# The role of autophagy in bone remodeling

> **NIH NIH P20** · UNIV OF ARKANSAS FOR MED SCIS · 2023 · $294,196

## Abstract

PROJECT SUMMARY/ABSTRACT – PROJECT 1
 Osteoblasts are bone-forming cells that produce large amounts of collagen and must maintain protein
homeostasis to prevent cell dysfunction and death. Altered protein homeostasis in osteoblasts may contribute to
the pathology of skeletal diseases such as Osteogenesis Imperfecta (OI). Autophagy recycles cellular
components by delivering them to lysosomes for degradation. In macroautophagy, cargo, such as aggregated
protein, is sequestered in double-membrane vesicles and delivered to lysosomes, while in chaperone-mediated
autophagy (CMA), individual proteins are delivered by chaperones. We have shown that deletion of Atg7, a gene
essential for macroautophagy, from osteoblasts causes low bone mass and fractures. This was associated with
low osteoblast number and disruption of the osteocyte network. Osteocytes, which differentiate from osteoblasts,
are buried in the bone matrix and sense changes in biomechanical load to orchestrate bone formation and
resorption. The mechanisms by which loss of macroautophagy in osteoblasts and osteocytes cause low bone
mass remain unclear. To examine the role of CMA in osteoblasts and osteocytes, we created mice lacking
Lamp2a, which is essential for CMA, and this also caused low bone mass, but to a milder degree than loss of
macroautophagy. Studies in other cell types suggest that CMA may be important mainly under conditions of
cellular stress, such as endoplasmic reticulum stress. In line with this, we found that osteoblasts lacking CMA
are more vulnerable to apoptosis induced by endoplasmic reticulum stress and produce more RANKL, a cytokine
that stimulates formation of bone-resorbing osteoclasts. Based on this, we hypothesize that macroautophagy
and CMA promote the differentiation, survival, and function of osteoblast lineage cells by maintaining
proteostasis and we propose the following aims. Aim 1 will identify mechanisms by which deletion of Atg7
reduces osteoblast number by measuring proliferation and apoptosis, and by using single cell RNA sequencing
to examine differentiation. We will also determine if loss of Atg7 alters the response of the tibia to mechanical
loading. Aim 2 will determine if loss of CMA worsens the skeletal phenotype of a murine model of OI to reveal if
CMA protects osteoblasts and osteocytes from endoplasmic reticulum stress. Aim 3 will determine whether
genetic stimulation of macroautophagy improves osteoblast function and reduces endoplasmic reticulum stress
in a murine model of OI. Successful completion of these studies will clarify the role of macroautophagy and CMA
in osteoblast lineage cells may identify new targets for therapeutic intervention in conditions such as OI.

## Key facts

- **NIH application ID:** 10495747
- **Project number:** 2P20GM125503-06
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** Melda Onal
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $294,196
- **Award type:** 2
- **Project period:** 2018-02-16 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10495747

## Citation

> US National Institutes of Health, RePORTER application 10495747, The role of autophagy in bone remodeling (2P20GM125503-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10495747. Licensed CC0.

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