Pannus Invasion into Cartilage and Bone in Rheumatoid Arthritis

11 technology). The role of one of the most interesting bone degradative enzymes, cathepsin K, was studied more closely by using a pycnodysostosis arthritis patient as a human cathepsin K “knock-out” arthritis model. Matrix metalloproteinases (MMPs) form a large “neutral” proteolytic enzyme family, which upon release from intracellular to the extracellular space are therefore able to degrade extracellular matrix. We observed significant expression of MMP-3 in pannus tissue, especially when stimulated by IL-1β. It could be one of the key enzymes in RA and is likely to contribute to joint destruction by directly degrading cartilage. In contrast, TNF-α stimulated MMP-1 was hypothesized to be involved in pannus invasion in early RA, both in inflammation and in degradation of extracellular matrix. Both these MMPs activate other proproteinases in complex cascades leading to joint destruction. Interestingly, MMP-13 was not found in traumatic synovium tissue samples, but was expressed in RA. However the increased expression was more prominent in osteoarthritis than RA samples. Bone resorption requires demineralization of bone matrix by osteoclast-derived hydrochlorid acid as the first step. Osteoclasts have naturally been implicated in bone destruction in RA and we showed that pannus fibroblasts express a receptor activator of nuclear factor kappa B ligand (RANKL) able to stimulate osteoclast differentiation in the bone-pannus junction. The relation between RANKL and its natural inhibitor, a decoy receptor osteoprotegerin (OPG), in pannus tissue is imbalanced in favour for osteoclastogenesis. Some proteins of a disintegrin and a metalloproteinase (ADAM) family have been implicated in cell fusion. A recombinant protein of ADAM8 has been shown to be capable to induce osteoclast-like multinuclear cell formation and activity, perhaps by fusion of mononuclear precursor cells via interactions mediated by its disintegrin and/or cysteine-rich domain. We found an increased expression of ADAM8 in the pannus-hard tissue junction. Cathepsin K, a lysosomal acidic cysteine endoproteinase, is secreted outside the cell, especially into acidic environment between osteoclast and bone, where it degrades demineralized bone collagen matrix. However, absence of this important enzyme did not prevent bone degradation as was shown in our pycnodysostosis patient, who also had erosive arthritis, indicating that other enzymes can take over the role of cathepsin K. In this study we explored pannus tissue in RA and its capability to invade into rheumatoid cartilage and bone by stimulating degradative enzymes or proteins, which can stimulate the