Met suppressed the NOP activity, suggesting the involvement of the HGF signaling pathway in the in vitro NOP activity of the CS preparation. Since the specific binding of HGF to the CS preparation was also demonstrated by surface plasmon 3 resonance spectroscopy, the CS chains were fractionated using an HGF-immobilized column into unbound and bound fractions accounting for 44 and 56% of the total yield,

The biological functions of chondroitin sulfate (CS) are executed by the interaction of specific oligosaccharide sequences in the polysaccharide chain with effective proteins. Thus, CS oligosaccharides are expected to have pharmacological applications. Furthermore, the demand for CS in health food supplements and medication is growing. However, the absorbency of CS polysaccharides in the digestive system is very low. Since the activity of orally administered CS is expected to increase by depolymerization, industrial production of CS oligosaccharides is required. In this study, hydrolysis with subcritical and super-critical water was applied to the depolymerization of CS for the first time, and hydrolytic conditions for oligosaccharide production were examined. CS oligosaccharides principally containing an N-acetyl-Dgalactosamine residue at their reducing ends were successfully obtained. No significant desulfation was found in CS oligosaccharides prepared under optimized conditions. The production of CS oligosaccharides by this method will have a strong influence on the CS-related materials market.

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Background: The increased rate of population aging in Japan has led to an increase in the incidence of osteoarthritis (OA). Chondroitin sulfate has been reported to reduce the pain and swelling associated with OA and to improve knee function. Objective: We evaluated the safety and effects of oral chondroitin sulfate oligosaccharides on knee function in a randomized, double-blinded, placebo-controlled parallel group comparison study of healthy Japanese subjects with knee joint pain. Methods: Subjects were randomly divided into test and placebo groups and given either active-test capsules containing 100 mg of chondroitin sulfate oligosaccharides or placebo capsules daily for 8 weeks. The Japanese Knee Osteoarthritis Measure (JKOM), Visual Analog Scale (VAS), blood and physical examinations, and medical interviews were performed at weeks 0, 4, and 8, and the locomotive syndrome risk test was performed at weeks 0 and 8 during the test intake period. Results: The JKOM scores did not significantly differ between the test groups. However, among subjects with worse VAS scores, those in the active test group had significantly lower JKOM scores at 8 weeks, compared to those in the placebo group. Moreover, chondroitin sulfate oligosaccharide treatment tended to improve the subjects' scores on the stand-up test, which evaluates the risk of locomotive syndrome. Furthermore, no abnormal changes or severe adverse events were observed during physical or blood examinations or medical interviews. Conclusion: Our results suggest that chondroitin sulfate oligosaccharides improve knee pain and are safe for 8-week intake.