# ATP-Citrate Lyase As A Novel Metabolic Target for Osteoarthritis

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2020 · —

## Abstract

Aging and obesity are the major risk factors for development of osteoarthritis (OA), the most common
form of arthritis. Veterans are at high risk of developing OA, because over 12.4 millions veterans are age 65 or
older, and nearly 80% of veterans are obese. For veterans and others, developing effective disease-modifying
therapy for OA is a major unmet medical need. As OA progresses, failure of the synovial joint organ frequently
develops, with degeneration of articular cartilage as a core disease feature. Chondrocytes, the sole cells in
articular hyaline cartilage, are responsible for maintaining the homeostatic balance between extracellular
matrix anabolism and catabolism. Dysfunction of chondrocytes in OA, amplified by local inflammatory
processes, leads to an excess of chondrocyte catabolic activity, medicated by factors including nitric oxide
(NO), matrix metalloproteinasess (MMPs) and aggrecanases. Cellular metabolism can intersect with certain
epigenetic and transcription factor modifications to mediate cellular re-programming. ATP citrate lyase (ACLY)
is a metabolic enzyme that converts citrate generated from mitochondria to acetyl-CoA in the cytosol and
nucleus, which serves as an acetyl donor for de novo lipid synthesis and acetylation of proteins in the cytosol,
and acetylation of histones and transcription factors in the nucleus, thereby modulating gene expression. Our
preliminary studies reveal that human knee OA chondrocytes/cartilages have increased ACLY activity,
associated with increased acetylation of histones. Pharmacologic inhibition of ACLY in OA chondrocytes
increases anabolic and decreases inflammation-mediated catabolic activities through modulating acetylation of
histones and transcription factors. Building on these findings in this translational project, we propose to test our
central hypothesis that chondrocyte ACLY is a druggable metabolic target for OA in vivo. We will test
hypotheses that (1) activation of Akt signaling by IL-1β and IGF-1, both of which are known to associate with
aging and obesity and are upregulated in OA cartilage, drives increased ACLY activity in human chondrocytes;
(2) Chondroprotection by limiting ACLY activity is mediated by increased chondrocyte autophagy; (3)
Suppression of ACLY activity protects mice from OA development and progression in both obesity-induced OA
via high-fat diet (HFD) and age-related spontaneous OA in vivo. Completion of these studies will provide new
insights into how metabolic alterations modulated by ACLY influence cartilage tissue integrity, and may provide
a novel approach by limiting ACLY activity to suppress or delay OA development and progression, particularly
in those at increased risk due to aging and/or obesity.

## Key facts

- **NIH application ID:** 9842265
- **Project number:** 5I01BX002234-06
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** RU BRYAN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2014-10-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9842265

## Citation

> US National Institutes of Health, RePORTER application 9842265, ATP-Citrate Lyase As A Novel Metabolic Target for Osteoarthritis (5I01BX002234-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9842265. Licensed CC0.

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