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.