Differentially regulated expression of growth differentiation factor 5 and bone morphogenetic protein 7 in articular cartilage and synovium in murine chronic arthritis: Potential importance for cartilage breakdown and synovial hypertrophy

Abstract

To examine whether the endogenous expression of growth differentiation factor 5 (GDF-5) and bone morphogenetic protein 7 (BMP-7) is altered in the cartilage and synovium of human tumor necrosis factor alpha (TNFalpha)-transgenic (hTNFtg) mice with chronic arthritis, and to investigate the response of hTNFtg chondrocytes as well as fibroblast-like synoviocytes (FLS) to these morphogens in vitro. Analyses were performed in hTNFtg mice with chronic destructive arthritis and in wild-type (WT) mice as controls. Expression of GDF-5 and BMP-7 in the articular cartilage and synovium was examined by real-time polymerase chain reaction and immunohistochemistry. Human TNFtg cartilage explants, chondrocytes, and FLS monolayer cultures were assessed for basal matrix biosynthesis as well as growth factor responsiveness, using (35)S-sulfate incorporation assays. In addition, the DNA content/cell proliferation rate was measured. The expression of GDF-5 and BMP-7 was decreased in articular cartilage from hTNFtg mice, whereas expression of both morphogens was increased in arthritic synovium from hTNFtg mice, as compared with the levels in WT controls. Isotope incorporation revealed a marked reduction of matrix synthesis in hTNFtg cartilage as well as a decrease in responsiveness to GDF-5 and BMP-7. The DNA content did not change in arthritic cartilage as compared with WT cartilage. In hTNFtg FLS, growth factor stimulation increased the rate of cell proliferation and the production of extracellular matrix. In this murine model of TNFalpha-mediated arthritis, the expression of GDF-5 and BMP-7 is regulated differentially in articular cartilage and synovium. In articular cartilage, the down-regulation of GDF-5 and BMP-7, which function to maintain matrix integrity, could potentially compromise tissue repair, whereas in synovium, the increased expression of GDF-5 and BMP-7 might contribute to synovial hypertrophy.