# Ferroptosis as a Potential Mechanism of Blood-Induced Chondrocyte Cell Death

> **NIH NIH F31** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $45,520

## Abstract

Project Summary
Hemophilia is an X-linked genetic disorder that prevents blood from clotting normally due to a deficiency in either
coagulation factor VIII or factor IX. Uncontrolled internal bleeding can occur during surgery and from blunt force
trauma-induced breakage of blood vessels in the synovial membrane. Recurrent episodes of hemarthrosis lead
to complete destruction of the articular cartilage, known as hemophilic arthropathy. While the exact mechanisms
of blood-induced cartilage damage remain unclear, apoptosis is implicated as the primary form of regulated cell
death (RCD) in chondrocytes due to elevated concentrations of pro-inflammatory cytokines. However, other
forms of RCD may play roles in inducing damage to cartilage as well as the surrounding synovium. Ferroptosis
is a recently discovered, iron-dependent, nonapoptotic form of RCD associated with excessive intracellular
accumulation of lipid hydroperoxides formed from free hydroxyl radicals and polyunsaturated fatty acids. This
proposal explores ferroptosis as a potential mechanism of joint tissue damage caused by excess intra-articular
iron released from blood. In addition, ferroptosis inhibitors such as Ferrostatin-1, which prevent the formation of
lipid hydroperoxides, are explored as potential therapeutics against blood-induced cell death.
This new F31 proposal will fill a large gap in the current understanding of hemophilic arthropathy. Better
understanding of the dose-response of blood exposure and duration may yield potential therapeutic windows of
intervention that abrogate the sequela of joint bleeding. The role of physiologic joint loading and the synovium
on blood-induced cartilage damage will also be addressed using a synovial joint model system coupled with
modern bioengineering and molecular biology techniques (e.g., metabolomics). Isolating the effects of blood on
cartilage, synovium, and their co-culture will inform new targets aimed at chondroprotection from joint bleeding.
Hypothesis 1: Blood-induced cartilage damage is due in part to ferroptosis of articular chondrocytes. Specific
Aim 1: A) Perform dose-response to blood on mechanical and biochemical properties of articular cartilage.
Assess relative contribution of necrosis, apoptosis and ferroptosis in blood-induced cartilage damage. B) Study
respective contribution of blood constituents to joint tissue damage and compare with ferroptosis inducers. C)
Subject blood to fluid-induced shear and monitor erythrocyte viability and blood-cell related products in the
synovial fluid. D) Assess ability of Ferrostatin-1 to mitigate blood-induced changes to cartilage.
Hypothesis 2: Blood related cartilage damage is exacerbated by blood-induced changes to synovium. Specific
Aim 2: Repeat Specific Aim 1 on synovium and cartilage-synovium co-culture. A) Perform reciprocating shear of
synovium-on-cartilage and cartilage-on-cartilage. B) Perform conditioned media experiments that transfer media
from reciprocal shear loading of...

## Key facts

- **NIH application ID:** 10068825
- **Project number:** 1F31AR078004-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Andy Jaehan Lee
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 1
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10068825

## Citation

> US National Institutes of Health, RePORTER application 10068825, Ferroptosis as a Potential Mechanism of Blood-Induced Chondrocyte Cell Death (1F31AR078004-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10068825. Licensed CC0.

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