Identification of Novel Osteocyte-Regulatory Therapies to Prevent and Treat PTOA in Warfighters
Abstract
This project seeks to develop novel therapies that prevent or mitigate post-traumatic osteoarthritis (PTOA) and osteonecrosis. Warfighters are disproportionately affected by both joint diseases, with osteoarthritis at a rate 26% higher than civilians in the 20- to 24-year age group and twice as high relative to those over 40. Discovery of new therapies for these "cartilage" diseases may unexpectedly depend on a search for agents that restore function to the bone underneath the cartilage. Such therapies may indirectly lessen the severity of PTOA and osteonecrosis in our military and civilian population. Rationale: Our joints have evolved to manage impressive mechanical loads while allowing smooth pain-free motion. In the joint, a thin layer of cartilage rests on another thin layer of bone, known as subchondral bone. The cartilage cushions the bone and lubricates the joint, whereas the underlying bone defines joint shape and absorbs the shock of motion. These tissues cooperate to support healthy joint function, and damage to either tissue contributes to joint disease and pain. However, the mechanisms by which this cooperation occurs are unclear. Understanding these mechanisms could reveal preventative or therapeutic strategies to protect joints from degenerative disease. While studying these mechanisms, we found new evidence that cells in subchondral bone behave differently in PTOA and in osteonecrosis, and that these cells indirectly act on cartilage to drive joint degeneration. The most abundant cells in subchondral bone are the osteocytes. Normally, osteocytes continually digest and replace their surrounding bone tissue to keep it strong and healthy. When osteocytes fail to "remodel" their surroundings, bone and cartilage become more susceptible to degeneration following joint injury. We hypothesize that rescuing the ability of osteocytes to remodel their surrounding tissue can prevent the breakdown of cartilage following injury to protect against joint disease. This hypothesis represents an advance beyond what is known because the ability of osteocytes to remodel, and to strengthen bone and protect cartilage, has only recently been recognized. Consequently, the possibility of targeting osteocytes with new drugs to prevent or treat PTOA or osteonecrosis has not previously been explored. Objective: Our objective is to identify new drugs that can rescue osteocyte remodeling and to test their ability to protect cartilage from conditions that drive PTOA or osteonecrosis. We use high-tech screens of U.S. Food and Drug Administration (FDA)-approved drugs, cell lines, and mouse models to accomplish this goal. This approach is powerful because agents that limit signs of joint disease in animal models may quickly be translated to clinical and military use. In addition, this screen may reveal that some currently used medications have unanticipated negative side effects on bone and cartilage. Therefore, our objective supports the clear goal of identifying new agents that can be used to mitigate joint disease in order to improve the short and long-term health of the military population. Impact: Warfighters have increased risk, earlier onset, and a worse prognosis for both PTOA and osteonecrosis, removing them from the line of duty. Thus, identifying agents that block the progression of these joint diseases has clear military relevance. Therapies that delay the onset or reduce the incidence of PTOA or osteonecrosis will allow Service men and women to remain active longer and minimize disability into the future. Given that the quality and continuity of care for military injuries is reliable and extensive, interventions are possible during the early, sensitive post-injury period when rescuing osteocyte function could potentially suppress joint degeneration. Timetable: In the long term, this research will lead to new drugs to prevent or treat PTOA or osteonecrosis. In the short term (less than 10 year
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810155
Entities
People
- Tamara Alliston
Organizations
- United States Army
- University of California, San Francisco