Lactoferrin activates BMP7 gene expression through the mitogen-activated protein kinase ERK pathway in articular cartilage

Rheumatoid arthritis (RA) is a chronic inflammatory disease leading to destruction of cartilage in joints. Neutrophil granulocytes are the predominant cell type in the synovial fluid of affected joints. Neutrophils release stimulants that alter the chondrocyte metabolism. Lactoferrin (LF) is a marker of neutrophil granulocyte activation. Local concentrations of LF in synovial fluid are much higher in the joints of RA patients. However, the effect of LF on articular cartilage of joints is not well understood. Effect of LF on gene expression in primary chondrocytes of articular cartilage was investigated in this study. We found that LF preferentially activated BMP7 expression rather than BMP2 or BMP4, and that LF activated BMP7 expression in a dose-dependent and time-dependent manner. Interestingly, a specific mitogen-activated protein kinase ERK inhibitor U0126, but not JNK kinase inhibitor SP600125, abrogated LF activation of BMP7 gene expression. LF-induced increase in BMP7 protein level was in parallel with the phosphorylation of ERK in primary chondrocytes. Taken together, we provide the first evidence to demonstrate that LF activates BMP7 expression through the mitogen-activated protein kinase ERK pathway in primary chondrocytes of articular cartilage. Since BMP7 is important for the maintenance of homeostasis in articular cartilage, we speculate that there is a protective function of LF at the site of joint inflammation.

► LF preferentially activated BMP7 expression rather than BMP2 or BMP4.
► LF activated BMP7 expression in a dose- and time-dependent manner.
► LF-induced BMP7 increase was in parallel with ERK phosphorylation.
► ERK inhibitor U0126 abrogated LF activation of BMP7 expression.