Chondrocyte responses to neurovascular peptides, cytokines, and a 3D environment: focus on ADAMs

Abstract

Chondrocyte exposure to inflammatory stimuli in several arthritic conditions, including osteoarthritis, results in the well-characterized induction of extracellular matrix degrading pro-teinases, notably members of a disintegrin and metalloproteinase (ADAM) with thrombospondin domains and matrix metalloproteinase families. Here we briefly review the less-studied ADAM family of proteinases in chondrocyte and cartilage biology. Following damage, cartilage is exposed to neurovascular peptides, and in this study we hypothesized that substance P and bradykinin, alongside inflammatory cytokines, may modulate chondrocyte steady-state messenger RNA levels for the proteolytic ADAM family members as well as for key cytokines and neuropeptides. We compared chondrocytes cultured in both two-dimensional and three-dimensional (3D) environments and found that 3D culture generally resulted in repression of expression of the genes under investigation, with the exception of anti-inflammatory interleukin 10 which was markedly upregulated in a 3D environment. Substance P and bradykinin had little effect on ADAM family expression, but further investigation revealed that a combination of bradykinin and cytokines led to enhanced expression of ADAM28 and a synergistic upregulation of interleukin 6, also observed under hypoxic conditions. Overall these data reveal wider chondrocyte responses to neurovascular peptides which may have an impact in an osteoarthritis context.