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

> **NIH NIH R01** · RUSH UNIVERSITY MEDICAL CENTER · 2023 · $274,299

## 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. Biomechanical and inflammatory factors play an important role in both joint
pain and damage, but exactly how these pathways interact and promote mechanical sensitization of sensory
neurons is unknown. Recently, we identified the sensory neuron mechanosensitive ion channel Piezo2 as a key
contributor to mechanical sensitization in the destabilization of the medial meniscus (DMM) mouse model of OA.
In addition, we have demonstrated that NGF-induced joint inflammation is dependent on nociceptor expression
of Piezo2, suggesting that Piezo2 signaling may contribute to neuroimmune interactions. Finally, we have
demonstrated that macrophage infiltration is a key contributor to the development of mechanical sensitization in
OA. Nociceptor signaling helps to facilitate this recruitment of immune cells, but how the Piezo2 pathway is
involved is not yet known. Therefore, this supplement represents an expansion of the existing Specific Aim 1 of
the parent program. In particular, we will leverage our ongoing studies in nociceptor-specific Piezo2 conditional
knock-out mice to now include examination of the neuroimmune changes happening in these mice, in both sexes.
This will include using a novel imaging technology – light sheet imaging of cleared knee joint and spinal
column/DRG tissue in order to visualize macrophages in these tissues in a volumetric representation. The
research outlined here will fill the gap in knowledge by providing information on the interaction of inflammation
and mechanical stimuli in producing mechanical sensitization. This proposal aims to answer the questions of:
What is the role of Piezo2 in inflammatory mechanical sensitization? And, Can light sheet imaging be used to
quantify macrophage numbers in the lumbar DRGs? We hypothesize that mechanical stimuli are necessary for
inflammatory mechanical sensitization. In addition, we hypothesize that macrophage recruitment in the DRGs is
a fundamental part of mechanical sensitization, and that recruitment will be inhibited by knocking out Piezo2.
Successful completion of this supplement will improve our understanding of how nociceptors and immune cells
communicate with the help of the Piezo2 pathway to promote mechanical sensitization in OA, which may lead to
the identification of novel pathways to target both pain and joint damage therapeutically.

## Key facts

- **NIH application ID:** 10861577
- **Project number:** 3R01AR077019-03S1
- **Recipient organization:** RUSH UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Rachel Elizabeth Miller
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $274,299
- **Award type:** 3
- **Project period:** 2021-04-02 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10861577

## Citation

> US National Institutes of Health, RePORTER application 10861577, The Role of Mechanosensation Pathways in Osteoarthritis Joint Damage and Pain (3R01AR077019-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10861577. Licensed CC0.

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