# The Role of PGRN Growth Factor in Osteoarthritis. - Renewal - 1

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $372,900

## Abstract

Project Summary
Osteoarthritis (OA) is the most common joint disease, and currently there is no effective means of preventing
or slowing joint degeneration. However, growth factors and cytokines are strongly implicated in initiating and
aggravating OA lesions. Thus, a molecular understanding of the interplay among these molecules will provide
invaluable information toward the search for novel therapeutic targets for OA. Our genome-wide screen for dif
ferentially expressed genes in OA led to the isolation of progranulin (PGRN) as an OA-associated growth factor, and genetic screen for PGRN binding partners led to the isolation of TNFR as the PGRN-binding receptor
(Tang, Science, 2011). We have developed an engineered protein named Atsttrin which is composed of three
TNFR-binding domains of PGRN, and Atsttrin surpassed PGRN in treating inflammatory arthritis. During the
initial funding period, we have successfully identified 14-3-3ε, an important intracellular signaling molecule, as
a novel component of TNFR2 complexes in response to PGRN stimulation in a proteomics screen. In addition, knockout of 14-3-3ε in chondrocytes abolished PGRN's signaling. Further, we recently isolated DR3, the highest homology to TNFR1, as a novel additional TNFR member that binds to PGRN/Atsttrin, and PGRN/Atsttrin
disturbed the interaction between DR3 and TNF-like ligand 1A (TL1A). Thus, this competitive continued application is primarily based on 1) the identification of 14-3-3ε as a novel component of PGRN/TNFR2 pathway,
and 2) the isolation of DR3 as a novel additional PGRN-binding receptor. The central hypothesis of this renewal is that PGRN exerts its chondroprotective role in the pathogenesis of OA through its a) recruitment of
14-3-3ε to TNFR2 and activation of the PGRN/TNFR2 anabolic pathway; and b) interplay with and inhibition of TNFα/TNFR1 and TL1A/DR3 inflammatory/catabolic pathways. The Specific Aims are: (1) What are
the molecular mechanisms and signaling pathways by which PGRN and Atsttrin regulate chondrocyte metabolism? We will determine the effects of PGRN, Atsttrin, TNFα and TL1A on chondrocyte metabolism, their signaling pathways, target gene expression profiling and interplay in chondrocytes (SA#1A); whether PGRN and
Atsttrin signaling and target gene expressions depends on 14-3-3ε in chondrocytes (SA#1B); and whether the
PGRN/Atsttrin regulates chondrocytes through modulating TL-1A/DR3 pathway as well (SA#1C). (2) Does
PGRN/Atsttrin have therapeutic and protective role in OA, and what are the mechanisms of its action in OA?
We will determine whether recombinant Atsttrin, similar to PGRN, reverses the susceptibility of PGRN-/- mice
to OA challenge, and whether PGRN and Atsttrin ameliorate existing OA(SA#2A); whether chondrocyte-
expressed 14-3-3ε is important for PGRN/Atsttrin's role in OA(SA#2B); and whether DR3 pathway also contributes to PGRN/Atsttrin's protective role in OA (SA#2C). Completion of the proposed research will not only
elucidate the...

## Key facts

- **NIH application ID:** 9976454
- **Project number:** 5R01AR061484-09
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Chuanju Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $372,900
- **Award type:** 5
- **Project period:** 2011-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976454

## Citation

> US National Institutes of Health, RePORTER application 9976454, The Role of PGRN Growth Factor in Osteoarthritis. - Renewal - 1 (5R01AR061484-09). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9976454. Licensed CC0.

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