Applicant:

Name: Prof. Dr. Wiltrud Richter, Heidelberg

E-mail: Wiltrud.richter@med.uni-heidelberg.de


Role of microRNAs in cartilage function, pathology and progression of osteoarthritis

MicroRNAs (miRs) are post-transcriptional regulators of gene expression which are involved in the timely response of the cell to alterations in the environment. MiR clusters are regulated during chondrogenesis and manifestation of OA pathophysiology and have been associated with mechanosensitivity and mechanotransduction in cardiovascular biology and mechanical airway ventilation. Surprisingly little is, however, known on the role of mechanosensitive miRs in cartilage function and pathophysiology of OA. Aim of this study is to gain a better understanding of the role of miRs in mechanotransduction in chondrocytes and to identify and functionally characterize mechanosensitive miR clusters which may serve as novel diagnostic tools or putative future therapeutic targets of developing OA.

 

By profiling miR expression in biomechanically challenged human chondrocytes from healthy and OA cartilage compared to unloaded controls we will extract and validate mechanosensitive miRs, identify and verify putative, OA-relevant targets and characterize the function of selected miRs in chondrocytes by overexpression and knockdown experiments (Aim 1). This validated and characterized miR panel will then be further tested for diagnostic suitability in human healthy and OA cartilage samples and for differential expression in mouse and human OA models. We will analyze and functionally characterize expression of mechanosensitive miR clusters in integrin- and heparan sulfate-dependent mechanotransduction in cooperation with SP1 and SP2. Alterations in expression of our mechanosensitive miR panel will be assessed in cartilage samples during OA development in integrin-deficient mice provided by SP1 and in heparan-sulfate deficient mice provided by SP2 (Aim 2 and 3). MSC undergoing in vitro chondrogenesis which will additionally be exposed to biomechanical loading and/or to an osteoarthritic milieu, will serve as human in vitro OA model in SP7. From this model we will try to extract miRs differentially regulated by beneficial versus non-beneficial loading (Aim 5). Together with SP4 we will investigate whether miRs targeting the sensory neurotransmitter receptors NK1R and CGRP receptor are differentially expressed during the pathogenesis of OA and may hold potential to affect osteochondral regeneration and subchondral bone remodeling (Aim 4).

 

In the end we will, thus, have obtained new insight into mechanotransduction in chondrocytes and know whether our validated panel of mechanosensitive miRs can serve as novel diagnostic markers for OA development and may help to identify new therapeutic targets for OA treatment.