# Synovial lymphatics and osteoarthritis in aging

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2021 · $389,326

## Abstract

Project Summary/Abstract
Osteoarthritis (OA) affects ~35M people in the US and ~250M world-wide, but there is no effective therapy. OA
is characterized by cartilage loss, synovial inflammation and subchondral bone remodeling, associated with the
accumulation of numerous catabolic mediators and inflammatory cells in the synovial space. How these factors
are cleared and if the “clearance” process contributes to the pathogenesis of OA is unknown. Using imaging
tools that we developed in past 10 years, we identified a Synovial Lymphatic System (SLS) in mouse joints, the
function of which is impaired in joints of mice with age-related OA. Thus, strategies to improve lymphatic
function may benefit OA patients. In this application, we hypothesize that 1) aged joints have impaired SLS
function and VEGFR3-mediated signaling, accompanied by reduced VEGF-C expression and elevated
VEGFR3 degradation; 2) RANKL promotes ubiquitination and lysosomal degradation of VEGFR3 in LECs; and
3) the combination of VEGF-C and agents preventing VEGFR3 degradation improves the SLS and attenuates
the development of OA during aging. We will use an age-related OA mouse model to test our hypotheses. In
Aim 1, we will determine if the SLS becomes defective during aging and causes OA tissue damage, associated
with reduced VEGFR3-mediated signaling in lymphatic endothelial cells. In Aim 2, we will determine the
molecular mechanisms whereby VEGFR3 is degraded in aging joints and if a combination of VEGF-C and the
inhibition of VEGFR3 degradation prevent OA in aging mice. The results of our study will establish a role for
SLS dysfunction in the pathogenesis of OA, and augmentation of SLS functions could be a promising
therapeutic approach to prevent or delay age-associated joint damage. This will provide preclinical evidence
for agents targeting lymphatic vessels as a potential therapeutic strategy for OA in aging.

## Key facts

- **NIH application ID:** 10076746
- **Project number:** 5R01AG059775-02
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** LIANPING XING
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $389,326
- **Award type:** 5
- **Project period:** 2020-01-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10076746

## Citation

> US National Institutes of Health, RePORTER application 10076746, Synovial lymphatics and osteoarthritis in aging (5R01AG059775-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10076746. Licensed CC0.

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