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Abstract
Biglycan is a member of the family of small leucine-rich proteoglycans. It is an important structural component of articular cartilage and participates in the assembly of the chondrocyte extracellular matrix through formation of protein interactions with collagen type VI and large proteoglycan aggregates. Biglycan also possesses signaling properties. In articular chondrocytes, short-term activation of epidermal growth factor receptors (EGFR) with biglycan initiated mitogen-activated protein kinase and phosphatidylinositol 3-kinase (PI3K) signaling events, similar to the effect of epidermal growth factor (EGF) observed in other cell types. The extent and duration of intracellular signaling resolves biological effects initiated by EGFR stimulation, thus, establishing cell fate. In this study, we elucidate a novel regulatory mechanism of EGFR expression in human articular chondrocytes that is modulated by prolonged biglycan treatment and is in contrast to changes detected in the expression of EGFR following EGF stimulation. Treatment of chondrocytes for 24 hr with biglycan upregulated EGFR mRNA and protein expression, whereas treatment with EGF downregulated EGFR message and protein levels. Biglycan and EGF treatment protracted extracellular signal-regulated kinases (ERK1/2) and Akt phosphorylation, albeit to different extents. Mechanistic studies with mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathway-specific inhibitors revealed that biglycan and EGF distinctly modulate the expression of EGFR in chondrocytes. Biglycan promoted the coactivation of ERK1/2 and Akt, however, phosphorylated Akt induced a prolonged inhibition of ERK1/2. Consequently, total EGFR mRNA and protein expression was increased. This regulatory mechanism contrasts the modulation of EGFR expression by exogenous EGF, which strongly protracts ERK1/2 activation, therefore, inducing a decrease of EGFR message and protein levels. Thus, biglycan might impinge on the expression of total EGFR and possibly, on the cell-surface expression of the receptors. These observations suggest that biglycan might play a critical role in the regulation of chondrocyte and pericellular matrix homeostasis.