Integrative preclinical strategies for targeting the local mesenchyme as a regulator of tissue specificity in inflammatory musculoskeletal disorders (IMDs)

Coordinator:  Univ.-Professor Dr. Thomas Pap

Chronic inflammatory musculoskeletal diseases (IMDs) share significant overlap and similarities yet at the same time show a certain organ specificity, with the affected mesenchyme being at the centre of pathophysiology.

For example, rheumatoid arthritis (RA) may affect different organs but primarily attacks synovial joints leading to their progressive destruction. Other IMDs, such as those of the connective tissue, while also affecting joints and presenting with similar cytokine profiles and immune alterations, primarily hit connective tissues with distinct yet overlapping organ involvement.

Likewise, some commensal microorganisms can interact specifically with the local mesenchyme in the bone and induce an inflammatory tissue response including bone damage. The respective underlying mechanisms that determine tissue specificity of IMDs and the role of the local mesenchyme therein are poorly understood.

Consequently, most therapies including novel, highly molecule-specific or antibody based drugs largely target common pathways of inflammation, infection and immunity. Whereas some of them have revolutionized the treatment of IMDs and led to scientific cross-fertilization with new agents studied systematically in different entities, the success of this strategy is still variable and difficult to anticipate. Furthermore, it has been understood that even with these effective novel drugs, lasting and true remission is hard to achieve in individual patients and even more difficult to predict. At the same time, the increasing socioeconomic burden of IMDs requires novel strategies that go beyond the inhibition of inflammatory and immune-mediated pathways.

Therefore, we intend to set up an interdisciplinary research consortium that studies and validates new preclinical strategies for targeting the local mesenchyme in IMDs. As the key hypothesis, we postulate that in IMDs, local factors within the mesenchyme critically regulate disease manifestation and severity and that targeting these factors will provide novel and more specific therapeutic strategies for IMDs.

Therefore, our consortium will work across different IMDs and their preclinical models, including rheumatoid arthritis (RA), systemic sclerosis (SSc), granulomatosis with polyangiitis (GPA), idiopathic inflammatory myopathies (IIM), chronic osteomyelitis (cOM) and bone loss in periodontal disease (PD). In an interdisciplinary approach involving cartilage and bone biologists, immunologists, microbiologists, rheumatologists, neurologists and dentists we will compare the role of specific cellular compartments of the mesenchyme such as cartilage and bone, the role of extracellular vesicles (EVs), miRNAs and tissue-specific antibodies as well as the potential of mesenchymal stem cells.

Importantly, the consortium also involves an innovative start-up company and builds on a strong involvement of patient organisations in frame of a structured ‘research partnership’. As an innovative element, each project will focus on a distinct pathophysiologic theme that is worked on by an interdisciplinary team of PI’s combining their expertise, either pairing clinicians with basic scientists or different research areas. Moreover, all projects will feed into and in turn be supported by a ‘Clinical Translational Platform’ (CTP) that will integrate the translational efforts by a systematic cross-project utilisation of samples and disease models as well as a coordinated preclinical testing and validation of novel targets as developed in the projects and the start-up company partner.

Subprojects (themes)