The potential therapeutic effects of insulin-like growth factor-1 (IGF-1) and sodium pentosan polysulfate (PPS) were evaluated in an anterior cruciate ligament-deficient canine model of osteoarthritis (OA). A control group of animals received no treatment or surgery (N). The remaining four groups of animals received anterior cruciate transection and either no treatment (OA), intra-articular IGF-1 (IGF-1), intra-muscular PPS (PPS), or a combination of intra-articular IGF-1 and intra-muscular PPS (IGF-1/PPS). All therapy was begun 3 weeks after surgery and continued for 3 weeks. At 6 weeks, articular cartilage from the femoral condyle was evaluated for anatomy, histology (Mankin grade) and biochemistry. Anatomically, only cartilage from dogs in the IGF-1/PPS group approximated that found in N. Mankin scores indicated less severe disease in both PPS and IGF-1/PPS groups compared with the OA group. Consistent with histology, the level of active neutral metalloproteinase was lower in cartilage from the PPS group compared with the OA group. Active and total neutral metalloproteinase, tissue inhibitor of metalloproteinases (TIMP), total collagenase, uronate and hydroxyproline contents were all near normal in the IGF-1/PPS group. In a model of mild OA, therapeutic intervention with IGF-1 and PPS appeared to successfully maintain cartilage structure and biochemistry. From these data, it is hypothesized that proteinase activity was successfully blocked by PPS, and that this allowed the observed growth factor induced effects. As we unravel the various factors that regulate cartilage metabolism, it is becoming apparent that combinations of agents will be needed to effectively control cartilage repair in OA. The addition of PPS to IGF-1 shows promise as a therapeutic intervention and introduces a new rational approach to therapy of OA.