Faculty Bibliography

Human and other annotated genome sequences have facilitated generation of vast amounts of correlative data, from human/animal genetics, normal and disease-affected tissues from complex diseases such as arthritis using gene/protein chips and SNP analysis. These data sets include genes/proteins whose functions are partially known at the cellular level or may be completely unknown (e.g. ESTs). Thus, genomic research has transformed molecular biology from 'data poor' to 'data rich' science, allowing further division into subpopulations of subcellular fractions, which are often given an '-omic' suffix. These disciplines have to converge at a systemic level to examine the structure and dynamics of cellular and organismal function. The challenge of characterizing ESTs linked to complex diseases is like interpreting sharp images on a blurred background and therefore requires a multidimensional screen for functional genomics ('functionomics') in tissues, mice and zebra fish model, which intertwines various approaches and readouts to study development and homeostasis of a system. In summary, the post-genomic era of functionomics will facilitate to narrow the bridge between correlative data and causative data by quaint hypothesis-driven research using a system approach integrating 'intercoms' of interacting and interdependent disciplines forming a unified whole as described in this review for Arthritis

Destruction of articular joints occurs progressively in patients with rheumatoid arthritis (RA). Although the exact aetiology of RA has not been fully elucidated, a large body of evidence supports a role for interleukin-1 (IL-1) in cartilage and bone erosion. In vitro studies suggest that IL-1 can cause cartilage destruction by stimulating the release of matrix metalloproteinases and other degradative products, and it can increase bone resorption by stimulating osteoclast differentiation and activation. In animal models of RA, blocking the effects of IL-1 with either IL-1 receptor antagonist (IL-1Ra; endogenous), anti-IL-1 monoclonal antibodies, or soluble IL-1 type II receptors significantly reduced cartilage destruction and bone erosion. Gene therapy with IL-1Ra was also effective in reducing joint destruction in experimental RA and osteoarthritis (OA) models. In clinical studies, anakinra, a human recombinant IL-1 receptor antagonist (IL-1ra; exogenous), significantly slowed radiographic progression of RA relative to placebo and significantly reduced clinical symptoms when used as monotherapy or in addition to existing methotrexate therapy. These results demonstrate that blocking IL-1 protects bone and cartilage from progressive destruction in RA