Final Report Summary - OSTEOIMMUNE (OSTEOIMMUNE - Unraveling the Interactions between the Immune System and Bone)
1. Osteoimmune pubishable project summary
Inflammatory rheumatic diseases affect millions of European citizens causing chronic pain, disability and premature death. Curative treatments are lacking. Conventional research often focuses on one single organ system such as the bone or the immune system and ignores interactions between organsystems. OSTEOIMMUNE is a supra-disciplinary training network that targets this gap by providing comprehensive, structured and coherent training. The scientific training within OSTEOIMMUNE reflects the participants‘ common research programme aiming to unravel the interactions between the immune system and the skeleton. A group of outstanding European scientists in genetics, (osteo-)immunology, rheumatology and drug development has joined to form OSTEOIMMUNE to provide12 ESRs and 1 ER with training in a broad range of laboratory and complementary skills and capacities under the 7th framework programme. Moreover, OSTEOIMMUNE has established a long-lasting consortium for cutting edge research in the field of osteoimmunology, leading to accelerated and integrated discoveries, which can become commercially exploitable first by European industry.
The main objective of the Osteoimmune network was intended to involve trainees in cutting edge research designed to decipher key molecular, cellular and clinical mechanisms in the interplay between the bone and the immune systems.
The four pillars carrying this challenging issue are:
1. Definition of the key molecular pillars which drive bone and cartilage loss resulting from immune activation and inflammation in mice and humans
2. Understanding of the protective and regulatory interactions between the skeletal and immune systems, including including the role of the bone marrow as niche for pathogenic immunological memory.
3. Elucidation of the genetic control of the osteo-immunological interactions and definition of modulatory pathways.
4. New therapeutical approaches to for patients with inflammatory disease
The OSTEOIMMUNE participants have achieved important results that contribute significantly to elucidating the interactions between bone diseases and the immune systems.
They have made progress in the characterisation of genetic regulation of bone destruction (analysis of transcriptomes of T cells and genomic and epigenomic changes in fibroblasts) and analysing effector mechanisms (interaction pathogenic/protective anti-collagen type II antibodies and chondrocytes) involved in joint destruction and how inflammation drives osteoclasts and synovial fibroblasts. We have also used new genetically modified mouse models such as Fra-2 deficient, FcγRI/II/III-/- and FcgRI/II/III/IV-/- mice, and are using murine models of arthritis such as G6PI-induced arthritis and Collagen induced arthritis (CIA). In addition, in vitro studies on murine and human cells are complementing the in vivo experimental work. The transcriptomes analyses of pro-inflammatory Th cells repeatedly stimulated in vitro, effector-memory Th cells from inflamedtissue of RA patients, and resting memory Th cells isolated from the bone marrow were successfully performed. Factors mediating the interaction of Th cells with bone marrow stromal cells and synovial fibroblasts are under investigation.
Moreover, the characterisation of miRNA expression patterns has already started in synovial fibroblasts (SF) from G6PI-induced arthritis mice with acute, self-limited or non-remitting arthritis. Selected miRNA candidates are currently targeted in experimental treatments of G6PI-induced arthritis. Complementing the preclinical work, the role of miR-196a, has been studied in SF from patients with rheumatoid arthritis (RA) and patients with osteoarthritis (OA)SF. mIR-196a and pre-miR-196a2 is increased in OASF compared to RASF. A new anti-mouse TLR4 mAb, 5E3 was generated. To evaluate the role of TLR4 and its ligands in the mouse CIA model, a time-course treatment with 5E3 has been performed, and demonstrated that preventive treatment with 5E3 reduced disease severity and bone erosion in the CIA mouse model. In addition, we have also generated two new genetically modified mouse models, where the transcription factor AP-1, Fra-2 was deleted in adipocytes (Fra-2Δadip) or in B-cells (Fra-2ΔB-cells) to determine the interactions between immune cells and fibroblast-like synovial cells. Therapeutic JAK/SYK inhibition prevented and ameliorated arthritis in the G6PI mouse model of arthritis. Preliminary data suggest that dual JAK/SYK inhibition results in tolerable immunotoxicity profile in mice.
Alltogether result, 34 peer-reviewed articles with open-access have been published. More are still in revision or preparation.
By the end of the project, long-lasting collaboration among the Osteoimmune participants has been established. The fellows have received a very sound scientific and complementary skills training, which will help them mould their future career in the scientific fields, specially in the understanding of the interdisciplinary aspects of diseases. They will leave the network with a set of aptitudes that will enable them to be instrumental in developing curative therapies towards rheumatic diseases, be it in an academic, clinical or industrial setting.
Finally OSTEOIMMUNE contributed to the structuring of existing high-quality initial research training capacity throughout Europe and enhances industry-academia cooperation. Future generations of entrepreneurial researchers have been created, thus contributing to intersectoral employability of researchers and attract young people to start a research career. The aim has been to establish long-term collaborations and lasting structured training programmes combining in a synergistic fashion research carried out at national or international level. OSTEOIMMUNE contributed to innovation, disseminated its results widely and engaged itself in outreach activities towards the general public.
The socio-impact of this research project is very high. Understanding the interplay among several factors affecting patients with inflammatory rheumatic diseases, a targeted medication may be developed which not only tackle the chronicity of the diseases, but also its aggressiveness and sources. Thus, a better quality of life may be given to these patients and absenteism due to illness may be decreased, which can only be positive for the working population and for the economy of a country. This research work could be interesting for policy makers, the medical world, the civil society and last not least for the patient organisations.
Open:
Illustrations: project logo and any other diagrams or photographs, illustrating and promoting the work of the project:
Project Coordinator: Prof. Thomas Kamradt
Contact: Osteoimmune@med.uni-jena.de
Organisation Name: Universitätsklinikum Jena
Project No.: 289150
Website: www.osteoimmune.eu
Facebook: www.facebook.com/Osteoimmune
Inflammatory rheumatic diseases affect millions of European citizens causing chronic pain, disability and premature death. Curative treatments are lacking. Conventional research often focuses on one single organ system such as the bone or the immune system and ignores interactions between organsystems. OSTEOIMMUNE is a supra-disciplinary training network that targets this gap by providing comprehensive, structured and coherent training. The scientific training within OSTEOIMMUNE reflects the participants‘ common research programme aiming to unravel the interactions between the immune system and the skeleton. A group of outstanding European scientists in genetics, (osteo-)immunology, rheumatology and drug development has joined to form OSTEOIMMUNE to provide12 ESRs and 1 ER with training in a broad range of laboratory and complementary skills and capacities under the 7th framework programme. Moreover, OSTEOIMMUNE has established a long-lasting consortium for cutting edge research in the field of osteoimmunology, leading to accelerated and integrated discoveries, which can become commercially exploitable first by European industry.
The main objective of the Osteoimmune network was intended to involve trainees in cutting edge research designed to decipher key molecular, cellular and clinical mechanisms in the interplay between the bone and the immune systems.
The four pillars carrying this challenging issue are:
1. Definition of the key molecular pillars which drive bone and cartilage loss resulting from immune activation and inflammation in mice and humans
2. Understanding of the protective and regulatory interactions between the skeletal and immune systems, including including the role of the bone marrow as niche for pathogenic immunological memory.
3. Elucidation of the genetic control of the osteo-immunological interactions and definition of modulatory pathways.
4. New therapeutical approaches to for patients with inflammatory disease
The OSTEOIMMUNE participants have achieved important results that contribute significantly to elucidating the interactions between bone diseases and the immune systems.
They have made progress in the characterisation of genetic regulation of bone destruction (analysis of transcriptomes of T cells and genomic and epigenomic changes in fibroblasts) and analysing effector mechanisms (interaction pathogenic/protective anti-collagen type II antibodies and chondrocytes) involved in joint destruction and how inflammation drives osteoclasts and synovial fibroblasts. We have also used new genetically modified mouse models such as Fra-2 deficient, FcγRI/II/III-/- and FcgRI/II/III/IV-/- mice, and are using murine models of arthritis such as G6PI-induced arthritis and Collagen induced arthritis (CIA). In addition, in vitro studies on murine and human cells are complementing the in vivo experimental work. The transcriptomes analyses of pro-inflammatory Th cells repeatedly stimulated in vitro, effector-memory Th cells from inflamedtissue of RA patients, and resting memory Th cells isolated from the bone marrow were successfully performed. Factors mediating the interaction of Th cells with bone marrow stromal cells and synovial fibroblasts are under investigation.
Moreover, the characterisation of miRNA expression patterns has already started in synovial fibroblasts (SF) from G6PI-induced arthritis mice with acute, self-limited or non-remitting arthritis. Selected miRNA candidates are currently targeted in experimental treatments of G6PI-induced arthritis. Complementing the preclinical work, the role of miR-196a, has been studied in SF from patients with rheumatoid arthritis (RA) and patients with osteoarthritis (OA)SF. mIR-196a and pre-miR-196a2 is increased in OASF compared to RASF. A new anti-mouse TLR4 mAb, 5E3 was generated. To evaluate the role of TLR4 and its ligands in the mouse CIA model, a time-course treatment with 5E3 has been performed, and demonstrated that preventive treatment with 5E3 reduced disease severity and bone erosion in the CIA mouse model. In addition, we have also generated two new genetically modified mouse models, where the transcription factor AP-1, Fra-2 was deleted in adipocytes (Fra-2Δadip) or in B-cells (Fra-2ΔB-cells) to determine the interactions between immune cells and fibroblast-like synovial cells. Therapeutic JAK/SYK inhibition prevented and ameliorated arthritis in the G6PI mouse model of arthritis. Preliminary data suggest that dual JAK/SYK inhibition results in tolerable immunotoxicity profile in mice.
Alltogether result, 34 peer-reviewed articles with open-access have been published. More are still in revision or preparation.
By the end of the project, long-lasting collaboration among the Osteoimmune participants has been established. The fellows have received a very sound scientific and complementary skills training, which will help them mould their future career in the scientific fields, specially in the understanding of the interdisciplinary aspects of diseases. They will leave the network with a set of aptitudes that will enable them to be instrumental in developing curative therapies towards rheumatic diseases, be it in an academic, clinical or industrial setting.
Finally OSTEOIMMUNE contributed to the structuring of existing high-quality initial research training capacity throughout Europe and enhances industry-academia cooperation. Future generations of entrepreneurial researchers have been created, thus contributing to intersectoral employability of researchers and attract young people to start a research career. The aim has been to establish long-term collaborations and lasting structured training programmes combining in a synergistic fashion research carried out at national or international level. OSTEOIMMUNE contributed to innovation, disseminated its results widely and engaged itself in outreach activities towards the general public.
The socio-impact of this research project is very high. Understanding the interplay among several factors affecting patients with inflammatory rheumatic diseases, a targeted medication may be developed which not only tackle the chronicity of the diseases, but also its aggressiveness and sources. Thus, a better quality of life may be given to these patients and absenteism due to illness may be decreased, which can only be positive for the working population and for the economy of a country. This research work could be interesting for policy makers, the medical world, the civil society and last not least for the patient organisations.
Open:
Illustrations: project logo and any other diagrams or photographs, illustrating and promoting the work of the project:
Project Coordinator: Prof. Thomas Kamradt
Contact: Osteoimmune@med.uni-jena.de
Organisation Name: Universitätsklinikum Jena
Project No.: 289150
Website: www.osteoimmune.eu
Facebook: www.facebook.com/Osteoimmune