Serum YKL-40 Is Associated with Osteoarthritis and Atherosclerosis in Nonhuman Primates

Osteoarthritis (OA) is the leading cause of chronic disability in the US (1). Because individuals with early stages of the disease are often asymptomatic, a biomarker of early OA may be useful. Adult cynomolgus macaques develop naturally occurring OA that closely resembles the human disease (2)(3)(4). Radiographic, histologic, and immunohistochemical analyses show a high frequency of lesions in the knee joints of these animals. Lesions are most severe in the medial tibial plateau and are characterized by fibrillation, clefting, and loss of articular cartilage with a concomitant, marked thickening of the subjacent subchondral bone (4). YKL-40 (also known as human cartilage glycoprotein-39 or 38-kDa heparin-binding glycoprotein), a major secretory protein of human chondrocytes and synovial cells (5), is increased in the serum and synovial fluid of individuals with joint or cartilage disease (5)(6)(7)(8)(9). YKL-40 mRNA expression is also increased in the cartilage of patients with rheumatoid arthritis (10). YKL-40, first identified as a major product secreted by osteosarcoma MG63 cells (11), is also produced by fibrotic liver cells and breast cancer cells and not by skin or lung fibroblasts [for a review, see Ref. (8)]. YKL-40 expression is induced during the late stages of differentiation in the transition of monocytes to activated macrophages (12)(13), and YKL-40 mRNA is present in macrophages in human atherosclerotic lesions (14). The N-terminal amino acid sequence of YKL-40 begins with Tyr-Lys-Leu (YKL), and the protein migrates at 40 kDa on sodium dodecyl sulfate polyacrylamide gel electrophoresis; hence the YKL-40 designation. YKL-40 binds heparin (15)(16) and chitin and has structural similarity to chitinolytic enzymes, although it lacks chitinase activity (10)(15). Thus, YKL-40 may function as a lectin or glycohydrolase of unknown specificity. YKL-40 expression patterns suggest …