Project Grant R01AR084248

NEGATIVE REGULATION OF OSTEOCLASTOGENESIS - MANY PATHOLOGICAL CONDITIONS ASSOCIATED WITH EXCESSIVE BONE LOSS ARE CHARACTERIZED BY INCREASED GENERATION OF OSTEOCLASTS, MYELOID LINEAGE CELLS THAT RESORB BONE. THE LONG TERM GOALS OF THIS PROJECT ARE TO ELUCIDATE MOLECULAR PATHWAYS AND MECHANISMS THAT REGULATE MYELOID CELL FUNCTION AND OSTEOCLASTOGENESIS UNDER PATHOLOGICAL INFLAMMATORY CONDITIONS, WITH THE ASSOCIATED GOAL OF USING THIS INFORMATION TO DEVELOP NEW THERAPEUTIC APPROACHES TO SUPPRESS PATHOLOGICAL BONE RESORPTION. INFLAMMATION IS AN IMPORTANT DRIVER OF PATHOLOGICAL BONE LOSS IN DISEASES SUCH AS RHEUMATOID ARTHRITIS AND INFECTIONS. PATHOLOGICAL INFLAMMATION-ASSOCIATED BONE LOSS IS RESISTANT TO STANDARD ANTI-RESORPTIVE THERAPIES; THUS, DEVELOPMENT OF NEW TREATMENTS REPRESENTS AN IMPORTANT UNMET MEDICAL NEED. IN THE PREVIOUS CYCLE OF THIS APPLICATION, WE DEFINED EPIGENETIC AND METABOLIC MECHANISMS BY WHICH INFLAMMATORY CYTOKINES, INTERFERON- (IFN-) AND HYPOXIA REGULATE OSTEOCLASTOGENESIS. WE TESTED THE PATHOPHYSIOLOGICAL IMPORTANCE OF THESE MECHANISMS IN MODELS OF INFLAMMATORY BONE LOSS INCLUDING ARTHRITIS, IMPLANT LOOSENING, SUPRACALVAREAL OSTEOLYSIS, AND ORTHOPEDIC PERIPROSTHETIC JOINT INFECTION (PJI). PJI IS A DEVASTATING COMPLICATION OF JOINT REPLACEMENT SURGERY THAT IS RESISTANT TO TREATMENT AND A MAJOR CAUSE OF MORBIDITY, AND EVEN MORTALITY, IN ORTHOPEDICS. ONE ASPECT OF PJI IS BIOFILM-ASSOCIATED INFECTION AT THE BONE- IMPLANT INTERFACE WHICH RESULTS IN BOSS LOSS AND IMPLANT LOOSENING. USING A CLINICALLY RELEVANT TIBIAL IMPLANT MODEL OF PERSISTENT BIOFILM-ASSOCIATED STAPHYLOCOCCUS AUREUS PJI, WE OBSERVED BONE LOSS AND FAILURE OF OSSEOINTEGRATION. THIS WAS ASSOCIATED WITH SUSTAINED INFLAMMATION AT SITES OF INFECTION, BUT ADAPTIVE IMMUNE T CELLS WERE SUPPRESSED. ADVANCING THE LITERATURE DEMONSTRATING MYELOID-DERIVED SUPPRESSOR CELLS (MDSCS) THAT SUPPRESS T CELLS IN S. AUREUS INFECTIONS, WE NEWLY IDENTIFIED EXPRESSION OF INHIBITORY GENES IN THE SETTING OF A STRONG IFN- SIGNATURE, AN OSTEOCLASTOGENIC PROGRAM SELECTIVELY AT THE BONE-IMPLANT INTERFACE, AND ALTERED MYELOPOIESIS IN THE DISTAL BONE MARROW. INHIBITORY GENE EXPRESSION WAS MARKEDLY HIGHER IN TISSUE ADJACENT TO THE IMPLANT AND BIOFILM, RELATIVE TO SOFT TISSUES INFECTED WITH PLANKTONIC PHASE S. AUREUS. BASED ON THESE RESULTS, OUR OVERARCHING HYPOTHESIS IS THAT S. AUREUS PJI INFECTION INDUCES SUSTAINED INFLAMMATION THAT DRIVES OSTEOCLASTOGENESIS, BUT CONCOMITANTLY INDUCES FEEDBACK INHIBITORY MECHANISMS THAT SUPPRESS ADAPTIVE IMMUNITY AND ATTENUATE CLEARANCE OF INFECTION, RESULTING IN SUBSTANTIAL MORBIDITY. WE PROPOSE THAT GREATER UNDERSTANDING OF THE INFLAMMATORY AND BONE MARROW RESPONSES THAT DRIVE OSTEOCLASTOGENESIS, AND OF FEEDBACK MECHANISMS THAT SUPPRESS THE ADAPTIVE IMMUNE RESPONSE TO PJI, WILL PROVIDE KNOWLEDGE THAT CAN BE USED TO DEVELOP NEW APPROACHES TO SUPPRESS PATHOLOGIC BONE RESORPTION AND TO DEVELOP ADJUVANT IMMUNOTHERAPIES TO HELP CLEAR THIS DEVASTATING CONDITION.