Identification of Novel Genes Impacting Osteoblast Activity

PROJECT SUMMARY/ABSTRACT
Osteoporosis can be defined as the progressive loss of bone mass and strength with age, leading to increased
risk of fragility fracture. Osteoporotic fracture and fracture-related traits, such as bone mineral density (BMD),
are highly heritable and Genome-wide association studies (GWAS) for BMD have identified over 1100
associations for the phenotype of BMD. Further, there are many mono-allelic conditions, such as osteogenesis
imperfecta, that lead to low BMD and low-trauma fractures in children. Bone is in a constant state of
remodeling, with formation mediated by the osteoblast and resorption by the osteoclast and when these
processes remain balanced, there is no net change in BMD. Imbalances in remodeling results in the loss of
bone seen in osteoporosis, but a GWAS done for BMD cannot determine which of these physiological
processes are affected by each locus. All current fracture prevention therapies focus on tipping the remodeling
balance away from bone loss. There are three bone anabolic therapies approved by the FDA, but each of
these has black box warnings, each can only be used for a limited time (1 to 2 years respectively) and none of
them can be used in children. We have shown in previous work that bone mineralization by the osteoblast is a
highly heritable, complex genetic trait and that genetic mapping for the absolute amount of mineralization
possible yields information that is complementary to that identified by GWAS for BMD. However, the osteoblast
is a highly regulated, complex cell that undergoes an as of yet incompletely described differentiation process,
must be able to migrate to the site of bone remodeling, must be able to produce the proteinaceous extracellular
matrix of bone and then must be able to execute mineralization. The goal of this application is to identify the
key genes and pathways that control these aspects of osteoblastogensis and osteoblast function. In Aim 1, we
will map high-resolution quantitative trait loci (QTL) for osteoblast maturation, migration and rate of mineral
apposition. In Aim 2, we will use cutting edge Bayesian network analyses based on single cell RNA seq and
single cell ATAC seq to define master control genes of various stages of osteoblast development. In Aim 3 we
conduct functional follow up on genes found via our preliminary analyses that control the late stages of
osteoblast function. We expect that this comprehensive and complementary approach to identify key genes for
osteoblastic processes will provide critical insight into how bone is formed by the osteoblast. More importantly,
the genes that we identify will serve as potential therapeutic targets capable of increasing bone formation in the
setting of osteoporosis and in other formation disorders.

Grant Number: 5R01AR079839-05
NIH Institute/Center: NIH
Principal Investigator: Cheryl Ackert-Bicknell