# Inhibitory G protein (Gi) signaling in bone disease and repair

> **NIH VA I01** · VETERANS AFFAIRS MED CTR SAN FRANCISCO · 2020 · —

## Abstract

The differentiation of mesenchymal progenitor cells (MPCs) in the bone marrow environment is a crucial
determinant of bone mass, whole body metabolism, and bone repair. However, the mechanisms that
regulate MPC differentiation are poorly understood. This proposal is based on the hypothesis that MPCs
serve to sense metabolic stress which then directs their differentiation. In this view, the control of
adipogenic vs. osteogenic differentiation of MPCs is a mechanism for balancing structural/biomechanical
and metabolic needs. Excessive marrow adipogenesis is associated with bone loss and metabolic
adaptation whereas excessive osteoblast differentiation favors acquisition of bone mass possibly at the
cost of reduced capacity for metabolic adaptation. Conditions of high metabolic stress, such as diet-
induced obesity, drive adipogenic differentiation in preference to osteoblast differentiation. We propose
that G protein signaling is a key participant in metabolic sensing in MPCs, with the inhibitory G protein (Gi)
signaling pathway promoting the production of reactive oxygen species (ROS) that drives increased
marrow adipogenesis and bone loss. These concepts will be tested in three specifics aims. In specific
aims 1 and 2, we will utilize mouse genetic models to effect constitutive Gi signaling (Aim 1) or blockade
of Gi signaling (Aim 2) in MPCs. We will investigate the effect of these manipulations on bone marrow
adipose tissue, bone mass, fracture repair, and adaption to metabolic stress (high fat diet). In specific aim
3, we will use cellular and molecular approaches to elucidate the mechanisms by which MPC
differentiation is regulated by Gi signaling and by metabolic stress. Successful completion of these
studies will identify novel mechanisms for the control of skeletal and metabolic homeostasis, will provide
new insights into the basis for the well-established relationship between bone mass and bone marrow
adipose tissue, and may provide new opportunities for developing therapies aimed at improving bone and
metabolic health.

## Key facts

- **NIH application ID:** 9815455
- **Project number:** 5I01BX003212-04
- **Recipient organization:** VETERANS AFFAIRS MED CTR SAN FRANCISCO
- **Principal Investigator:** Robert Nissenson
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2016-10-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9815455

## Citation

> US National Institutes of Health, RePORTER application 9815455, Inhibitory G protein (Gi) signaling in bone disease and repair (5I01BX003212-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9815455. Licensed CC0.

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