R01AR077146

WNT7A-Mediated Competence to Resist Osteoarthritis Progression - Abstract

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.

Trustees Of Tufts College

THE NATIONAL INSTITUTE OF AND MUSCULOSKELETAL AND SKIN DISEASES (NIAMS) MISSION IS TO SUPPORT RESEARCH INTO THE CAUSES, TREATMENT, AND PREVENTION OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES, TRAINING OF BASIC AND CLINICAL SCIENTISTS TO CARRY OUT THIS RESEARCH, AND DISSEMINATION OF INFORMATION ON RESEARCH PROGRESS IN THESE DISEASES. THE EXTRAMURAL PROGRAM PROMOTES AND SUPPORTS BASIC, TRANSLATIONAL, AND CLINICAL STUDIES OF SYSTEMIC RHEUMATIC AND AUTOIMMUNE DISEASES, SKIN BIOLOGY AND DISEASES, BONE BIOLOGY AND DISEASES, MUSCLE BIOLOGY AND DISEASES, AND JOINT BIOLOGY AND DISEASES AND ORTHOPAEDICS. NIAMS SYSTEMIC RHEUMATIC AND AUTOIMMUNE DISEASES PROGRAMS ADDRESS BASIC, TRANSLATIONAL, AND CLINICAL RESEARCH, INCLUDING CLINICAL TRIALS AND OBSERVATIONAL AND MECHANISTIC STUDIES, FOCUSED ON IMMUNE-MEDIATED ARTHRITIS AND AUTOIMMUNE-RELATED ACUTE AND CHRONIC DISORDERS IN ADULTS AND CHILDREN. NIAMS SKIN BIOLOGY AND DISEASES PROGRAMS SUPPORT BASIC, TRANSLATIONAL, AND CLINICAL RESEARCH IN SKIN, INCLUDING BOTH COMMON AND RARE SKIN DISEASES. THESE PROGRAMS INCLUDE INVESTIGATIONS OF THE BASIC MOLECULAR, CELLULAR, AND DEVELOPMENTAL BIOLOGY OF SKIN, AS WELL AS STUDIES OF SKIN AS AN IMMUNE, SENSORY, ENDOCRINE, AND METABOLIC ORGAN. NIAMS BONE BIOLOGY AND DISEASES PROGRAMS SUPPORT RESEARCH ON THE CONTROL OF BONE FORMATION, RESORPTION, AND MINERALIZATION AS WELL AS THE EFFECTS OF SIGNALING MOLECULES ON BONE CELLS. THEY SUPPORT CLINICAL STUDIES OF INTERVENTIONS TO PREVENT FRACTURES ASSOCIATED WITH OSTEOPOROSIS AND RESEARCH INTO LESS COMMON BONE DISEASES. NIAMS MUSCLE BIOLOGY AND DISEASES PROGRAMS ENCOURAGE RESEARCH ON MUSCLE DEVELOPMENTAL BIOLOGY, GROWTH, MAINTENANCE, AND HYPERTROPHY, PHYSIOLOGY OF CONTRACTION, STRUCTURAL BIOLOGY OF THE CONTRACTILE APPARATUS, DISEASE MECHANISMS, BIOMARKERS AND OUTCOME MEASURES, AND DEVELOPMENT AND CLINICAL TESTING OF THERAPIES FOR CONDITIONS INCLUDING THE MUSCULAR DYSTROPHIES. NIAMS JOINT BIOLOGY, DISEASES, AND ORTHOPAEDICS PROGRAMS SUPPORT A BROAD SPECTRUM OF RESEARCH CENTERED ON THE INTERPLAY AMONG THE BODY'S MUSCLES, BONES, AND CONNECTIVE TISSUES. THEY ENCOURAGE TISSUE ENGINEERING AND REGENERATIVE MEDICINE RESEARCH, MOLECULAR BIOLOGY, IMAGING, AND CLINICAL RESEARCH, AND THE TREATMENT AND PREVENTION OF ORTHOPAEDIC CONDITIONS. NIAMS PARTICIPATES IN THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) AND SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAMS. THE SBIR PROGRAM IS INTENDED TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE STTR PROGRAM IS INTENDED TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.846 - Arthritis, Musculoskeletal and Skin Diseases Research

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [HHS - NIH]

Massachusetts United States

State-Wide

Research Supplements to Promote Diversity in Health-Related Research (Admin Supp Clinical Trial Not Allowed) (PA-23-189)

Amendment Since initial award the End Date has been shortened from 01/31/26 to 01/15/25 and the total obligations have increased 479% from $567,271 to $3,282,434.