# Characterizing the mechanism by which endogenous negative regulators of osteoclasts control bone homeostasis under physiological and pathological conditions in mouse models

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $326,700

## Abstract

The immediate goal of this application is to understand how osteoclast (OC) differentiation is regulated through
negative endogenous regulators, which may provide novel therapeutic targets for bone diseases, such as
osteoporosis and rheumatoid arthritis (RA). Although positive regulators of OC differentiation through the
receptor activator of nuclear factor kB (RANK) ligand (RANKL)-RANK signaling axis have been extensively
studied, understanding of negative regulators of OC differentiation is elusive. To identify key negative regulators
of OC differentiation, we utilized microarray, gene downregulation, and osteoclastogenesis assays, leading to
the isolation of guanine protein alpha subunit 13 (Gα13, encoded by the Gna13 gene) as a potential OC negative
regulator. To enable in vivo investigation of the role of Gα13 in OC differentiation, we generated an OC-lineage
specific Gna13 conditional knockout (CKO) mouse model by crossing Gna13f/f mice with LysM-Cre (OC
precursor specific) mice. Our preliminary data showed that Gna13f/fLysM-Cre mice exhibited a severe
osteoporosis from a drastic increase in OC differentiation. We also noted that Gα13 deficiency attenuates RhoA
activity and promotes Akt activity in OCs. Consistently, we showed that, as a proof of principle strategy, local
constitutively active Gα13 overexpression can protect against bone and cartilage loss while also attenuating
inflammation in a mouse model of RA. Based on our preliminary data, we hypothesize that Gα13 is a key
negative regulator of OC that controls OC cell lineage commitment and differentiation for bone homeostasis
under physiological and pathological conditions through activating RhoA and attenuating AKT signaling pathway.
Three specific aims are proposed to test our hypothesis. In Aim 1, we will characterize the bone phenotypes of
Gnα13f/fLysM-Cre mice and elucidate the mechanism underlying how Gα13 activates RhoA signaling and
attenuates Akt signaling to negatively regulate OC cell lineage commitment and differentiation. In Aim 2 we will
determine the upstream Gα13 signaling cascade in OCs through characterization of G protein coupled receptors
(GPCRs) coupled with Gα13. We will characterize the mechanism underlying the roles of Gα13 in bone
remodeling and pathological bone loss by using dendritic cell (DC)-, monocyte- and OC-specific Gna13 CKO and
overexpression transgenic mice in the loss-of-function and gain-of-function analysis, respectively. This study
may provide important insights into the roles of negative regulators of OC differentiation in bone homeostasis
and osteolytic bone diseases of excessive OC differentiation. Knowledge gained from this study may generate
potential therapeutic targets, through characterization of Gα13 signaling in OCs that may be targeted in treating
osteolytic bone diseases by mimicking normal OC inhibitory signaling pathway to control OC formation. A
multidisciplinary research team, including a bone biologist with expertise in OC bio...

## Key facts

- **NIH application ID:** 9908042
- **Project number:** 5R01AR070135-04
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Wei Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $326,700
- **Award type:** 5
- **Project period:** 2017-04-01 → 2021-01-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9908042

## Citation

> US National Institutes of Health, RePORTER application 9908042, Characterizing the mechanism by which endogenous negative regulators of osteoclasts control bone homeostasis under physiological and pathological conditions in mouse models (5R01AR070135-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9908042. Licensed CC0.

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