Removal of Trauma-Induced Senescent Cells as a New Treatment for Osteoarthritis
Abstract
Arthritis is a major medical concern for the military population. This disease is characterized by progressive loss of cartilage, the tissue that lines the surface of articulating joints and, when healthy, provides a low-friction surface for painless movement. Osteoarthritis (OA) is the leading cause for disability and medical discharge in the United States military population. Active duty and Veterans suffer from arthritis at significantly greater rates compared to the civilian population. The combat-wounded Warrior, in particular, has a high rate of developing post-traumatic osteoarthritis (PTOA), with nearly all injuries to the knee joint resulting in PTOA. To further exacerbate the problem, the PTOA develops much sooner after injury compared to those in the civilian population. Current pharmacologic OA treatment options are analgesics, non-steroidal anti-inflammatory drugs, and viscosupplementation (e.g., hyaluronic acid) with intra-articular injections. These treatments focus on short-term symptomatic pain relief and care of joint function; however, with advances in the understanding of OA pathogenesis, there is a focus now on disease-modifying OA drugs designed to block or reverse OA progression by targeting specific OA catabolic pathways and pathophysiological signaling pathways. The proposed project, Removal of Trauma-Induced Senescent Cells as a New Treatment for Osteoarthritis, is directly responsive to the Fiscal Year 2016 Peer Reviewed Medical Research Program Topic Area of PTOA and the specific areas of encouragement including (1) research on therapies that target multiple phases of the cellular response pathways that are implicated in development of PTOA and (2) sustained release delivery of drugs in intra-articular injection. The research project will also highlight the importance of the immune system in regeneration and repair and thus the deleterious effects of steroid on disease modification. The overall goal of this proposal is to treat arthritis through a novel cellular target, senescent cells (SnCs). Cellular senescence prevents the proliferation of damaged and dysfunctional cells, thereby protecting multicellular organisms against cancer development, but can also contribute to the tissue deterioration that underlies aging and many age-related pathologies. SnCs accumulate in many tissues with age, where they promote age-related phenotypes and pathologies, presumably through the senescence-associated secretory phenotype (SASP): the transcriptional upregulation and secretion of several extracellular proteases, pro-inflammatory cytokines, chemokines, and growth factors. Senescent chondrocytes are associated with both post-traumatic and age-related OA and are found in cartilage tissue isolated from patients undergoing joint replacement surgery. We believe these cells, along with their inflammatory cytokine secretions, are responsible for OA development in otherwise young and healthy Service members. We will use novel drugs to selectively eliminate senescent cells, generating a new therapeutic platform that targets underlying disease mechanisms.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710627
Entities
People
- Jennifer Elisseeff
Organizations
- Johns Hopkins University
- United States Army