# EGFR signaling in osteoarthritis and treatment

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $480,335

## Abstract

Project Summary
 Osteoarthritis (OA) is a classic age-related disorder and the most common cause ofpain and disability in
the
elderly.
It is primarily characterized by the progressive destruction of articular cartilage. This past decade
has witnessed significant advances in deciphering the basic mechanisms by which OA develops. However, to
date, no disease modifying drug therapy is available for preventing OA development and repairing the
degenerative cartilage. The uppermost superficial zone of articular cartilage is the first line of defense against
OA initiation. We recently found that epidermal growth factor receptor (EGFR), a tyrosine kinase receptor, is
expressed abundantly throughout the articular cartilage with its active form (p-EGFR) predominantly located in
the superficial zone. Interestingly, at the onset of OA, p-EGFR amount, along with two major EGFR ligands
(TGFα and HBEGF), were markedly attenuated while the amount of Mig6, a negative inhibitor of EGFR, was
enhanced, suggesting a potential role for EGFR signaling pathway in cartilage homeostasis and diseases.
Using a series of mouse models with deficient or overactivated EGFR activity by genetic manipulation of Egfr
and Mig6 genes, we and others have demonstrated that EGFR signaling is critical for maintaining the number
and mechanical properties of superficial chondrocytes, suppressing their hypertrophy, promoting proteoglycan
4 (Prg4) expression, and stimulating surface lubrication function. Most strikingly, in aging- and surgery-induced
OA models, mice with chondrocyte-specific (Col2-Cre) EGFR deficiency developed the most severe OA
phenotypes, including a complete loss of articular cartilage, subchondral bone sclerosis, and escalated joint
pain. Hence, we hypothesize that EGFR signaling is essential for maintaining the structure and function of the
superficial layer in the articular cartilage and thus, can be targeted for OA treatment. Our objectives are to
understand the role of this novel signaling pathway in articular cartilage homeostasis and diseases, and to
seek approaches targeting this pathway for OA treatment. To achieve these, we will perform the following
aims: 1) determine the temporal role of EGFR signaling in OA pathogenesis; 2) elucidate the mechanisms of
the protective action of EGFR on articular cartilage; 3) investigate whether EGFR signaling is a promising
target for OA treatment. Complementary genetic approaches, such as EGFR vs Mig6, loss of function vs gain
of function, and aggrecan-CreER vs Prg4-CreER, will be used throughout the proposal. Moreover, we have
designed and synthesized TGFα-conjugated nanoparticles with prolonged retention and penetration abilities in
knee cartilage. A proof-of-principal experiment will be performed to examine its therapeutic effects on cartilage
degeneration at different OA stages. This proposal will uncover critical EGFR actions in knee articular cartilage
and provide crucial evidence for targeting this novel pathway in OA...

## Key facts

- **NIH application ID:** 10138221
- **Project number:** 1R01AG067698-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Ling Qin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $480,335
- **Award type:** 1
- **Project period:** 2020-09-30 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10138221

## Citation

> US National Institutes of Health, RePORTER application 10138221, EGFR signaling in osteoarthritis and treatment (1R01AG067698-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10138221. Licensed CC0.

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