Dr. Alan J. Nixon
Traumatic injury to joints such as the knee and fetlock are common in racehorses, often chipping off bone fragments, but also precipitating more widespread cartilage injury that culminates in osteoarthritis (OA). Joint injury and OA rank second only to tendon injury as the leading cause of racehorse retirement. A significant unmet need in medical research is the evolution of regenerative medical approaches that bolster both cartilage restoration and quell the reaction in the joint that follows impact injury. The primary problem in traumatic joint injury is that no cell based injectable therapy can heal cartilage in the face of ongoing cytokine flares that constantly breakdown new cartilage matrix as it forms. Our previous studies show both interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α) are major players in equine traumatic arthritis. We have developed a stem cell line that carry IL-1β and TNF-α silencing genes embedded in their genome. Our group, including collaborators at the University of Minnesota, have used Sleeping Beauty transposon based systems to integrate these silencing motifs into autogenous stem cells for direct joint injection. Stem cells have the capability of cartilage repair as well as directly seeding the joint lining to change the secretory function of the joint as a whole. This project aims to further develop multipotent stem cells that carry both cartilage enhancing and inflammatory dampening characteristics, and inject these cells to damaged joints. The aim is to be able to re-dose with additional cells as necessary to further this process by simple cell injection during the convalescent period. These regenerative approaches provide a new mode of medical care for joint injury that replaces or supplements the strictly pharmaceutic approach currently used in equine practice. The fundamental goal is to use stem-cell based cartilage repair to lessen arthritis and hasten return to performance. Presently, joint disease is still one of the leading causes of retirement in racehorses. Treatment costs have spiraled without emerging curative techniques. We hypothesize that osteoarthritis can be quelled by implantation of adult marrow-derived stem cells that are pre-programmed by gene induction to combine cartilage repair with environmental anti-inflammatory cues. This hypothesis will be tested by the following objectives: 1) Evaluate the efficiency and interactions of stem cells carrying RNA interference genes directed against IL-1 and TNF-α to optimize cytokine silencing; 2) Determine in vitro paracrine and remote effects of these cells on cartilage matrix degradation by stem cell/ arthritic cartilage explant co-culture; and 3) Evaluate long-term cartilage repair and joint health after implantation of gene packaged stem cells programmed for cartilage repair and local anti-inflammatory effects. Progenitor layers are substantially diminished in the adult, and seem poorly positioned to contribute to cartilage repair. This proposal evaluates stem cell implantation to arthritic joints, but more importantly, examines the additional benefit of stem cells that combine cartilage repair with local and regional cell-based anti-inflammatory action. Together, both effects should limit the long-term detrimental impact of joint injury and osteoarthritis.