# Deconstructing Cartilage Mechanotransduction by Piezo Channels

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $18,585

## Abstract

Osteoarthritis (OA) is the most common degenerative joint disease, affecting more than 350 million people
worldwide. Along with inflammation and pain, a hallmark of OA is the degradation of articular cartilage (AC), an
avascular tissue that coats and facilitates the bending of diarthrodial joints. AC withstands millions of cyclic
mechanical loads annually, and chondrocytes, the only cellular substrate in the tissue, sense these loads
through mechanically gated ion channels. Piezo1 is a highly expressed calcium ion channel in chondrocytes
that can be activated through mechanical loading or chemically with Yoda1, a Piezo1-specific agonist. Our lab
recently demonstrated that Piezo1 expression is elevated in osteoarthritic cartilage and interleukin-1α (IL-1α), a
pro-inflammatory cytokine present in OA, drives the upregulation Piezo1. The increased expression of Piezo1
in IL-1α-challenged chondrocytes led to a sustained increased intracellular calcium transient and the
rarefication of the actin cytoskeleton. Herein, our overall goal is to understand how Piezo1-mediated changes
in chondrocyte physiology contribute to the progression of OA during periods of high inflammation and injurious
loading. Mechanical loading and subsequent calcium influx through calcium ion channels leads Calcium-
mediated Actin Reset (CaAR) and nuclear softening via chromatin remodeling. CaAR is a transient cell
response in which F-actin rapidly depolymerizes from the periphery of the cell and polymerizes around the
nucleus to create a protective kinetic barrier that shields the nucleus from mechanical deformation. Nuclear
softening driven by a decrease in heterochromatin was shown to be Piezo1 dependent and play a role in
minimizing DNA damage during periods of high mechanical strain. While CaAR and nuclear softening have
been characterized independently as mechanoprotective responses, their potential interplay in mediating
nuclear mechanoprotection and regulation of transcription during mechanical loading has yet to be explored.
The Linker of Nucleoskeleton and Cytoskeleton (LINC) complex physically tethers the nuclear lamina and the
actin cytoskeleton, and it is known play a role in chromatin remodeling. Given the structure and function of the
LINC complex, it is a strong candidate for mediating chromatin fluidification during nuclear softening and
transcriptional responses during CaAR. Together these findings suggest that Piezo1-mediated CaAR could
alter nuclear mechanical properties through chromatin remodeling via the LINC complex and lead to
transcriptional changes that could ultimately affect chondrocyte cell fate during OA. Therefore, we hypothesize
that elevated Piezo1 expression, as seen in OA cartilage, leads to a prolonged CaAR response which in turn
triggers chromatin fluidification via the LINC complex thereby leading to an increase nuclear softening and pro-
inflammatory gene expression in IL-1α-challenged chondrocytes.

## Key facts

- **NIH application ID:** 10533155
- **Project number:** 3R01AR072999-02S1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Farshid Guilak
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $18,585
- **Award type:** 3
- **Project period:** 2022-01-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10533155

## Citation

> US National Institutes of Health, RePORTER application 10533155, Deconstructing Cartilage Mechanotransduction by Piezo Channels (3R01AR072999-02S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10533155. Licensed CC0.

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