# A critical role for PLD1 in osteoclast fusion

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2021 · $333,104

## Abstract

Abstract
 Cell-cell fusion is a cellular event that is critical to several developmental and physiological processes
including bone homeostasis. Bone homeostasis is maintained by bone-forming osteoblasts and bone-resorbing
osteoclasts. The fusion of osteoclasts is critical for osteoclast activation and function. Elevated
osteoclastogenesis and bone resorption leads to osteoporosis that is a severe health problem characterized by
imbalanced bone remodeling in aging and pathological conditions. Current anti-resorptive treatments for bone
loss, which target early osteoclast differentiation and/or viability, have been limited by low response rates or
side effects. Recent studies suggest that targeting molecules controling osteoclast fusion may be a better anti-
resorptive therapeutic strategy for bone loss. However, very little is known about the molecular mechanisms
underlying osteoclast fusion. We recently found that phospholipase D1 (PLD1), through generating the
signaling phospholipid phosphatidic acid (PA), plays a critical role in osteoclast fusion. Our In vitro experiments
show that PLD1 activity is activated during osteoclastogenesis. Inhibition or genetic deletion of PLD1 inhibit the
fusion of mononucleated osteoclasts to multinucleated osteoclasts. PLD1 promotes osteoclast fusion through
regulating the formation of the protrusive membrane structure at fusogenic synapses. Through both a PA-
binding protein screen and RNA-Seq, we have identified a potential mechanism through which PLD1 regulates
osteoclast fusion. Finally, global deletion of Pld1, the gene encoding PLD1, protects mice from bone loss.
Based on these data, we hypothesize PLD1-generated PA plays a critical role in osteoclast fusion through
regulating the formation of the protrusive fusogenic synapse. We will test our hypothesis with the following
specific aims. In Aim 1, we will demonstrate that the spatiotemporal production of PLD1-genereated PA is
critical for osteoclast fusion. In Aim 2, we will elucidate the mechanisms through which PLD1 coordinates actin
cytoskeletal reorganization and membrane remodeling during osteoclast fusion. In Aim 3, we will define the
role of osteoclast PLD1 in bone homeostasis in both physiological and pathological conditions using knockout
mouse models. The goals of this project are to elucidate the role of PLD1 in osteoclast fusion and bone
homeostasis and identify new and more effective therapeutic targets for osteoporosis and other bone diseases.

## Key facts

- **NIH application ID:** 10216177
- **Project number:** 5R01AR075830-03
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** GUANGWEI DU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $333,104
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10216177

## Citation

> US National Institutes of Health, RePORTER application 10216177, A critical role for PLD1 in osteoclast fusion (5R01AR075830-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10216177. Licensed CC0.

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