FOR 2722:  Novel molecular determinants for musculoskeletal extracellular matrix homeostasis – a systemic approach (M2)

• Subject Area: Medicine
• Term: since 2018
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 384170921

The FOR2722 research unit has identified novel functions of the ECM across musculoskeletal tissues and gained novel mechanistic insights into connective tissue disorders. Our new discoveries underscore the interdependency between metabolism, secretion pathway-dependent extracellular matrix (ECM) formation and its cellular recognition and recycling. We now hypothesize that a fine-tuned balance between inside-out ECM production and outside-in ECM recognition and remodelling defines musculoskeletal integrity and function across tissues. In the next funding period, the overarching goal of the FOR2722 will be to understand how changes in ECM production, recognition and remodelling can affect the function of musculoskeletal tissues and cause chronic connective tissue disorders. In our four research areas, we will focus on key fundamental questions in musculoskeletal ECM homeostasis emerging from our research in the first funding period: Metabolism - Through which metabolic signalling mechanisms can mtRC dysfunction be translated into disturbed vesicle-mediated ECM secretion and assembly processes in cartilage? Which mechanisms regulate bioavailability and cellular responses of asprosins? Biosynthesis and assembly - To which extent and through which mechanisms are the distinct muscle cell populations affected by mutated collagen VI and how do they contribute to myopathies? How do collagens XII and XIV organize the ECM and the presentation of ECM-encoded bioactive signals to drive neuromuscular development, regeneration and degeneration processes? Cellular communication - Does integrin α11 constitute an invadopodia-associated sensing element of cartilage damage in Fibroblast-like synoviocytes during rheumatoid arthritis and is it linked to their transformation by transmitting signals through collagen fragments into cell-specific alterations that in a perpetuating loop favour further cartilage destruction? How do extracellular microfibrillar networks participate in cell-ECM communication at musculoskeletal junctions? Degradation - How does deficiency or overexpression of Plastin3 disrupt fundamental cellular processes dependent on F-actin dynamics and vesicle trafficking resulting in bone and cartilage ECM-related diseases? Which factors are involved in the onset of osteogenesis imperfecta and can they be targeted to develop suitable new therapies for non-classical osteogenesis patients? How is the reciprocal communication between cells and their ECM fine-tuned at the mechanistic level? It is our overarching goal is to understand how these molecular processes contribute to the onset and progression of musculoskeletal disease and to translate this newly generated knowledge into additional therapeutic options.

• DFG Programme: Research Units

Projects

• Collagen VI assembly and function in musculoskeletal disorders (Applicants Paulsson, Mats ;  Schiavinato, Ph.D., Alvise )
• Coordination Funds (Applicant Brachvogel, Bent )
• Deciphering the role of secretory pathways in the reciprocal connection between the cellular nutrient sensing machinery and the extracellular matrix (Applicants Demetriades, Ph.D., Constantinos ;  Nuechel, Julian )
• Disease mechanisms and therapeutic interventions in non-classical osteogenesis imperfecta (Applicants Semler, Jörg Oliver ;  Zaucke, Frank )
• FACIT collagens XII and XIV and their role in musculoskeletal homeostasis and regeneration (Applicants Koch, Manuel ;  Krüger, Marcus )
• Matrix mediated fibroblast activation in rheumatoid arthritis (Applicants Korb-Pap, Adelheid ;  Pap, Thomas )
• Metabolically active hormones derived from the musculoskeletal system (Applicants Dötsch, Jörg ;  Hucklenbruch-Rother, Eva ;  Sengle, Gerhard )
• Microenvironmental regulation of muscle homeostasis and its role in musculoskeletal diseases (Applicants Hammerschmidt, Matthias ;  Sengle, Gerhard )
• Mitochondrial dysfunction in cartilage and its consequences for extracellular matrix and joint homeostasis (Applicants Brachvogel, Bent ;  Etich, Julia )
• Unravelling of pathomechanisms for plastin 3 associated bone and cartilage diseases (Applicants Niehoff, Anja ;  Wirth, Brunhilde )

• Spokesperson: Professor Dr. Bent Brachvogel