Friday, September 13, 2024
9/13/2024
Abstract: Wnt7a-mediated competence to resist osteoarthritis progression Osteoarthritis (OA) is a highly prevalent and debilitating disease that currently has no effective therapy. OA has many risk factors, such as joint injury and aging. However, many people with these risk factors do not develop OA or develop it to a lesser extent. Individual responses to the same treatment are often also highly variable, hampering the testing of therapy in a reasonable-sized population. Thus, there is an urgent need to understand the basis for the diverse manifestations of OA. One driving factor of OA is proposed to be local inflammation. As prolonged inflammation elicits catabolic changes in the joint, the ability of each individual to resist inflammation could be directly linked to the trajectory of disease progression. Identifying factors that provide the competence to resist inflammation may be key to elucidating the cause of OA progression in individuals. Our long-term goal is to investigate OA pathogenesis to improve its treatment. The goal of this grant is to investigate the competence to resist inflammation and joint destruction conferred by an underexplored molecule (Wnt7a) from the Wnt signaling family. This proposal is based on our study that showed a striking negative-exponential relationship between Wnt7a and catabolic genes in individual human cartilage specimens. When Wnt7a expression was below a certain threshold, the samples were almost always of OA background, as if low levels of Wnt7a signify a higher risk of OA. In this way, Wnt7a may be a key factor associated with OA variability. Ectopic expression of Wnt7a under normal conditions did not impact cartilage matrix levels, but strongly halted joint destruction in experimental OA, suggesting that Wnt7a provided the joint with a certain ability to resist OA. Thus, we hypothesize that the level of Wnt7a within articular cartilage determines the competence against inflammation and impacts the trajectory of OA in each individual, forming the basis for OA variability. This hypothesis will be tested in two Specific Aims by 1) investigating whether Wnt7a alters the course of inflammation and the trajectory of cartilage loss and joint destruction in OA and 2) identifying downstream pathways and upstream regulators of Wnt7a. We will use gain- and loss-of function approaches on mouse OA and human cartilage specimens. The novelty of this study lies in the concept of Wnt7a as a competence factor for OA resistance in individuals to explore the mechanism of heterogeneity in OA, and in the use of advanced imaging technologies to test these concepts. These studies will define the role of Wnt7a in curtailing prolonged inflammation and the propensity for degenerative changes in OA. Furthermore, it will identify fundamental mechanisms for enhancing or preserving endogenous Wnt7a function in cartilage for joint protection. Thus, this work will provide important mechanistic insights into OA progression and its variability and the design of strategies to treat this disease.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
