Project Grant R01AR082386

DEFINING THE UNIQUE CAPACITY OF THE MINIATURE JOINT MODEL FOR INVESTIGATING THE ROLE OF ADIPOSE TISSUE AND ITS IMPACTS ON OSTEOARTHRITIS - ABSTRACT: OSTEOARTHRITIS (OA) IS THE MOST PREVALENT FORM OF ARTHRITIS AND RESULTS IN REDUCED MOBILITY AND PAIN. EPIDEMIOLOGICAL AND CLINICAL DATA HAVE SHOWN A CORRELATION BETWEEN OA AND SPECIFIC RISK FACTORS LIKE OBESITY. PARTICULARLY, OVERWEIGHT HUMANS HAVE A 4-5 INCREASED RISK OF KNEE OA. CURRENTLY, THE ASSOCIATION IS NOT FULLY UNDERSTOOD, AND THERE ARE NO FDA-APPROVED DRUGS THAT CAN CURE OBESITY-ASSOCIATED OA. FOR DECADES, ANIMALS, PARTICULARLY RODENTS, HAVE BEEN THE MOST COMMONLY USED DISEASE MODELS THAT PROVIDED INVALUABLE INSIGHTS INTO OA PATHOGENESIS. HOWEVER, ONE ANIMAL MODEL IS UNLIKELY TO SIMULATE ALL OA PHENOTYPES IN HUMANS. FURTHERMORE, A LOW RATE OF SUCCESSFUL TRANSLATION FROM CURRENT OA ANIMAL MODELS TO CLINICAL TRIALS WAS REPORTED. A COMPLEMENTARY MODEL THAT USES HUMAN CELLS AND ENABLES TISSUE CROSSTALK SIMULATING HUMAN PHYSIOLOGY WOULD THUS BE A VALUABLE TOOL FOR RECAPITULATING SPECIFIC FEATURES OF HUMAN OA THAT CANNOT BE MODELED IN ANIMALS. RECENTLY, OUR TEAM HAS ENGINEERED AN IN VITRO MICROPHYSIOLOGICAL JOINT CHIP (MINIJOINT) THAT INTEGRATES THE OSTEOCHONDRAL, SYNOVIAL, AND ADIPOSE ANALOGS WITH IMMUNE CELL (MACROPHAGE) COMPONENTS. IN THIS NEW PROJECT, WE WILL CONTINUE THE DEVELOPMENT AND APPLICATION OF THE MINIJOINT BY INTRODUCING "OBESE" ADIPOSE TISSUES AND MECHANICAL LOADING MECHANISMS TO DETERMINE WHETHER THIS NOVEL IN VITRO SYSTEM CAN BE USED TO INVESTIGATE HOW NON-OBESE AND OBESE ADIPOSE TISSUES INTERACT WITH OTHER TISSUES DURING OA PATHOGENESIS. THE HYPOTHESIS OF THE PROPOSED STUDIES IS THAT "NORMAL" ADIPOSE TISSUE DRIVES CARTILAGE DEGRADATION IN RESPONSE TO INTERLEUKIN-1B OR MECHANICAL INJURIES, WHEREAS "OBESE" ADIPOSE TISSUE SECRETES DETRIMENTAL BY-PRODUCTS CAUSING CARTILAGE DEGRADATION AND SYNOVIAL INFLAMMATION, WHICH IS FURTHER EXACERBATED BY INTERLEUKIN-1B TREATMENT OR EXCESSIVE MECHANICAL LOADING. THE HYPOTHESIS WILL BE TESTED BY PERFORMING THE FOLLOWING THREE SPECIFIC AIMS. IN AIM 1, WE WILL DEFINE THE INFLUENCE OF NORMAL ADIPOSE TISSUE IN THE PATHOGENESIS OF OA IN THE MINIJOINT. SPECIFICALLY, WE WILL USE INTERLEUKIN-1B OR AN IN-HOUSE DEVELOPED UNIT TO INTRODUCE INJURIES TO THE MINIJOINT. IN AIM 2, WE WILL DEVELOP AN "OBESE" FAT MODEL IN THE MINIJOINT AND EXAMINE IF THE BY-PRODUCTS FROM DYSFUNCTIONAL ADIPOSE TISSUE IN THE MINIJOINT WILL RESULT IN INFLAMMATION IN THE SYNOVIAL TISSUE AND THE DEGRADATION OF CARTILAGE. WE EXPECT THAT INCREASING MECHANICAL LOADING WILL LEAD TO SIGNIFICANT CARTILAGE DEGRADATION WHEN THE CARTILAGE IS SIMULTANEOUSLY EXPOSED TO THE BY-PRODUCTS FROM "OBESE" ADIPOSE TISSUE. IN AIM 3, WE WILL CONDUCT COMPREHENSIVE COMPARISONS AMONG CARTILAGE SAMPLES FROM THE MINIJOINT, ANIMAL MODELS, AND HUMAN DONORS TO DEFINE THE UNIQUE CAPACITY OF THE MINIJOINT TO ACCURATELY MODEL HUMAN OA. THE SUCCESS OF THE PROPOSED STUDIES WILL DEFINE CRITICAL ASPECTS OF HUMAN OA THAT CAN BE READILY MODELED IN THE MINIJOINT. THROUGH COMPLEMENTARY STUDIES IN THE MINIJOINT AND ANIMAL MODELS, THE MECHANISTIC BASIS OF OBESE ADIPOSE TISSUE-MEDIATED PATHOLOGICAL CHANGES OF JOINT ELEMENTS IN HUMANS WILL BE ELUCIDATED AND HELP GUIDE THE DEVELOPMENT OF NOVEL TREATMENTS. IN ADDITION, THIS IN VITRO MODEL CAN BE EASILY ADAPTED FOR USE AS A ROBUST PLATFORM FOR NOVEL DRUG SCREENING.