We studied the effects of intraarticular (ia) administration of hyaluronic acid (HA) (Mw approximately 9 x 10(5)) (Artz) on cartilage integrity and release into synovial fluid (SF) of keratan sulfate peptides (KS-pep) in an ovine model of early osteoarthritis (OA) induced by meniscectomy. Five consecutive weekly injections of HA (2 ml, 10 mg/ml) or saline (2 ml) were initiated 16 weeks after meniscectomy, and animals were sacrificed 5 weeks after the last injection. SF was sampled 8, 16, 23, and 26 weeks postoperation. In the saline injected animals KS-pep levels increased progressively in SF, relative to nonoperated controls (p < 0.05). KS-pep levels in SF of the HA treated group also increased, but were not statistically different from controls. Using a modified Mankin histological scoring system, cartilage at necropsy of HA injected joints showed less damage than similar regions of saline treated animals. A new mechanism for the protective effects of HA on cartilage is proposed.