# PHLPP inhibition and Osteoarthritis-Associated Pain

> **NIH NIH R21** · MAYO CLINIC ROCHESTER · 2024 · $169,653

## Abstract

ABSTRACT
Osteoarthritis (OA) is a progressive and debilitating disease characterized by deterioration of articular cartilage
and pathologic changes to other tissues leading to joint stiffness and pain. Non-surgical treatments focus on
behavior modifications and pain relief, but little is known about the molecular pathways controlling nociception
during OA pathogenesis. In this project, we will examine how controlling the activity of PHLPP phosphatases
contributes to joint innervation in vivo and neurite extension in vitro.
We identified PHLPPs as suppressors of chondrocyte regeneration and pain-related behaviors. PHLPP1 and
PHLPP2 are present in human and mouse sensory neurons and abnormally expressed in human OA cartilage.
In an animal model of OA, intra-articular injection of PHLPP inhibitors prevented joint hypersensitivity and
cartilage degradation and reduced sensory neuron innervation of joint tissues (e.g., subchondral bone,
periosteum). PHLPP inhibitors suppressed outgrowth of small/medium sensory neurons and expression of
neurotransmitters and neurofilaments in vitro. The goal of this project is to determine the mechanisms by
which small molecule inhibitors of PHLPP phosphatases suppress OA-associated pain. The central
hypothesis is that PHLPP inhibitors prevent innervation of osteoarthritic joints and alter molecular pathways
controlling sensory neurite extension. We will study mechanisms by which PHLPP inhibitors prevent neurite
extension and joint pain after knee injury with sensitive murine reporters of innervation and with human iPSC-
derived sensory neuron model systems.

## Key facts

- **NIH application ID:** 10768679
- **Project number:** 5R21AR082134-02
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Nathan P Staff
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $169,653
- **Award type:** 5
- **Project period:** 2023-02-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10768679

## Citation

> US National Institutes of Health, RePORTER application 10768679, PHLPP inhibition and Osteoarthritis-Associated Pain (5R21AR082134-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10768679. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*