Our research group is interested in two major topics, both concerned with tissue regeneration. First the role of progenitor cells for musculo-skeletal regeneration, here especially the repair of hyaline cartilage in late stages of osteoarthritis and, second, the pathogenesis of periodontitis.
New research findings on cartilage regeneration published in stem cell
The Research Group led by Prof. Dr. Nicolai Miosge has discovered a previously unknown repair mechanism in diseased cartilage tissue. Chondrogenic progenitor cells (CPCs) are responsible for the generation of fibrocartilaginous tissue.
To view the full publication see “Cell Stem Cell” on this website under: Research>Publications
Progenitor cells in osteoarthritis and rheumatoid arthritis for cartilage repair in humans
Regeneration of diseased hyaline cartilage tissue in osteoarthritis (OA) and rheumatoid arthritis (RA) continues to be a great challenge, because degeneration overrides the tissue´s self-renewal capacity. Recently, we identified multipotent, clonogenic and migratory cells, which are present in repair tissue of late stages of OA, as well as in RA in humans. The chondrogenic potential of these chondrogenic progenitor cells (CPCs) in OA taken from human diseased cartilage tissue is controlled by the transcription factors runx-2 and sox9. Down-regulation of runx-2 enhances the sox9 expression and thereby the production of hyaline matrix molecules in vitro. We aim to fully characterize the CPCs in RA taken from human tissues and compare them with the ones in OA. With the help of quantitative proteomics, small molecules directly or indirectly inhibiting runx-2 leading to the up-regulation of sox9 and molecules up-regulating sox9 will be identified. These will be applied to enhance the chondrogenic potential of CPCs. These measures will help to manipulate the CPCs in situ to produce a more hyaline cartilage-like extracellular matrix to enhance tissue repair. These investigations will elucidate basic mechanisms in OA and RA pathology and cartilage regeneration. In the long run, they will help to postpone total knee replacements and will open new avenues for the treatment of these debilitating diseases.
This project is currently funded by the German Research Council (Mi 573⁄10-1 and Mi 573⁄10-2).
Chondrogenic progenitor cells in rheumatoid arthritis
In cooperation with Prof. Dr. med. Sabine Blaschke (Dept. of Nephrology) and PD Dr. med. Alexander Beham (Dept. of Surgery) we examine the effect of interleukin-17 to control the cell biological behaviour of chondrogenic progenitor cells derived from patients with rheumatoid arthritis. This project is integreted into the SPP IMUNNOBONE 1468⁄1 of the German Research Council under the title: “Molecular mechanisms of IL-17/Th17 T cell function on cartilage and bone matrix destruction in rheumatoid arthritis and its modulation via osteopontin” and contains further investigations of the role of osteoclasts and variable immunreceptors.
This project is funded by the German Research Council.
Gene expression profiling of periodontal ligament cells in periodontitis and periimplantitis
The functional strength of the tooth is the basis for the prosthetic therapy. Here the focus is especially on the periodontal ligament (PDL). A key criterion is the degree of periodontal imflammation, which is caused by bacteria, however also the quality of the immune system and they control of inflammatory mediators are involved periodontal inflammation leads to destruction of the extracellular matrix of the PDL. We study the gene expression patterns in the periodontal ligament in patients with periodontitis compared to healthy patients by using microarrays. This is the basis for further functional studies. Thus, for example the role of integrin alpha11 in the PDL-integrin knock-out mice. The peri-implantitis is defined as an inflammatory process that leads inevitably to the loss of the surrounding bone tissue and is reflected by an increased mobility of the implant along with a periodental pocket formation. Using microarrays, gene expression patterns of human periodontitis tissues are compared to human periodontal tissues.
This project was funded by the Medical Faculty of Goettingen and the German Society of Implantation (DGI)
The pathogenesis of osteoarthritis of the temporomandibular joint
Discoidin domain receptor 1 (DDR-1) deficient mice exhibit a high incidence of osteoarthritis (OA) in the temporomandibular joint (TMJ) at an early age. Young DDR-1 knock-out (KO) mice show typical histological signs of OA, including surface fissures in the articular cartilage of the knee, loss of proteoglycans, chondrocyte cluster formation, altered collagen types and atypical collagen fibril arrangement. Isolated chondrocytes from the TMJs of DDR-1 deficient mice maintain an osteoarthritic character when placed in culture, expressing high amounts of Runt-related transcription factor 2 (runx-2) and collagen type I and low levels of sex determining region (SDR) Y-box 9 (sox-9) and aggrecan. The amount of discoidin domain receptor 2 (DDR-2), a key player in OA, is noticeably increased. The gene and protein expression of DDR-1-deficient chondrocytes from the TMJ may be positively influenced by a three-dimensional matrix combined with a knockdown of runx-2 or by stimulation with extracellular matrix components such as nidogen-2. Such stimulation results in a gene expression signature more like that of normal articular cartilage, suggesting that DDR-1 regulation could offer new regenerative treatment options for temporomandibular disorders such as OA of the TMJ.
In former years, we were interested in matrix biology, mainly concerning basement membrane architecture.
Molecular architecture of basement membranes in vivo
The main basement membrane molecules are well-characterized biochemically in vitro. Their organization and interactions within basement membranes in vivo were less well understood. Our analysis has shown that basement membranes exhibit great complexity and diversity, despite their homogeneous appearance at the ultrastructural level. Basement membranes are composed of networks of laminin and collagen type IV molecules. Nidogens play a special role as an adapter molecule: In the absence of both, nidogen-1 and nidogen-2 a wide variety of defects during the formation of basement membranes occur. As part of our investigation of cell-matrix interactions, we also explored their importance in the pathogenesis of muscular dystrophy, for example, the absence of alpha 7 integrin alters the molecular composition of basement membranes at the muscle-tendon junction and disrupts the power transmission chain.
The project has been funded by the German Research Council (Mi 573⁄1-3).
Extracellular matrix and embryonal development
We have investigated a number of matrix molecules during organogenesis in humans and where able to locate, for example, laminin-5, COMP, nidogen-2, perlecan or SMOC-1 during the embryonic development. The origin of Reicherts membrane in the early mouse embryo has been elucidated as a collaboration of both the trophoblast cells and the parietal endoderm cells. We have also shown that ultrastruturally identical-looking cells of the mouse morula can be distinguished by their glykoprotein patterns detected via lectin histochemistry.
Tumor Biology and Angiogenesis
Tumorigenesis repeats in many parts physiological processes of embryonic development. We detected the oncoproteins c-erb-B2, c-fos and p53 during early human development and discussed relations between the occurrence of these oncoproteins in the embryo and its potential significance for tumor formation in adults. Tumors can metastasize only when exceeding a critical stage of their growth and after that, they have to form new blood vessels. Therefore, we investigated and recognized the importance endostatin from collagen type XVIII. Endostatin appears bound as c-terminal domain of collagen type XVIII and exerts structural importance for the formation of basement membrane networks in vivo. Cleaved from collagen XVIII as a free endostatin anti-angiogenic effect can develop. We demonstrated for the first time that endostatin can be isolate in large quantities, especially from the aorta, where it is connected via a ternary complex to the matrix component snidogen-2 and fibulin-2, in turn, bound to the elastic fibers of the tunica media.
This project was funded by the DFG (Mi 573⁄2-1).