Research Aims

WP1: The role of genetic factors, the circadian clock and signalling pathways in tendinopathies
Tendons connect muscle to bone and are essential for movement, absorption of ground reaction forces (e.g. during running) and anchoring muscles to the skeleton.  Overuse  of  tendons can lead to ‘tendinopathies’ that affect  1 in  3 adults and are associated with time off work, and impaired ability  to  perform  simple  household and  personal hygiene tasks. Symptoms  range  from  tenderness  through  chronic  pain associated with  calcification of the mid‐substance, the area of the tendon closest to the muscle. The mechanisms through which tendinopathies occur (especially calcific tendinopathy), are unknown. WP1 aims to address this knowledge gap, taking into particular consideration the influence of genetic factors and the circadian clock.

WP2:  ER stress, intracellular signalling cascades and biomechanic consequences in heritable CTDs
Heritable connective tissue disorders (hCTDs) are a distinct group of over 500 unique rare genetic disorders. Recent studies have  demonstrated  that  several  key  mechanisms are shared among many of these pathologies: mutant protein misfolding and Endoplasmic Reticulum (ER) stress; dysregulated TGFβ signalling; changes in cell phenotype and the structure and function of the extracellular matrix (ECM); disruption of autophagy. In WP2, we will exploit an extensive portfolio of cell and mouse models of hCTDs to identify and study common and discrete disease signatures and pathomolecular mechanisms.

WP3: The role of lipocalin 2 in bone and tendon biology and biomechanics 
Unloading  is  associated  with  several  human  conditions  ranging  from  weightlessness  in space to the very common situation of reduced movement capabilities in the elderly. Central to the adverse effect of unloading on  bone  is  Lcn2,  a  protein  determined  by  UNIVAQ  to  increase  in  osteoblasts (bone-forming cells) subjected  to  reduced  mechanical  forces  obtained  in  a  laboratory  artificial  microgravity  system developed by NASA. Lcn2  is able to reduce the activity of osteoblasts and concomitantly favouring bone-resorbing cells (osteoclasts). The  relationship  between  Lcn2  and  mechanical  forces  is  demonstrated  by  the  observation  that  physical  exercise  counteracts bone loss and decreases Lcn2 expression.  We  hypothesise  that  Lcn2  plays  a  role  also  in  the response to mechanical forces of other connective tissues, and in this WP we will investigate its involvement in the bio-mechanical response of tendons.

WP4: Impact of ECM and oxygen tension on the interaction of osteogenesis and angiogenesis 
Blood vessel formation (angiogenesis) and bone  formation (osteogenesis) are  coupled during  bone remodelling to  obtain  normal  bone  homeostasis. In  the  previous INTERBONE project, ERASMUS and UNIVANNA studied the interaction between human osteogenesis and angiogenesis in low oxygen conditions. In these conditions, osteoblasts stimulate endothelial  morphogenesis,  and  the  osteoblast‐derived  proteins  involved  are  currently  being  scrutinized. Many questions remain concerning the impact of ECM on osteogenesis and angiogenesis as well as the impact of oxygen concentration, ECM composition, structure and/or undesired tendon calcification. These questions are  addressed as the core aims of WP4.