Defining the role of aggrecan and type IX collagen in osteoarthritis and osteochondritis dissecans through in vivo studies of genetic bone diseases
Lead Research Organisation:
Newcastle University
Department Name: Biosciences Institute
Abstract
Diseases that affect the bones and joints of the human body can range from rare diseases, which result from mutations in a single gene (monogenetic bone diseases) to common conditions that result from a number of factors including a combination of complex genetic mutations, injury and lifestyle. Rare and common skeletal diseases share many features and disease pathways in common. It is therefore long recognised that studying disease processes in the rare skeletal diseases can help our understanding of disease processes in common conditions such as arthritis.
To this end we have been using genetically engineered mice to study disease processes in a group of rare human bone diseases, which also cause osteoarthritis (OA) and another painful condition known as osteochondritis dissecans (OCD), a disease that primarily affects children. We have shown that specific malformed structural proteins - the building blocks of cartilage - can cause problems with the way that cartilage is made and this renders it more susceptible to OA and OCD. We therefore plan to study these genetically engineered mice 'models' of human bone disease in greater detail, to understand disease process, which will eventually allow us to develop new therapies for these currently incurable common diseases.
To this end we have been using genetically engineered mice to study disease processes in a group of rare human bone diseases, which also cause osteoarthritis (OA) and another painful condition known as osteochondritis dissecans (OCD), a disease that primarily affects children. We have shown that specific malformed structural proteins - the building blocks of cartilage - can cause problems with the way that cartilage is made and this renders it more susceptible to OA and OCD. We therefore plan to study these genetically engineered mice 'models' of human bone disease in greater detail, to understand disease process, which will eventually allow us to develop new therapies for these currently incurable common diseases.
Technical Summary
Musculoskeletal diseases present an enormous healthcare burden across the UK, which is set to rise rapidly with the increase in ageing of the population. Skeletal diseases are a genetic continuum ranging from a large and heterogeneous group of rare monogenic diseases through to highly prevalent polygenic diseases such as osteoarthritis (OA) and osteochondritis dissecans (OCD). There is clear interdependency between rare and common skeletal diseases and studying genetically tractable rare skeletal diseases can be highly informative for dissecting disease pathways in the more common diseases such as OA and OCD.
The chondrodysplasias are a clinically variable and genetically heterogenous group of skeletal diseases that result from disrupted endochondral ossification. Although individually rare, as a group of related conditions, they have an approximate incidence of 1/3,500 and to date over 450 distinct phenotypes have been characterised. Many chondrodysplasia phenotypes present with age related changes such as early onset OA and also OCD.
We have previously shown that ER-stress, induced through the intracellular accumulation of misfolded mutant proteins in growth plate chondrocytes, is a core disease mechanism in a several chondrodysplasias; specifically, those caused by mutant COMP, type X collagen and matrilin-3. Equally, however, we have also shown that mutant cartilage structural proteins can also be secreted and exert a dominant-negative effect on the structure and/or function of the cartilage extracellular matrix (ECM). This is particularly the case for type IX collagen and aggrecan mutations; however, these novel disease mechanisms are poorly understood and require further investigation.
In this current study we will use our targeted mouse models of type IX collagenopathies (multiple epiphyseal dysplasia and Stickler disease) and aggrecan induced OCD to identify the disease mechanisms that underpin the development of generalised OA and OCD.
The chondrodysplasias are a clinically variable and genetically heterogenous group of skeletal diseases that result from disrupted endochondral ossification. Although individually rare, as a group of related conditions, they have an approximate incidence of 1/3,500 and to date over 450 distinct phenotypes have been characterised. Many chondrodysplasia phenotypes present with age related changes such as early onset OA and also OCD.
We have previously shown that ER-stress, induced through the intracellular accumulation of misfolded mutant proteins in growth plate chondrocytes, is a core disease mechanism in a several chondrodysplasias; specifically, those caused by mutant COMP, type X collagen and matrilin-3. Equally, however, we have also shown that mutant cartilage structural proteins can also be secreted and exert a dominant-negative effect on the structure and/or function of the cartilage extracellular matrix (ECM). This is particularly the case for type IX collagen and aggrecan mutations; however, these novel disease mechanisms are poorly understood and require further investigation.
In this current study we will use our targeted mouse models of type IX collagenopathies (multiple epiphyseal dysplasia and Stickler disease) and aggrecan induced OCD to identify the disease mechanisms that underpin the development of generalised OA and OCD.
