Proteomics of Knee Osteoarthritis
Abstract
Overview: Osteoarthritis (OA) is a common disease, causing pain and limitations in joint function. Damage to the joint tissues, in particular to the articular cartilage, develops slowly and progresses to relatively severe stages before joint pain becomes noticeable. In most cases, patients engage their medical team to treat OA only when the pain level is no longer bearable, and the joint damage is affecting their mobility. No drug therapies are available to reverse joint damage or prevent its further progression once diagnosed. More than half of individuals who have sustained a severe knee injury, such as a meniscus or anterior cruciate ligament (ACL) tear, will go on to develop post-traumatic osteoarthritis (PTOA) within 10-20 years post-injury. Additional risk factors, such as diabetes and other metabolic diseases, have also been implicated in contributing to OA progression or exacerbating injury-mediated OA. Aging is also a big contributing factor to OA, and with people living longer than previous generations, it is estimated that by 2030 about 20% of the US population will be diagnosed with OA and will suffer from OA symptoms. Furthermore, it is estimated that 15% of all OA cases are preceded by a traumatic event to the ailing joint. Most OA patients do not show any symptoms until significant joint damage has occurred and, once diagnosed, the main treatment options are joint replacement surgery and/or pain management. While many factors can influence the development of OA, injury-mediated OA is the most promising for the development of effective pharmacologic interventions because a drug therapy (prophylactic) can be administered at the time of surgery or immediately post-injury. Studies in humans, while highly informative, are limited to examining late stages of the disease. Animal models offer a great advantage because they can be interrogated from the moment of injury until late stages of the disease to obtain a detailed picture of disease progression. Recently, scientists have discovered that an inbred strain of mice, MRL/MpJ, are protected from cartilage degradation after knee injury, and therefore this animal model can help us determine how to keep the knee healthy after a ligament tear. We hypothesize that in response to injury, MRL/MpJ mice synthesize proteins that (1) protect the joint from cartilage degradation and/or (2) promote cartilage regeneration. To test this hypothesis, we propose to generate an atlas of the injury-activated group of proteins expressed (proteome) in mouse models with varying susceptibility to PTOA: (1) C57BL/6 (moderately susceptible); (2) C57BL/6 treated with streptozotocin (STZ), a model of type 1 diabetes; (3) MRL/MpJ (super healers); and (4) Str/ORT (spontaneous OA). By conducting comparative analyses of the proteomes of injured and uninjured joints, we will identify novel protein candidates for further exploration as potential therapies for treating injured joints. Our study represents the first of its kind, aiming to conduct a high-throughput proteomic interrogation of the injured knee in several strains of mice with varying susceptibility to OA. We will achieve this by labeling newly synthesized proteins from the time of injury and through a combination of highly sensitive quantitative methods to identify all the proteins that are made de novo and infiltrate the knee after an acute traumatic event. Impact: Advances in proteomic technologies that can interrogate early events in PTOA are highly promising for identifying candidate biomarkers and therapeutic targets. Alterations in the proteomes of specific cell types present in the joint or at the systemic level can greatly influence disease outcomes; thus, a thorough catalog of proteomic and transcriptomic changes is critically needed to advance our understanding and, ultimately, to facilitate the development of PTOA treatments. The proposal addresses topic areas: (1) arthritis, (2) diabetes, (3) PTOA, and (
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910335
Entities
People
- Blaine A Christiansen
Organizations
- United States Army
- University of California, Davis