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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - CarBon (Controlling Cartilage to Bone Transitions for Improved Treatment of Bone Defects and Osteoarthritis)

Teaser

Summary

The CarBon project is a Marie Curie Innovative Training Network project . The aims are to increase our understanding of how healthy cartilage can turn into bone during disease (such as osteoarthritis) in order to prevent this process and how to induce the formation of healthy cartilage and bone for the repair of defects as a result of trauma or surgery via various regenerative medicine approaches.Cartilage and bone are inextricably linked during development, pathology and repair. During skeletal development most bones of the body are formed via a cartilage intermediate through the process of endochondral ossification. In the context of bone healing, endochondral ossification is also critically important. Normally, bone fractures are healed mainly via this process: the defect is bridged by a cartilage template that later mineralises and is replaced by bone. When bone healing is impaired, the defects are characterised by the formation of cartilage tissue that fails to undergo full endochondral ossification. At the joint surface, in the absence of disease, cartilage is a stable tissue that provides the mechanical environment required for healthy joint motion. However, in osteoarthritis, the articular cartilage fails to remain stable. Undesirable endochondral ossification occurs whereby the cartilage becomes vascularised, mineralised and is eventually replaced by bone. Damage and disease related to cartilage and bone as described above place a huge burden on society in socioeconomic terms.
Within this project we investigate and manipulate several biological aspects, namely cell behaviour, the extracellular matrix and the mechanical environment to better control cartilage formation and cartilage to bone transition, in order to ultimately develop new treatment options for large bone defect repair and the prevention or treatment of osteoarthritis. Important critical biological steps during the formation of cartilage and bone, such as cellular differentiation, the migration of cells and the generation of a vasculature are investigated using a broad range of models.
To achieve these ambitious aims, 14 early stage researchers (ESRs) have been employed. The combination of biologists and engineers, academics and non-academics has created a dynamic environment in which these researchers can develop their ideas. The first 3 work packages (WPs) of this project investigate the role of cell-secreted signaling molecules, extracellular matrix components and mechanical loading. WPs 4 and 5 link all knowledge using various types of models.

Work performed

In WP1 several potential interesting molecules have been identified based on large genetic screens performed prior to this project by the consortium members. A shortlist of cell secreted molecules that are potentially involved in the formation of blood vessels in cartilage (a key process in cartilage to bone transition) is created. In vitro models for stable and transient cartilage have been used to collect cell-secreted molecules and these molecules are being tested in several assays for blood vessel formation. Next to molecules, cells also secrete microvesicles, which carry a wide range of signaling molecules that can affect cellular processes. We have found that different inflammatory conditions can affect the release profile of these microvesicles.

In WP2 we are interested in understanding the role of the extracellular matrix (ECM) in the generation of new cartilage or bone and their maintenance. We are examining the role of several cartilage ECM molecules and their degradation products in the induction and maintenance of the processes leading to cartilage and bone formation in development and disease. These processes include differentiation of precursor cells to bone or cartilage cells, the formation of a mineralised matrix (as would be found in bone), the induction of migration of various cells and the formation of new blood vessels. We have identified up to 5 extracellular matrix molecules generated by cartilage cells or fragments of these molecules that are relevant for some or all of these processes. These molecules will be further investigated and promising candidates will be placed into existing scaffolds and used for bone and/or cartilage repair. The process of adding extracellular matrix molecules to the existing collagen type I based scaffold is being optimized.

In WP 3 consortium partners are examining the role of mechanical stimulation in the very same processes. Overloading of a joint is one example of how osteoarthritis can occur. However, it is also important for some mechanical stimulation to occur in order to maintain healthy bones and cartilage. Many of the mechanisms behind this are still poorly understood. Here we aim to shed new light on these processes and possibly to identify signaling pathways that are important for the modulation of biomechanical stimuli. Significant progress has been made in and we are now ready to use new matrices to study the effects of mechanical loading as well as a device that can model the overloading that occurs in patients with osteoarthritis. The first studies have revealed specific chemical inhibitors that might be used as a drug therapy to prevent or reduce the negative effects observed as a result of such overloading.

In WP 4 two different computer models of cell and tissue behaviour in cartilage are being developed based on existing knowledge from the labs, literature and new data generated in the consortium. Inflammatory pathways have been incorporated in the first model. This model has revealed several pathways that might be of importance for cartilage to bone transition and these are now tested in the first in vitro models set up in the consortium. The other model, that is including physiological mechanical loading, is under development.

WP 5 represents the culmination of all of the work performed within this project to test novel findings from the other work packages in small animal models for their ability to modulate osteoarthritis disease progression and bone formation/healing and secondly to develop and test a drug/material screening path that can be used beyond the life of this project to identify further new targets in a robust and efficient manner. Most progress to date has been made in the development of a screening path. The development of a useful pipeline for quantitative 3D microscopy to study the interaction between osteoprogenitors and blood vessels in bone development, post-natal growth and fracture healing is underway and several in vitr

Final results

Beyond the scientific progress, ESRs have been actively involved in training organised within the consortium but also within their institutions. Most have already performed secondments to some of the partner institutes. New knowledge generated within this project is combined with pre-existing knowledge into computational models for different biological processes. This will enable the consortium members to test different hypotheses much faster without the need to go into the lab. The goal of this project is to identify new factors that can control the transition of cartilage to bone in physiological and diseased states to develop new therapies for musculoskeletal related disorders.