# Nitric Oxide and Bone Homeostasis in Patients with Argininosuccinate Lyase Deficiency

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $418,440

## Abstract

Project Summary
 Nitric oxide (NO), a ubiquitous signaling molecule, is important for most physiological
processes including bone homeostasis. However, extensive in vitro and in vivo studies that have
assessed the role of NO in bone biology have often yielded contrasting results. This is at least in part
due to the fact that pharmacologic inhibition of nitric oxide synthases (NOS) or genetic models of
NOS deficiency are limited by the redundancies of the NOS isoforms and cannot address the cell-
autonomous roles of NO. Argininosuccinate lyase (ASL), is a urea cycle enzyme is not only required
for the de novo synthesis of arginine, the substrate for NOS, but also to maintain the structural
integrity of a NO-synthesis complex containing NOS, argininosuccinate synthase (ASS1), the arginine
transporter CAT-1, and HSP90. Loss of ASL leads to non-redundant and cell-autonomous loss of
NOS-dependent NO production and thus ASL deficiency (ASLD) is a human genetic disorder of NO
production.
 The overall goals of this proposal are to study the role of NO in bone turnover, density, and
architecture in a human model of NO deficiency and to understand the mechanistic basis by which
NO affects bone metabolism. By leveraging an ongoing trial in this rare genetic disorder, we will
address these specific questions: 1) Do patients with ASLD have abnormalities in bone turnover and
bone mass and does NOS-independent NO supplementation affect these endpoints? 2) Do patient-
derived induced pluripotent stem cells (iPSC) show differentiation defects along the osteoblastic
lineage and how does this impact osteoclastic differentiation? 3) Do osteoblasts derived from patient-
iPSC exhibit dysregulation of NO production due to dominance of a caveolin-dependent negative
regulatory NOS complex?
 These studies could have a significant impact on the basic understanding of bone biology and
foster translational studies in utilizing NOS-independent NO supplementation as a therapeutic
intervention in the more common disorders like osteoporosis.

## Key facts

- **NIH application ID:** 9896758
- **Project number:** 5R01AR071741-04
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Brendan Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $418,440
- **Award type:** 5
- **Project period:** 2017-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896758

## Citation

> US National Institutes of Health, RePORTER application 9896758, Nitric Oxide and Bone Homeostasis in Patients with Argininosuccinate Lyase Deficiency (5R01AR071741-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9896758. Licensed CC0.

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