Report
Teaser, summary, work performed and final results
Periodic Reporting for period 1 - RUBICON (Training network for Research on molecUlar and Biomechanical Interactions in CONnective tissue disorders)
Teaser
Connective tissue is the most abundant and widely distributed tissue in vertebrates. It protects, supports and links other tissues and organs, and is made by specialised cells which build the tissue, store energy, defend from pathogens and support other important functions. In...
Summary
Connective tissue is the most abundant and widely distributed tissue in vertebrates. It protects, supports and links other tissues and organs, and is made by specialised cells which build the tissue, store energy, defend from pathogens and support other important functions. In humans, there are three types of connective tissues: connective tissue proper, cartilage and bone, plus the blood, which is considered a fluid connective tissue. Blood vessels are integral parts of the connective tissues through which blood feeds and clears all other body tissues.
Connective tissue disorders (CTDs) have a high prevalence in the general population. Over 500 different inherited and congenital CTDs have been described. While they are individually rare (1:10,000), heritable CTDs comprise the most abundant group of heritable diseases in humans.
Other CTDs can arise from injuries, altered vascular supply, autoimmune conditions, inflammatory status, hormonal dysfunctions and impaired biomechanics. Injuries to tendon and ligaments alone affect 20% of the general population. This vast disease heterogeneity and the abundance of different connective tissues in our body make this family of diseases very expensive in terms of suffering, heath care and economic burdens.
RUBICON is a network of 10 research groups from Europe and around the world with expertise related to tendon, cartilage and bone diseases. The network will conduct a joint research programme to study the molecular and biomechanical interactions that contribute to conditions affecting various connective tissues, including tendinopathies, rare diseases, osteoporosis in the ageing population, and delayed fracture healing.
The overall research objectives of RUBICON are:
• To better understand the mechanisms of CTDs, in particular identifying any common factors. The new knowledge obtained will provide a strong basis for further research, treatment and prevention.
• To develop new experimental models for studying CTDs which can be used in further research.
• To identify targetable pathways, and other therapeutic strategies that can provide the basis for innovative and improved treatments for human CTDs.
Work performed
In its first two years RUBICON has secondments completed or in progress by 10 early stage researchers and 6 experienced researchers, with all ten participating organisations involved in sending and/or receiving of staff. Profiles of researches involved can be found at our website.
In general, research results obtained in these secondments cannot be yet disclosed as they must first be published in peer reviewed journals. Several publications are already in preparation. However, we can highlight the following achievements in terms of research training and general progress in P1.
University of L’Aquila has made good progress so far in its study of lipocalin 2 in bone and tendon biology, involving work in L’Aquila by Dharanibalan Kasiviswanathan (India), and at the University of Cape Town (UCT), South Africa, by Ricardo Paone. Studies of the rare disease autosomal dominant osteoporosis have also been performed, supported by training of Antonio Maurizi and Argia Ucci obtained during secondments to Australian partner Murdoch Children’s Research Institute (MCRI.)
Newcastle University has worked with MCRI on studies to test an existing drug CBZ that may be useful also for treatment of rare CTDs, with a secondment of Peter Bell to MCRI. Other collaborations are planned with RUBICON participants in India and Hong Kong.
University of Manchester researchers have obtained new data on the proteins in connective tissues that are regulated by the circadian clock, through collaboration with MCRI. They have also given training on in vitro 3D tendon models to Andrea Gibbon (South Africa) to support her investigation of genetic risk factors for tendinopathy, and for ER Shireen Lamande (Australia) who will use this approach to study a rare collagen defect.
Region Hovedstaden has also hosted Sharon Mkumbuzi from UCT who has analysed specific genes associated with tendinopathy pain in samples collected in Denmark, and have sent AnnSofie Thorup Olesen for training in proteomic analysis at MCRI.
USA partner Icahn School of Medicine at Mount Sinai, New York has hosted secondments of Alfredo Cappariello working on calcific tendinopathy, and Peter Tran and Tanja Skrba, investigating how variations in the expression of a specific gene affect tendon adaptation to exercise. All three researchers performed their experiments in mice including a mouse model of the rare CTD Marfan syndrome.
Erasmus Medical Centre working with visiting student Pavitra Kumar have identified specific proteins involved in the bone healing and will investigate these further. Further collaboration with Hong Kong University is in progress, with a secondment of Gerjo van Osch currently underway.
Final results
The research in RUBICON builds on exciting recent developments in our understanding of fundamental biology, in particular the influence of the circadian clock on biological processes throughout the organism, the cross talk between cells in connective tissue, and their interactions with mechanical forces. The research activities are in four work packages (WPs).
The mechanisms through which tendinopathies occur (especially calcific tendinopathy) are unknown. WP1 will provide a better understanding of the genetic and environmental factors affecting tendon health and repair. Improvements in tendon health are likely to have a major positive impact for the working population, elite athletes, and the ageing population, and for societal/healthcare costs. Results are to be exploited through non-proprietary innovations in clinical practice, sports training, physiotherapy and sleep hygiene.
Recent studies of rare heritable connective tissue disorders have identified several shared mechanisms, including mutant protein misfolding, Endoplasmic Reticulum (ER) stress and autophagy. WP2 aims to identify new therapeutic targets related to ER stress that should relate to multiple rare CTDs and will be attractive for exploitation in further translational research to improve treatment options.
Unloading is associated with several human conditions ranging from weightlessness in space to the very common situation of reduced movement capabilities in the elderly. The protein Lcn2 has been determined by University of L\'Aquila to increase in bone osteoblasts under artificial microgravity. They hypothesise that Lcn2 plays a role also in the response to mechanical forces of other connective tissues, and WP3 will investigate its involvement in the bio-mechanical response of tendons as well as bone. This research may open new avenues for the control of disorders of injured, paralysed, ageing and bed-bound people.
Fracture healing is a process that heavily depends on the cooperation between osteoblasts and endothelial cells in the context of low oxygen (hypoxia). It is also known that oxygen has a major impact on the growth of blood vessels during healing. WP4 is investigating the impact of extracellular matrix and hypoxia on bone and blood formation during fracture healing, and investigate how these processes also impact on tendinopathy. This research may also open up new avenues for improved treatment of fractures, tendinopathies and other connective tissue disorders.
Website & more info
More info: http://rubicon-network.org/.