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.