# Nitric oxide regulation of glycolysis in osteoblasts

> **NIH NIH P20** · UNIV OF ARKANSAS FOR MED SCIS · 2023 · $294,195

## Abstract

PROJECT SUMMARY/ABSTRACT – PROJECT 3
 Nitric oxide (NO) is an important signaling molecule that influences a wide range of biological processes,
including bone metabolism. Recently, we utilized argininosuccinate lyase deficiency (ASLD) as a model to study
cell-autonomous, nitric oxide synthase (NOS)-dependent NO deficiency. Argininosuccinate lyase (ASL) is the
only mammalian enzyme capable of synthesizing arginine, the sole precursor for NOS-dependent NO synthesis.
Moreover, ASL is also required for channeling extracellular arginine to NOS for NO production. Using ASLD as
a model, we reported that NO promotion of bone formation is associated with stimulation of glycolysis during
osteoblast differentiation. Accumulating evidence suggests that osteoblasts utilize glucose metabolism via
glycolysis as their main energy source. Importantly, some of the anabolic agents used to increase bone mass,
such as Wnt proteins have also been shown to stimulate glycolysis during osteoblast differentiation, thus
suggesting an essential role of glycolysis in bone anabolism. The overall goal of this project is to identify the
mechanisms by which NO stimulates bone formation in physiological conditions and during mechanical loading.
We also will examine whether NO effects on glycolysis are responsible for effects on bone mass. We reported
that NO-deficient cells had downregulated mRNAs encoding components of the glycolysis pathway, suggesting
that NO may modulate transcription factors that regulate expression of genes in the glycolysis pathway.
Moreover, NO-induced stimulation of glycolysis may be involved in load-induced bone formation, a process in
which abundant work has implicated NO as a critical mediator. The central hypothesis of this project is that NO
production by osteoblast-lineage cells promotes osteoblast differentiation and bone formation by stimulating
glycolysis. We will test this hypothesis with three specific aims. Aim 1 will determine whether NO promotes bone
formation and glycolysis in osteoblasts by activating cAMP-responsive element binding protein (CREB). Aim 2
will determine whether genetic upregulation of glycolysis is sufficient to stimulate bone formation or rescue the
bone mass deficiency in osteoblast-specific Asl knockout mice. Aim 3 will determine whether NO produced from
osteoblasts and osteocytes is required for load-induced anabolism. Successful completion this project should
advance knowledge of the molecular mechanisms underlying the effects of NO on bone. Furthermore, it may
provide new insights into therapeutic targets for bone anabolism.

## Key facts

- **NIH application ID:** 10495749
- **Project number:** 2P20GM125503-06
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** Zixue Jin
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $294,195
- **Award type:** 2
- **Project period:** 2018-02-16 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10495749

## Citation

> US National Institutes of Health, RePORTER application 10495749, Nitric oxide regulation of glycolysis in osteoblasts (2P20GM125503-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10495749. Licensed CC0.

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