R01AR080733

Is the Gut Important in Multiple Joint Osteoarthritis? A Multimodal Investigation in Humans and Pet Dogs - Project Summary

The central hypothesis of this work is that increased intestinal permeability (IP), either directly or via related comorbidities, promotes the development and worsening of multi-joint osteoarthritis (MJOA). Multiple joint osteoarthritis (MJOA), referring to OA in more than one joint site within an individual, is common but understudied. MJOA is progressive, and as the whole-body burden of OA increases, associated pain and disability increases, and treatments are less successful.

Despite the significant societal impact of MJOA, most OA research remains focused on individual joints. There is an urgent need to understand the factors that promote progression and worsening of MJOA. To address our hypothesis, our group has access to a large, longitudinal cohort of human patients and, uniquely, access to the naturally occurring MJOA model in pet dogs. There are no rodent models of MJOA, but dogs with naturally occurring MJOA have similar disease manifestations with more rapid progression compared with humans, making pet dogs an ideal model in which to explore underlying mechanisms of MJOA and potential therapies.

We have shown that inflammatory mediators are related to the overall burden of OA; these and other risk factors may at least partly derive from the gut microbiome via increased intestinal permeability (IP; "leaky gut"). We have evidence that lipopolysaccharide (LPS) and LPS-binding protein (LBP), reflecting increased IP and increased exposure to microbial products, promote OA. Additionally, serum LPS in humans (and serum LBP in dogs) is positively associated with the number of joints affected by MJOA.

To further elucidate the role of IP as a mechanism in MJOA, the proposed work will leverage human and dog studies: the JOCOOA, a longitudinal cohort of over 4000 black and white men and women aged 45 and older; the Johnston County Health Study (JOCOHS), an actively enrolling cohort (2019-, N~2000) including younger (35-70 years) and Hispanic individuals; and a large cohort of readily accessible naturally occurring MJOA in pet dogs. Data from all three cohorts will be used to address the following three aims.

In Aim 1, we will determine cross-sectional associations between altered IP, systemic inflammation, and radiographic and symptomatic MJOA in humans and pet dogs. Aim 2 will allow identification of biomarkers predictive of development and worsening of MJOA and determine longitudinal associations with markers of systemic inflammation and IP among JOCOOA participants and dogs. In Aim 3, we will test the effects of a prebiotic on IP, the microbiome, and MJOA symptoms by randomizing 70 dogs with MJOA (from Aim 1) to receive either a fructooligosaccharide supplement or placebo for 3 months followed by re-characterization of biomarkers of inflammation and IP.

These studies will both verify the association between increased IP and MJOA and robustly define biomarkers predictive of development and worsening MJOA, laying the groundwork for mechanistic studies to understand how increased IP promotes MJOA and to identify therapeutic targets, as well as provide means to identify at-risk individuals for preemptive management.

University Of North Carolina At Chapel Hill

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]

Chapel Hill, North Carolina 27599 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 349% from $707,028 to $3,176,745.