Mobility is important for human well-being and quality of life. Many people suffer from limitations in mobility because of traumatic injuries and diseases of the locomotor system that result in bone defects or osteoarthritis. The burden of musculoskeletal diseases in Europe is very high and expected to increase rapidly in the coming years. Despite the fact that the incidences of these conditions are due to rise as our population ages, the development of new treatments has not progressed sufficiently in the last 20 years.
Impaired bone healing and osteoarthritis
Although bone and cartilage are formed in concert during embryologic development, in the context of these diseases the relationship is often ignored. By training 14 young scientists in combined skills from the presently separate and distinct fields of tissue engineering, cartilage and bone developmental biology and pathobiology, this multidisciplinary consortium aims to identify targets to develop novel functionalised biomaterials and to discover therapeutic drugs that can be used to treat bone defects, disturbed fracture healing or osteoarthritis.
There is an urgent need for new treatments for impaired bone healing and osteoarthritis.
Every year up to 3% of the world-wide population fractures a bone. The prevalence of bone fractures in people over 65 years is 50%1. Men and women are equally affected, although the incidence in young people is higher in males whereas in aged people the incidence is higher in females. Up to 15 % of the bone fractures do not heal well and currently 20% of these cases remain a problem even after surgical intervention.
In addition there is the population of patients with large bone defects resulting from tumour resection. This equates to a large portion of the population requiring new treatment options for large bone defect repair. In most cases, patients could be treated with bone grafts harvested from other locations in the body. This, however, has significant drawbacks: surgery is more invasive due to the harvesting of bone grafts and is associated with significant donor site problems. Less invasive techniques proved to be less effective than expected; recently, significant patient safety issues have arisen from the off-label use of Bone Morphogenetic Protein (BMP).
This product, previously making up over 40% of the US sales for bone replacement materials, has dropped by more than 25% because of significant complications. With regard to cartilage damage, over 33% of people over 65 years of age suffer from osteoarthritis, a painful and disabling disease of the locomotor system2. In addition, an increasing number of young people also suffer from early onset osteoarthritis. This is predominantly due to sports-related injuries but also to the increasing prevalence of obesity in western society.
The biological problems
Cartilage and bone are inextricably linked during development, pathology and repair3,4. 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. This occurs in the articular cartilage layer as well as on the joint margins where osteophytes, bony outgrowths strongly associated with joint pain, are formed.
Current status of the research
The pathobiology of impaired bone healing and osteoarthritis is influenced by cell fate decisions. These ultimately dictate whether cartilage tissue in the healing bone defect site or in the articular joint becomes vascularised and mineralised or not. This control is mediated by intrinsic and extrinsic factors, i.e. cell phenotype, local paracrine factors, the mechanical environment and extracellular matrix molecules, and these determine whether the endochondral ossification pathway is activated or suppressed.
In developmental biology these same factors have been identified as being important; paracrine factors (such as vascular endothelial growth factor (VEGF), fibroblast growth factors (FGF) and Wnt), specific matrix molecules (such as matrilins and cartilage oligomeric matrix protein) and mechanical loading have been shown to be critical in the processes of cartilage formation and endochondral ossification. Furthermore, tissue engineering approaches have recently started to take into account the principles of developmental biology.
When aiming to generate either bone or cartilage, tissue engineers also face this chondrocyte (cartilage cell) fate decision from two perspectives. Cartilage tissue engineers face the challenge of creating stable permanent articular cartilage using mesenchymal stem cells (MSCs) in which the endochondral ossification process is prevented. Conversely, bone tissue engineers have adapted to using the endochondral ossification process for bone re-generation by stimulating MSCs to form a cartilage intermediate, which, upon implantation, becomes vascularised and mineralised and eventually forms bone, albeit of limited quantity.
Additional information for public and patients
On top of the information provided specifically on the CarBon project available on this website, you can also consult our partner organizations’ websites. Reumafounds, ORUK and Deutsche Arthrose-Hilfe constantly publish updated information on the status of the research:
http://actueel.reumafonds.nl/ (Dutch only)
http://www.arthrose.de/aktuelles.html (German only)
Specific pages for patients are also available:
http://www.arthrose.de/arthrose/was-ist-arthrose.html (German only)
If you are interested in additional scientific contents for patients we invite you to consult the Manual for patients and citizens panels regarding ethical, legal and social aspects of innovative therapies with adult stem cells, gene therapy and nanoparticles, available here.
For the Compendium to the Manual, please click here.