YKL-40 (cartilage gp-39), is a mammalian glycoprotein related in sequence to chitinases. Its function is unknown, but it is thought to be involved in tissue remodeling. Immunocytochemical staining of YKL-40 in guinea pig chondrocytes (GPC), rabbit chondrocytes (RC), and rabbit synoviocytes (RS) was higher in dividing cells than in confluent cells, suggesting a participation of YKL-40 in cell cycle events. As assessed by the MITT assay, YKL-40 at 1.9-7.6 nM had dose-dependent mitogenic activity toward the three cell types. At 7.6 nM, YKL-40 increased the number of cells of 42% in GPC, 75% in RC, and 86% in RS after 72 h. YKL-40 also stimulated total proteoglycan synthesis by chondrocytes in a dose-dependent manner as assessed by Na[(SO4)-S-35] incorporation and cetylpyridinium chloride precipitation. At 9.4 nM, YKL-40 increased proteoglycan synthesis of 42% in GPC and 58% in RC after 24 h. The growth factor properties of YKL-40 may explain the increased tissue remodeling associated with high levels of YKL-40 in joint diseases, and possibly, in malignant pathologies such as breast cancer or colorectal cancer.