The skeleton is a highly complex tissue, which is continuously remodelled in a process mediated by the coordinated activities of bone forming osteoblasts and bone resorbing osteoclasts. A relative increase in bone resorption, associated with impaired differentiation or activity of bone forming cells, results in osteoporosis (OPO), one of the most prevalent disorders in the aged population affecting differently females and males. Women ≥ 50 years of age have a four times higher rate of OPO and tend to have fractures 5-10 years earlier compared with men. The majority of known physiologically relevant molecules and cellular pathways controlling bone remodelling have been identified in the last two decades by the investigation of molecular genetics of rare inborn bone disorders such as osteogenesis imperfecta (OI) and new data pointed out that osteoblast defects are responsible for low bone mass in disorders previously reported as cartilage specific, such as achondroplasia and hypochondroplasia. Thus, the relevance of genetic research for bone diseases in ageing is undoubted.

 

In WP2 the DCs will apply deep phenotyping approaches paired with molecular studies to understand the ageing-associated bone pathologies in two monogenic disorders associated with early onset OPO. More specifically, two murine models carrying a dominant negative mutation in type I collagen (DC1) and a gain-of-function mutation in FGFR3 (DC6), respectively, will be analysed. Moreover, since the process of endochondral ossification, which is not only relevant for skeletal development and growth, but also for bone regeneration during fracture healing, depends on the poorly understood trans-differentiation of chondrocytes into osteoblasts, the impact of dysregulated signalling pathways on this process will also be addressed.

 

WP2 will particularly focus on identification of the early signs of ageing in mutant animals by ex vivo and in vivo μCT, histology, bone-specific histomorphometry and extracellular matrix analysis. These analyses will be complemented by experiments in primary skeletal cells as well as -omics analyses on in vivo and in vitro samples. Besides the close collaboration of the DCs in the context of WP2, there will be specific interactions with WP1, WP3 & WP4, since it is expected that the models will display age-associated phenotypes in other tissues, such as cartilage, muscle and the vascular system, potentially associated with ageing-related cell signatures. Moreover, the combined expertise of WP2 partners will provide a platform that can be used for bone-specific analyses in all models being primarily studied in WP1 and WP3.

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WP Lead: University of Pavia

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Doctoral candidates:

• DC1 - University of Pavia

• DC6 - IMAGINE

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