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-characterised induction of extracellular matrix (ECM) degrading proteinases, notably members of a disintegrin and metalloproteinase with thrombospondin domains (ADAMTS) and matrix metalloproteinase (MMP) families. Here we briefly review the less-studied a disintegrin and metalloproteinase (ADAM) family of proteinases in chondrocyte and cartilage biology. Following damage, cartilage is exposed to neurovascular peptides, and in this study we hypothesised 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 2-dimensional (2D) and 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 (IL10) which was markedly up-regulated 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 up-regulation of IL6, also observed under hypoxic conditions. Overall this data reveals wider chondrocyte responses to neurovascular peptides which may have an impact in an osteoarthritis context.