Musculoskeletal Disease Researchers Uncover Molecular Mechanisms of Extracellular Matrix Destruction

The completion of the Human Genome Project is a landmark development for musculoskeletal disease research. Exciting new information from the project facilitates the goal of understanding arthritis and other musculoskeletal diseases at the most fundamental molecular level. For several years, the Department of Biomedical Engineering at the Cleveland Clinic's Lerner Research Institute has been supplying the genome databases with gene sequence, protein and genetic information that is relevant to musculoskeletal disease, especially arthritis.

In turn, the department has used gene discovery information from the Human Genome Project to help us identify enzymes that may have the ability to destroy cartilage and extracellular matrix (ECM), as well as molecules that protect cartilage against the action of these enzymes.

Both the enzymes and protective molecules are being manufactured in our laboratory by recombinant DNA technology using cultured cells as protein factories. Once obtained in a pure form, these molecules can be used to conduct biochemical studies, develop diagnostic tests and antibodies, or engineer new cartilage.

Important studies under way now in our laboratory are designed to determine the structure of some of these molecules and identify their interactions with each other by manipulation of genes or proteins. The fundamental questions being asked about the molecules are: What do they look like? Where are they located? What controls their production? What are all the possible interactions and functions in which they participate? What roles do they have outside of cartilage?

Our group also uses genetic methods, such as introduction of mutations into proteases, to determine their function. Analysis of transgenic mice deficient in the enzymes provides information about their roles during skeletal development and can shed light on inherited skeletal disorders and orthopaedic disorders in children.

The evolution of medical advances from basic research such as this often takes many years. The biology and biochemistry of cartilage and arthritis are extremely complex and require in-depth studies of individual molecules. On the other hand, the impact of such fundamental work can be enormous. With the greater understanding of disease processes and the power of technology comes the potential to alter current thinking and develop innovative strategies to improve management of musculoskeletal disease. Someday, genes which protect cartilage from destruction could be harnessed for gene therapy to prevent the progression of the disease.

(Above) Growth-plate cartilage from mice with mutations in a protease gene. Compared with the normal growth plate at the top, the growth plate on the bottom clearly shows some structural changes which may be responsible for the dwarfism seen in these mice.

The Role of Extracellular Matrix (ECM)

All organs in the body are made of cells surrounded by ECM, the supporting and mechanical framework of tissues and organs. In cartilage and bone, which mainly function as mechanical support, ECM is extremely important, has a special structure and is much more abundant than in non-mechanical organ tissues.

Abnormalities in many of the numerous molecules which comprise ECM can lead to connective tissue disorders such as osteoarthritis, brittle bone diseases such as osteogenesis imperfecta or osteoporosis, idiopathic scoliosis, frozen shoulder and tennis elbow - diseases for which the precise cause has not been identified. Abnormalities may arise from inherited or congenital defects, or ECM molecules may be affected by inflammatory and autoimmune diseases.

Molecular research into ECM structure and function and its destruction, therefore, has occupied a front-line position in connective tissue biology and orthopaedic research. Our group focuses on the proteolytic processes by which ECM molecules are broken down. Excessive activity of protease enzymes is recognized as the key mechanism by which cartilage is lost from arthritic joints. The key to understanding how cartilage is broken down is to identify which proteases are responsible, how they are normally controlled and what goes wrong in arthritis.

The laboratory is funded currently by the National Institutes of Health, the National Arthritis Foundation and the Northeast Ohio Chapter of the Arthritis Foundation.