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D2 Frank Zaucke, Jörg Oliver Semler

The extracellular matrix in non-classical osteogenesis imperfecta

Prof. Dr. Frank Zaucke

Dr. Rolf M. Schwiete Research Unit for Osteoarthritis
Orthopedic University Hospital Friedrichsheim
Marienburgstr. 2, 60528 Frankfurt

 

PD Dr. Jörg Oliver Semler

University Hospital for Pediatrics and Adolescent Medicine
Faculty of Medicine, University of Cologne
Kerpener Str. 62, 50937 Köln

Summary

In approximately 90% of the cases, the clinical picture of Osteogenesis imperfecta (OI) is caused by mutations in collagen I coding genes. However, pathomechanisms of the remaining non-classical OI types are largely unknown. It is still unclear if structural changes of the ECM directly lead to increased bone fragility or if functional alterations of the ECM cause an impaired stability of the skeletal system. Only a better understanding of underlying mechanisms allows the development of new treatment strategies. Only the elucidation of disease mechanisms in non-classical OI type VI caused by mutations in SERPINF1 paved the way for a new anti-resorptive treatment.

The aim of the current project is to decipher mutations in new disease causing genes and analyze their pathogenic effects at the molecular and cellular level. 10 already recruited families will be characterized clinically and genetically using Whole Genome Sequencing.

Functional analysis will unravel the influence of mutations on protein stability and localization as well as on collagen folding, transportation and secretion also of other ECM components. The effects on cell proliferation and differentiation and on relevant signaling pathways will be investigated in vitro.

In addition to the identification of new pathologies the effects of currently used treatments like bisphosphonates in non-classical OI will be investigated in retrospective analysis. Thereby, we will define criteria for responders and non-responders and aim to develop more efficient therapeutic approaches.