# Molecular Regulation of MSC fate Decision  and Bone Formation by PGC-1a

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $442,451

## Abstract

Project Summary/Abstract
Bone marrow mesenchymal stromal/stem cells (MSCs) have multiple differentiation potentials and can be
induced to differentiate into osteoblasts and adipocytes. MSCs are believed to be the common progenitors
for both osteoblasts and adipocytes in bone. As commitment to these two lineages is mutually exclusive, the
osteogenic differentiation of MSCs requires coordinated inhibition of the adipogenic differentiation. Aging-
related dysfunctions of MSC fate commitment and bone formation have been related to osteoporosis,
periodontitis and other metabolic bone diseases. Osteoporosis is the most common metabolic bone disease,
and is a leading cause of morbidity and mortality in our aging population. In osteoporosis and skeletal aging,
it has been observed that aberrant lineage differentiation of MSCs leads to increasing marrow adipose tissue
(MAT) accumulation at the expense of bone formation. Therefore, understanding the molecular mechanisms
that control MSC fate determination is critical for developing novel therapeutic strategies for treating
osteoporosis and other chronic bone diseases. Peroxisome proliferator-activated receptor-γ coactivators 1α
(PGC-1α) is a master regulator of mitochondrial biogenesis and oxidative metabolism in liver, skeletal muscle,
brain and the heart, however, its role in bone homeostasis and metabolism remains to be investigated. In this
resubmission, we discovered that loss of PGC-1α not only accelerated bone loss, but also enhanced MAT
accumulation in osteoporotic and aging mice. Moreover, the specific deletion of Pgc-1α in multipotent
mesenchymal cells significantly accelerated MAT accumulation and impaired bone formation in osteoporosis.
Loss of PGC-1α reduced cytosolic β-catenin levels and impaired Taz expression, suggesting that PGC-1α
regulates MSC fate decision and bone formation. In addition, we found that there was a dramatic decrease in
PGC-1α expression in human MSCs during aging. Based on these exciting findings, we hypothesize that
PGC-1α plays a critical role in MSC fate decision and bone formation. To test our hypothesis, we propose
the following three specific aims: 1) Determine if PGC-1α intrinsically regulates osteogenic differentiation of
MSCs and bone formation in osteoporosis and skeletal aging; 2) Determine if PGC-1α intrinsically regulates
adipogenic differentiation of MSCs from bone marrow in osteoporosis and skeletal aging; and 3) Explore the
molecular mechanisms by which PGC-1α regulates the osteogenic and adipogenic commitment of MSCs.
New findings from our studies may identify a novel factor that regulates MSC fate decision and bone
formation, and thus presents a promising therapeutic target for osteoporosis and MSC-mediated craniofacial
bone regeneration.

## Key facts

- **NIH application ID:** 9852997
- **Project number:** 5R01DE024828-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** CHRISTINE HONG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $442,451
- **Award type:** 5
- **Project period:** 2017-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852997

## Citation

> US National Institutes of Health, RePORTER application 9852997, Molecular Regulation of MSC fate Decision  and Bone Formation by PGC-1a (5R01DE024828-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9852997. Licensed CC0.

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