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.
