Project Grant R00AR078352

ROLES OF THE SUPERFICIAL ZONE IN MATURE ARTICULAR CARTILAGE - PROJECT SUMMARY/ABSTRACT SYNOVIAL JOINTS ARE ESSENTIAL FOR FULL RANGE OF MOTION AND QUALITY OF LIFE. UNFORTUNATELY, THE JOINTS -AND ARTICULAR CARTILAGE IN PARTICULAR- ARE HIGHLY SUSCEPTIBLE TO CONGENITAL-, INJURY- AND AGE-RELATED DISEASES THAT LEAD TO DEGENERATION, A REFLECTION OF POOR INTRINSIC CARTILAGE REPAIR CAPACITY. CURRENT CLINICAL INTERVENTIONS DO NOT MEET THE WIDE RANGE OF DEMANDS ON ARTICULAR CARTILAGE DUE, IN LARGE PART, TO LACK OF CRUCIAL KNOWLEDGE ON THE CELLULAR MECHANISMS THAT GOVERN NORMAL FUNCTIONS OF ARTICULAR CARTILAGE SUCH AS LUBRICATION AND TISSUE MAINTENANCE GROWING ADOLESCENTS AND YOUNG ADULTS. IN ORDER TO ADVANCE THESE STRATEGIES, MORE INFORMATION IS NEEDED ON BASIC MECHANISMS OF ARTICULAR CARTILAGE DEVELOPMENT AND ADAPTATION/RESPONSE TO ENVIRONMENTAL CHANGES IN VIVO. THE SUPERFICIAL MOST LAYER OF ARTICULAR CARTILAGE IS RESPONSIBLE FOR SECRETING PROTEOGLYCANS (LUBRICANTS) INTO THE JOINT CAPSULE THAT ALLOW FOR FRICTIONLESS MOVEMENT. MANY STUDIES HAVE FOCUSED ON THIS AS THEIR PRIMARY FUNCTION, AND INCREASING LUBRICATION HAS SHOWN PROMISE FOR DISEASE TREATMENT. THIS PROJECT WILL TAKE A BROADER APPROACH TO CLEARLY DEFINE UNIQUE CHARACTERISTICS AND OTHER POTENTIAL FUNCTIONS FOR THESE CELLS THAT COULD BE TARGETED FOR THERAPEUTIC APPROACHES. IN PARTICULAR, THIS STUDY WILL FOCUS ON INTERACTIONS OF SUPERFICIAL ZONE CELLS WITH UNDERLYING ARTICULAR CHONDROCYTES. DEVELOPMENTAL STUDIES BY MY SPONSOR'S LAB AND PRELIMINARY DATA I HAVE GATHERED FROM ADULT MICE PROVIDE STRONG EVIDENCE THAT THE SUPERFICIAL ZONE DOES NOT FUNCTION AS A PROGENITOR POPULATION FOR UNDERLYING ARTICULAR CHONDROCYTES, AND INSTEAD SUGGESTS THAT SUPERFICIAL CELLS ARE UNIQUE FROM ARTICULAR CHONDROCYTES. THUS, I HYPOTHESIZE THAT SUPERFICIAL ZONE CELLS ARE MAINTAINED DISTINCTLY IN ARTICULAR CARTILAGE, BUT THAT THEIR COORDINATED FUNCTIONS WITH UNDERLYING ARTICULAR CHONDROCYTES PROMOTE SUSTAINED, FUNCTIONAL ORGANIZATION OF ARTICULAR CARTILAGE. TO TEST THIS HYPOTHESIS, IN AIM 1 I WILL CHARACTERIZE THE UNIQUE PROPERTIES OF SUPERFICIAL ZONE CELLS DURING GROWTH AND DURING THEIR RESPONSE TO DAMAGE COMPARED TO ARTICULAR CHONDROCYTES. IN AIM 2, I WILL DIRECTLY TEST THE REQUIREMENT OF THE SUPERFICIAL ZONE CELLS IN ADULT ANIMALS. IN AIM 3, I WILL EXPLORE MECHANISMS OF COORDINATED FUNCTIONS BETWEEN SUPERFICIAL CELLS AND ARTICULAR CHONDROCYTES TO MAINTAIN MATURE ARTICULAR CARTILAGE STRUCTURE. I WILL USE MULTIPLE ANALYTICAL TOOLS INCLUDING HISTOMORPHOMETRY, CONFOCAL IMAGING, AND NANO-SCALE MECHANICAL TESTING IN COMBINATION WITH RNA SEQUENCING AND IN SITU HYBRIDIZATION. CONDITIONAL MOUSE MODELS, INCLUDING OUR TRANSGENIC PRG4CREER ALLELE TO TARGET SUPERFICIAL ZONE CELLS, WILL BE EXAMINED AT ADULT STAGES AND FOLLOWING A TRAUMATIC INJURY (DMM-MODEL) THAT SIGNIFICANTLY ALTERS MECHANICAL LOADING IN THE JOINT. THE PROPOSED STUDIES WILL PROVIDE ESSENTIAL KNOWLEDGE ON MECHANISMS THAT UNDERLIE SUPERFICIAL ZONE CELL FUNCTIONS AND RESPONSES TO DAMAGE/ALTERED MECHANICAL LOAD. THE DATA AND INSIGHTS FROM THE PROJECT WILL PROVE ESSENTIAL TO ENVISION AND TEST FUTURE THERAPEUTIC JOINT STRATEGIES THAT TARGET SUPERFICIAL ZONE CELLS, PROVIDING BROAD RELEVANCE AND IMPORTANCE TO THE PROJECT AND OFFERING A SOLID PLATFORM ON WHICH TO ESTABLISH MY INDEPENDENT CAREER IN BIOMEDICAL AND TRANSLATIONAL MEDICINE RESEARCH.