Identification and characterization of load resistance mechanisms in development and disease

A. Vortkamp, Uni Essen, & C. Hartmann, Uni Münster

Abstract: Mechanical loading plays an important role in the differentiation and homeostasis of the joint tissue. Imbalances in the weight-bearing axis disturb the fine tuned mechanical forces leading to an accelerated progression of joint degenerating diseases (osteoarthritis). This research project aims to identify new factors required for the reception of loading forces and their translation into biological responses. We will perform RNAseq on tissue samples of defined areas of sheep articular cartilage after alteration of the weight-bearing axis generated by the MADRY group. After confirmation of the most promising candidates in sheep tissue, mouse homologs will be cloned and investigated for their expression during embryonic and postnatal joint development. Their expression will also be analyzed in established osteoarthritis  mouse models. Priority will be given to candidates regulating chondrocyte differentiation (VORTKAMP), mechanoreception (PAP), chondroprotective regulators (SCHULZE-TANZIL), TGF-ß/BMP signaling (KNAUS), pain regulation, (MACHELSKA)) and mechanical loading (DUDA). Genes linked to specific stages of joint degeneration will be explored for their potential as diagnostic tools using human material from the SHIP study (PERKA). As the development of a functional joint is dependent on movement-dependent loading during embryonic and postnatal stages, loading responsive genes are likely to play a critical role in joint cartilage formation. Hence, for a subset of interesting candidates mouse mutants will be generated and analyzed. Besides their impact on articular cartilage formation, their role in maintaining joint homeostasis will be investigated in postnatal life and after introducing osteoarthritis  by ACL (VORTKAMP, PAP, KNAUS). To identify universally relevant mediators of OA, data obtained in this study (VORTKAMP, PAP, DUDA) will be overlayed (KLEIST) with those from the small animal models of the PrevOP Consortium (SCHULZE-TANZIL, KNAUS, MACHELSKA) and data from the clinical study (FELSENBERG).


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