Localization of insulin-like growth factor-1 receptor in human normal and osteoarthritic cartilage in relation to proteoglycan synthesis and content.

Insulin-like growth factor-1 (IGF-1) plays a key role in the regulation of chondrocyte proteoglycan (PG) metabolism. We investigated whether chondrocyte PG synthetic activity correlates with the presence of chondrocyte IGF-1 receptor in the surface, middle and deeper zones of normal human articular cartilage and in cartilage known to display a shift in chondrocyte metabolism, i.e. cultured cartilage or osteoarthritic (OA) cartilage. Cartilage specimens were obtained post mortem from human knees within 18 h after death from donors without known clinical OA history. The samples were taken from macroscopically normal looking regions as well as from damaged regions with osteoarthritic appearance, yielding a range of OA grades from mild to moderate and severe OA. We examined chondrocyte PG synthesis by in situ autoradiography of incorporated [35S]sulphate and chondrocyte IGF-1 receptor localization by immunohistochemistry, followed by confocal laser scanning microscopical (CLSM) analysis in the same cartilage samples. In normal cartilage, both the amount of chondrocyte PG synthesis and the level of chondrocyte IGF-1 receptor localization are at low levels in the surface zone chondrocytes, but both are high in middle and deeper zone chondrocytes. Furthermore, after culture, the increase in chondrocyte PG synthesis in the surface layer coincides with increase in IGF-1 receptor expression. However, in mild OA particularly high levels of chondrocyte synthetic activity were found in the upper cartilage layer, whereas IGF-1 receptor expression was low in this layer, suggesting that factors other than IGF-1 are involved. High chondrocyte PG synthetic activity and chondrocyte IGF-1 receptor staining were found in the upper and deeper layers of moderate OA cartilage, whereas both low levels of chondrocyte activity as well as IGF-1 receptors were observed in cases of severe OA. Our data indicate that IGF-1 displays cellular heterogeneity in chondrocyte stimulation in the various cartilage zones in normal cartilage. Clear zonal correlation is lost in OA cartilage, and patterns of chondrocyte IGF-1 receptor expression and PG synthesis vary with the stage of OA.