Hypoxia upregulates the expression of angiopoietin-like-4 in human articular chondrocytes: role of angiopoietin-like-4 in the expression of matrix metalloproteinases and cartilage degradation.

The objective of this article was to investigate the role and expression of a novel adipocytokine, angiopoietin-like-4 (ANGPTL4), in arthropathy. Human chondrocytes were obtained from articular cartilage of patients with rheumatoid arthritis (RA) and osteoarthritis (OA), who underwent total knee or hip arthroplasty. Isolated chondrocytes were cultured under hypoxic (95% N(2), 5% CO(2)) or normoxic conditions. The effects of hypoxia on ANGPTL4 expression were determined by real-time reverse transcription polymerase chain reaction and Western blot analysis. We examined the role of ANGPTL4 using small interference RNA or by stimulating chondrocytes with recombinant ANGPTL4 protein. ANGPTL4 expression in the articular cartilage specimens was examined by immunohistochemistry. Hypoxia induced a significant increase in ANGPTL4 production (p < 0.05). Incubation of chondrocytes in vitro with recombinant ANGPTL4 enhanced the expression of matrix metalloproteinase (MMP)-1 and MMP-3. Downregulation of ANGPTL4 mRNA expression by siRNA diminished the expression of MMP-1, but not that of MMP-3, suggesting that each proteinase has a distinct response to ANGPTL4. Although the in vitro responses of chondrocytes to hypoxia were similar between RA and OA samples, the in vivo expression of ANGPTL4 had unique disease-specific patterns, suggesting differences in oxygen tension in vivo. Human chondrocytes expressed ANGPTL4 and the expression was enhanced by hypoxia. ANGPTL4 might modulate cartilage metabolism by regulating MMPs.