# An Epigenetic Axis in Bone Formation

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $323,400

## Abstract

Abstract
An Epigenetic Axis in Bone Formation
As over 53 million adults in the United States have low bone mass due to arthritis and osteoporosis, novel
therapeutic strategies that protect from progressive and chronic bone loss are clearly warranted. The purpose of
the proposed research is to refine our central hypothesis, based on my previous research, the miR-23a cluster
controls bone synthesis and homeostasis by regulating Runx2-dependent Ezh2 expression. Current studies do
not have any insight on how epigenetic repression by histone methylation of bone specific chromatin is
maintaining bone mass in vivo. Understanding of this gap is pivotal for further studies to identify specific targets
for future therapies, which protect against bone loss. In our previous work we found that miR-23a cluster
represses Runx2 expression, inhibits osteoblast specific genes, and finally blocks osteoblast differentiation in
vitro. However, the inhibitory role of miR-23a cluster during the development and remodeling of bone and the
chromatin repression mechanism, leading to this inhibition of essential genes required for bone formation, is
unrevealed. To address the above queries in vivo for this bone-regulating miRNA cluster, we created an inducible
anti-miR-23a cluster (miR-23aClZIP) knockdown mouse model. Interestingly, our miR-23a cluster knockdown mice
developed high cortical and trabecular bone. RNA sequencing from these mice displayed an increased
expression of Runx2, the master transcription factor essential for skeletogenesis, and decreased expression
of Ezh2, a chromatin repressor also vital for skeletogenesis. Furthermore, we observed that Runx2 decreased
the repressive activity of Ezh2 to the promoters of bone essential genes for osteogenesis. Together, our findings
strongly suggest that miR-23a cluster connection with a tissue specific RUNX2–EZH2 function is a very unique
regulatory mechanism. Thus, this mechanism will be key to the genetic basis of bone development, growth and
maintenance further. However, additional research is needed to clarify 1) bone phenotype of miR-
23aClZIP mouse during development and maintenance; 2) compositions of the EZH2 led PRC2 methylation
complex and their recruitment; finally, 3) histone modifications and mechanisms that led to enhanced bone
formation. We will refine our central hypothesis by testing two hypotheses derived from the central hypothesis
and stated in the Specific Aims below. Together these specific aims will address the unresolved issues outlined
above. Specific Aim 1. In vivo inhibition of miR-23a cluster enhances bone synthesis and remodeling. Specific
Aim 2. In vivo inhibition of miR-23a cluster decreases EZH2 controlled methylation and modifications of bone
gene promoters. Exploring our novel mouse model with cutting edge in vivo and in vitro molecular tools, we will
accomplish the above specific aims, and later translate these results into osteoporotic and osteopenic bone loss
models, to block this ...

## Key facts

- **NIH application ID:** 10004501
- **Project number:** 5R01AR069578-05
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Quamarul Hassan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $323,400
- **Award type:** 5
- **Project period:** 2016-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004501

## Citation

> US National Institutes of Health, RePORTER application 10004501, An Epigenetic Axis in Bone Formation (5R01AR069578-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10004501. Licensed CC0.

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