Osteoarthritis is the #1 disability in the United States. It affects 27 million adults, and the costs for healthcare and disability related to Osteoarthritis exceed $30 billion annually.
Osteoarthritis occurs when the articular cartilage that lines the surfaces of the joints becomes damaged. This can happen due to acute trauma, or as a result of aging.
Articular cartilage is a thin layer of white, glossy tissue that covers the ends of the long bones where they meet to form the joints of the arms and legs. The function of articular cartilage is to facilitate mobility by providing a smooth surface for the ends of the bones to glide against one another; and support for shock-absorption during load-bearing.
Cartilage tissue is comprised of cells called chondrocytes, and the material that surrounds the cells which is called matrix. Cartilage matrix contains fibers, proteins, glycosaminoglycans and water. It provides structural integrity and resilience to the tissue. The matrix is synthesized (and broken down) by the chondrocytes within it.
Under normal conditions, articular cartilage is a very stable tissue with almost no new matrix synthesis or breakdown. However, in response to injury, disease or aging, articular chondrocytes begin to break down matrix at a faster rate than they replace it. The result is formation of focal lesions of cartilage loss, known as articular cartilage defects, which eventually expose the underlying bone in large areas of the joint surfaces. These defects prevent smooth gliding motion of the joints and the exposed bone causes intense pain for patients. The end result of these changes is Osteoarthritis.
As no clinical approach is yet effective in treating Osteoarthritis, the key is prevention by restoring focal articular cartilage defects before damage becomes widespread. Clinical approaches for cartilage repair include filling the defects with pieces of donor cartilage, chondrocytes, or injections of “stem” cells obtained from fat or bone marrow. These attempts have not produced consistently durable articular cartilage repair. We propose this is because the cells used for repair in these clinical approaches don’t have the innate ability or preference to form native articular cartilage tissue.
Our goal is to regenerate damaged articular cartilage, not just repair it. Regeneration is a process of re-growth and re-development that forms replacement tissue identical to the original tissue. It requires “tissue-resident stem cells” that are capable of re-activating growth and differentiation pathways. These cells are present in the upper layers of the articular cartilage. We believe that only these cells have the inherent ability to regenerate true articular cartilage tissue and to successfully restore articular cartilage defects.
Our research has identified certain signals that can stimulate growth and regenerative responses by articular cartilage “stem cells”. These signals belong to the Epidermal Growth Factor Receptor (EGFR) family of tyrosine kinase receptors and ligands.
We found that in mice, genetic activation of EGFR signaling stimulated proliferation and matrix synthesis by articular cartilage stem cells, nearly doubling the thickness of the articular cartilage.
Our results suggest that EGFR signals may be useful in promoting growth and regeneration of damaged articular cartilage. In our ongoing studies, we are learning how resident articular cartilage stem cells respond to EGFR signals, and we are identifying the best EGFR signals to use to stimulate the regenerative responses we are looking for. We are working with orthopedic surgeons and biomedical engineers to develop arthroscopically-implantable scaffolds that deliver EGFR factors directly to the damaged regions within the joint.
We envision that in the future, articular cartilage regeneration by the body’s own resident articular cartilage cells could offer a simple, reliable approach for achieving seamless and durable articular cartilage defect repair, and a clinical tool for physicians to use to prevent Osteoarthritis in their orthopedic patients.