# Caveolae as a mediator of the catabolic response to biochemical and mechanical stress in primary human chondrocytes

> **NIH NIH F31** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $36,598

## Abstract

ABSTRACT
Macro-molecular complexes in the cell membrane, including caveolae, play a central role in receiving both
biochemical and mechanical cues. Through protein-protein interactions with signaling molecules, these
structures are poised to control the process of mechanotransduction and convert information from outside the
cell into altered cellular function. Caveolae are comprised of caveolin-1 and other proteins to form a subtype of
lipid raft that deform the cell membrane to generate flask-shaped pits. These membrane invaginations are
dynamic and disassemble to provide strain relief for cells under excessive membrane tension, which releases
proteins that were bound to caveolae into the cytosol. Similarly, the binding of matrix fragments to integrins
located within caveolae stimulates internalization of the complex. We hypothesize that the demands placed on
the caveolae system in chondrocytes under conditions that reflect osteoarthritis (excessive loading requiring
membrane tension relief and high levels of matrix degradation products) compromise chondrocyte function.
Specifically, chondrocytes will have a reduced capacity to respond to oxidative stress due to the release of
caveolae-associated proteins that interfere with antioxidant pathways, and excessive internalization of
fibronectin fragments will amplify catabolic signaling. The proposed work tests this hypothesis by modulating the
density of caveolae through caveolin-1 plasmid overexpression and CRISPR/Cas9 genetic knockout of caveolin-
1. In aim 1, we will use an innovative microfluidics approach to apply membrane tension to chondrocytes
embedded within a hydrogel to mimic excessive compressive loading. We will apply an oxidative challenge and
measure the cytosolic levels of reactive oxygen species, with assessment of peroxiredoxin hyperoxidation as a
readout of oxidative stress. In aim 2, we will apply fibronectin fragments to recapitulate matrix turnover. We will
quantify the effect of caveolae density on internalization through imaging of fluorescently-labeled fragment and
will use analysis of the MAP kinase pathway to determine the effect on catabolic cell signaling. The proposed
work will yield much needed insight into caveolae function in a cell type exposed to frequent loading and matrix
turnover demands. This work will also establish a high-throughput microfluidics platform for exposing cells to
physiologically relevant strains. Ultimately, successfully completion of this work will catalyze therapeutic
approaches that seek to delay the progression of osteoarthritis. Combined with a personalized training plan that
prioritizes career development, this training period will enable the applicant to continue on a trajectory towards
running an innovative research lab as an independent investigator.

## Key facts

- **NIH application ID:** 10068082
- **Project number:** 1F31AR078032-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Matthew Jeffrey Rich
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $36,598
- **Award type:** 1
- **Project period:** 2020-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10068082

## Citation

> US National Institutes of Health, RePORTER application 10068082, Caveolae as a mediator of the catabolic response to biochemical and mechanical stress in primary human chondrocytes (1F31AR078032-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10068082. Licensed CC0.

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