# Enhanced cartilage formation of chondrocytes in viscoelastic ECMs under mechanical loading

> **NIH NIH F32** · STANFORD UNIVERSITY · 2024 · $73,828

## Abstract

Project Summary
 Moderate exercise is often recommended to patients for maintaining joint health, due to the strong scientific
evidence showing that mechanical loading enhances cartilage formation from the chondrocytes in the joint tissue.
Despite this understanding of joint physiology, a detailed mechanism by which cartilage formation enhancement
occurs in chondrocytes under mechanical loading remains unclear. Seminal works have demonstrated the crucial
role of the mechanosensitive ion channel TRPV4 in sensing physiological mechanical loads and expressing
anabolic genes for matrix production. However, how TRPV4 is activated under such small mechanical loading
environments remains unclear, especially as TRPV4 has been demonstrated to be insensitive to direct
deformations of the cell membrane. Here, we present a hypothesis that TRPV4 activation and enhanced cartilage
formation arises in chondrocytes due to the cell volume expansion facilitated by the accelerated dynamic
remodeling of the constituents (i.e., viscoelasticity) of the surrounding extracellular matrix (ECM) under
mechanical loading. This hypothesis is supported by emerging evidence that cells can sense the mechanical
confinement by the ECM, wherein a dynamically remodeling ECM facilitates cellular volume expansion and thus
activates TRPV4, and that small-strain mechanical loading can accelerate the dynamic remodeling of gels and
biopolymer networks. We will explore this hypothesis through the following specific aims, by 1) exploring how
anabolic loading conditions are influenced by the viscoelastic properties of the ECM, 2) establishing the
biophysical consequence of anabolic loading on the viscoelastic ECM and the chondrocytes embedded within,
and 3) exploring the ramifications of these findings on healthy and osteoarthritic (OA) tissues. The pursuit of
these specific aims is innovative because it connects recently established physics of hydrogels to important
biological consequences in vivo, which will help us address important health questions in other biological
contexts in the future. Altogether, we will establish a detailed biophysical and biochemical understanding of
enhanced cartilage formation in chondrocytes under mechanical loading. These results will be medically
significant as they will advance our understanding of cartilage homeostasis in both healthy and OA patients,
improve tissue engineering strategies for the treatment of cartilage defects, and unravel important insights into
cell-ECM mechanotransduction overall. The project will be carried out at Stanford University, a leading institute
for medical research, and tackled by a diverse team of experts, including the trainee who is an expert in the
mechanics and viscoelasticity of soft materials, the sponsor Dr. Ovijit Chaudhuri who is an expert in cell-ECM
mechanotransduction, the co-sponsor Dr. Marc Levenston who is an expert in cartilage mechanics, and
collaborator Dr. Nidhi Bhutani who is an expert in cartilage disea...

## Key facts

- **NIH application ID:** 10900068
- **Project number:** 1F32AR084286-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Hyuk Joon Jake Song
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $73,828
- **Award type:** 1
- **Project period:** 2024-05-07 → 2027-05-06

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10900068

## Citation

> US National Institutes of Health, RePORTER application 10900068, Enhanced cartilage formation of chondrocytes in viscoelastic ECMs under mechanical loading (1F32AR084286-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10900068. Licensed CC0.

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