# The Role of Mechanosensation Pathways in Osteoarthritis Joint Damage and Pain

> **NIH NIH R01** · RUSH UNIVERSITY MEDICAL CENTER · 2021 · $351,926

## Abstract

Project Summary
Knee osteoarthritis (OA) is a painful chronic disease affecting 27 million people in the US. Knee OA is
characterized by progressive damage and remodeling of all joint tissues. Major hallmarks of OA are joint pain
and joint space narrowing on x-ray (cartilage loss). Biomechanical factors play an important role in both joint
pain and damage, but exactly how mechanical forces act on sensory neurons and cartilage to drive the
disease is unknown. Our long-term goal is to elucidate how mechanical loading is sensed by joint tissues and
how responses to loading contribute to OA. Cells sense mechanical forces through a variety of mechanisms,
including mechanosensitive ion channels. Recently, the sensory neuron mechanosensitive ion channel
PIEZO2 was identified as a key contributor to mechanical allodynia in murine models of inflammatory and
neuropathic pain, but the role of PIEZO2 expressed by nociceptors and in persistent pain is not clear.
Furthermore, the function of mechanosensitive ion channels in chondrocytes is less clear, but based on
previous work implicating a role for PIEZO1 in chondrocyte responses to mechanical stimuli, we hypothesize
that PIEZO1 contributes to tissue damage in OA. Overall it is unknown how PIEZO ion channel signaling
contributes to OA pathology (pain and joint damage). We aim to address this question by using novel
techniques we have developed that enable application of mechanical stimuli to intact tissues while performing
calcium or voltage imaging to assess cell function in real time. This proposal addresses the Central Hypothesis
that: PIEZO channel signaling in nociceptors and chondrocytes drives pain and joint damage in the initiation
and progression of OA. The central hypothesis will be tested in two specific aims: 1) To define the role of
PIEZO2 ion channel expressed by nociceptors in mediating peripheral sensitization and persistent pain
behaviors at different stages of the DMM model of OA; and 2) To investigate whether chondrocyte PIEZO1 ion
channel signaling promotes joint damage and pain in the DMM model. To perform these aims, we have
generated innovative techniques that enable application of mechanical stimuli to intact tissues while performing
real-time calcium or voltage imaging. We have created mice that express fluorescent calcium (GCaMP6s) or
voltage (ASAP2s) indicator proteins in either pain-sensing sensory neurons (nociceptors; NaV1.8 cre) or in
chondrocytes (Col2a1 cre). We also have two types of nociceptor-specific Piezo2 conditional knock-out mice
as well as chondrocyte-specific Piezo1 conditional knock-out mice. Successful completion of these aims will
improve our understanding of how nociceptors and chondrocytes use PIEZO channels to respond to
mechanical loading in OA, which may lead to the identification of novel pathways to target both pain and joint
damage therapeutically. By measuring both pain-related behaviors and joint damage in nociceptor-Piezo2
knock-out and chondrocyte-Pie...

## Key facts

- **NIH application ID:** 10121440
- **Project number:** 1R01AR077019-01A1
- **Recipient organization:** RUSH UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Rachel Elizabeth Miller
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $351,926
- **Award type:** 1
- **Project period:** 2021-04-02 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10121440

## Citation

> US National Institutes of Health, RePORTER application 10121440, The Role of Mechanosensation Pathways in Osteoarthritis Joint Damage and Pain (1R01AR077019-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10121440. Licensed CC0.

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