A novel gene therapeutic approach for rheumatoid arthritis by the systemic inhibition of a central inflammatory signaling mediator in the organism
The project group “Inflammation and Regeneration” gets down to the cellular core of chronic inflammations in order to develop new therapeutic modalities for rheumatoid arthritis.
Inflammations are mediated in general by cell-internal signaling cascades and a very central inflammatory signaling mediator is the MAP-kinase-kinase-kinase TAK1 (TGF-beta-activated kinase 1). We developed the notion that it should be possible to inhibit TAK1 in the organism by small inhibitory molecules, so-called “siRNAs” which would interfere with TAK1’s synthesis already in the nucleus of a cell. Indeed, by systemically applying these siRNAs in mice suffering from rheumatoid arthritis we observed a superb therapeutic response leading to strongly reduced inflammatory symptoms and to unaffected joint structures as well. During this investigation we could demonstrate that the excellent therapeutic effect of our “anti-TAK1 strategy” is predominantly based on the significantly reduced secretion of pro-inflammatory cytokines in the organism, e. g. the tumor necrosis factor-alpha (TNFα). The generation and number of inflammatory T-helper cells in spleen and lymph nodes was also reduced (Th1, Th17). It is well-known that the latter cell types are heavily involved in the generation and the maintenance of chronic inflammatory disorders such as the rheumatoid arthritis.
This study showed for the first time that therapeutic strategies involving inflammatory signaling mediators such as TAK1 may be an efficient approach to interfere with chronic inflammatory diseases. It should be emphasized, however, that TAK1-dependent signaling not only mediates inflammation but also plays a role in tissue development and regeneration. Therefore, the anti-inflammatory TAK1-strategy described before may be advantageous also in this regard.
In conclusion, TAK1 seems as promising new target for the treatment of rheumatoid arthritis and we now plan to expand these studies to other chronic inflammatory disorders.
Adult Stem Cell (MSC)-dependent formation of tendon-bone junctions
Chronic inflammation, for example rheumatoid arthritis, leads to the progressive destruction of cartilage, bone, tendon and tendon-to-bone junctions in joint regions. Tendon-to-bone junctions (tendon-to-bone insertions, osteotendinous junctions, entheses) anchor tendon and ligaments to bone and allow the musculo-skeletal movements of the organism. These structures have the ability to resist high stress concentrations but, unfortunately, they are very sensitive to overuse injuries and to chronic inflammatory diseases as well. The repair of tendon or ligament-bone insertions is difficult and still presents a major clinical challenge to orthopaedic medicine.
We established now a novel approach for the regeneration of tendon to bone attachment sites which have been destroyed by chronic inflammatory disorders, accidents or overuse injuries. We found that that tendon-bone insertions may form spontaneously when adult stem cells (mesenchymal stem cells, MSCs) possess both a tendon-forming (tenogenic) and a bone-forming (bony) capacity. The expression of a particular signaling mediator of the TGF-beta/BMP family of growth factors, Smad8, in combination with the growth factor BMP2 in human and murine MSCs provided a tenogenic and a bony capacity to these cells and enabled the spontaneous formation of tendon-bone junctions in vivo in a mouse model. These findings may contribute to the establishment of novel strategies involving stem cell-dependent regenerative therapies for the insertion of tendon grafts at bony attachment sites, eventually.
Information and details for interesting Bachelor’s-, Master’s- or Doctor’s-theses in our group you will obtain by Gerhard Gross.
