# Osteoarthritis Progression And Sensory Pathway Alterations

> **NIH NIH R01** · RUSH UNIVERSITY MEDICAL CENTER · 2020 · $162,778

## Abstract

Project Summary
There is an urgent need for new therapeutic agents that treat the pain associated with osteoarthritis (OA). OA
is a chronic disease, and as disease progresses, patients can describe different types of pain, including pain
on weightbearing or joint movement, and pain at rest. Some patients display signs of peripheral and/or central
sensitization. Compelling clinical evidence suggests that ongoing peripheral input from the OA joint drives pain
and sensitization. We have developed the murine DMM (destabilization of the medial meniscus) model to study
the chronic nature of the disease and the different pain behaviors associated with progressive joint damage.
The overarching aim is to characterize anatomical and functional alterations in the sensory innervation of the
joint. We have uncovered that in the course of experimental OA, NaV1.8 nociceptors undergo profound, and
previously unappreciated, plasticity at all levels (in the knee joint, in the DRG, and in the dorsal horn) in a
precisely evolving manner. Recently, it has become clear that sensory neurons can be classified based on
unique patterns of expression of molecules that underlie different aspects of somatic sensation. Specifically,
NaV1.8 neurons comprise distinct functional subsets, including heat-sensitive TRPV1 neurons,
mechanosensitive Mrgprd C-fibers, TH+ C-low threshold mechanoreceptors (C-LTMR), and silent CHRNA3
fibers. Another subset of potential relevance to OA pain is TrkA+, expressing the receptor for Nerve Growth
Factor. We hypothesize that specific temporospatial changes in these subpopulations mediate the evolution of
pain behaviors during OA progression. Our experimental plan considers two complementary aims to study (1)
temporal and spatial contributions (which nerves are present and functional in the OA joint, where and when?);
and (2) how we may target these specific neuronal subsets to examine effects on pain behaviors and joint
health. Specific Aim 1 aims to define temporal and spatial neuroplasticity of knee innervation in the context of
OA joint pathology and pain. We have used a variety of Cre/Flp drivers to produce lines of fluorescent reporter
mice specific for distinct subsets of nociceptive, mechanosensitive, and proprioceptive (parvalbumin, PV) DRG
neurons. We will use these mice to define anatomical and functional changes in knee innervation, using
confocal and lightsheet microscopy, in vivo Ca2+ imaging, and transient chemogenetic silencing of specific
neuronal subsets. Specific Aim 2 aims to target specific neuronal subsets and examine the effect on OA
disease (pain and joint damage), in order to explore how our findings may translate to new approaches for OA
pain. We will determine the effects of chronic chemogenetic silencing of neuronal subpopulations on OA pain
and joint damage. We will also study the “receptome” specific to DRG subpopulations in order to develop
targeted therapeutic interventions. We propose that the identification of neu...

## Key facts

- **NIH application ID:** 10169854
- **Project number:** 3R01AR064251-07S1
- **Recipient organization:** RUSH UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** RICHARD J MILLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $162,778
- **Award type:** 3
- **Project period:** 2020-09-15 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169854

## Citation

> US National Institutes of Health, RePORTER application 10169854, Osteoarthritis Progression And Sensory Pathway Alterations (3R01AR064251-07S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10169854. Licensed CC0.

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