Sexually dimorphic regulation of bone mass by the X-linked histone modifier KDM5C

PROJECT SUMMARY/ABSTRACT Women are disproportionally susceptible to osteoporosis with generally poorer treatment outcomes. For decades, research regarding this difference was focused on the action of sex hormones. More recently, genetic, and epigenetic mechanisms have been recognized to significantly contribute to sex differences in bone mass. There is a critical need to understand the contribution of genetic differences to sex-bias in bone mass regulation, especially those linked to sex chromosomes. We observed that loss of the X-linked chromatin modifying enzyme, KDM5C, increases bone mass exclusively in females. The objective of this proposal is to determine the mechanisms by which KDM5C regulates female bone mass. We hypothesize that KDM5C transcriptionally programs a wide spectrum of genes that act synergistically to regulate osteoclast (OC) differentiation and function, and that inhibition of KDM5C will prevent age and pathology-induced bone loss. We, Dr. Tao Yang (MPI, expert in skeletal biology) and Dr. Connie Krawczyk (MPI, expert in immunology and metabolism), have assembled a motivated team to address this hypothesis. We will first investigate how loss of KDM5C affects OC function, how OCs communicate with osteoblasts (OB) via cross-talk, and OC energy metabolism. We will also define how KDM5C regulates epigenetic programming in OC progenitors, using genomic and epigenetic profiling analyses. Finally, as a first step toward the development of therapeutics, we will examine the impact of KDM5C deletion and pharmacological inhibition on estrogen-deficiency induced, inflammation induced, or age-related mouse models of osteoporosis. Impact: In this study, we will define how KDM5C-mediated epigenetic programming of OC regulates bone mass in females. These results will help to establish a multifaceted molecular network integrating epigenetic status, gene expression, metabolism, and bone microenvironment for a better understanding of OC programming and bone mass regulation between sexes. This is an important step toward our long-term goal to uncover the genetic factors and their mechanisms that can be targeted to improve women’s bone health.