# WNT signaling in chondrocyte biology and osteoarthritis

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2024 · $644,887

## Abstract

Abstract
Hip osteoarthritis (OA) affects one in four people by the age of 85, and it is linked to abnormal hip morphology
including Cam-type femoroacetabular impingement (FAI). Hence, symptomatic FAI represents an ideal
condition to identify key regulators in hip OA progression. To this end, we performed RNA sequencing (RNA-
seq) comparing FAI and hip OA cartilage, revealing that WNT16 expression is negatively correlated with OA
severity. We also showed that WNT16 is decreased during cartilage cell (i.e., chondrocyte) hypertrophy (a
hallmark of OA) and that WNT16 is up-regulated in chondrocytes under mechanical loading. As Transient
Receptor Potential Vanilloid 4 (TRPV4), a Ca2+-permeable ion channel, is an essential mechanosensor in
chondrocytes, our results suggest a novel link between TRPV4, WNT16, and chondrocyte
mechanobiology. Our preliminary data predict that WNT16 in chondrocytes is potentially regulated by
TRPV4-mediated signaling pathways, and WNT16 inhibits chondrocyte hypertrophy via G protein-associated
signal transduction. Thus, to elucidate the functional role of WNT16 in hip OA pathogenesis and develop novel
therapies, we propose the following aims:
Specific Aim 1: To determine the genetic and epigenetic mechanism(s) of mechanoinduction of WNT16 in
chondrocytes. Agarose constructs encapsulating human stem cell-derived chondrocytes and hip primary
chondrocytes will be subjected to loading in combination of TRPV4 activator/inhibitor, and their effects on
WNT16 will be assessed. We will use novel next-generation sequencing to identify genetic and epigenetic
factors that regulate WNT16 expression in chondrocytes.
Specific Aim 2: To determine the effects of WNT16 gain- and loss-of-function on chondrocyte specification,
hypertrophy, and hip OA development. We will investigate if cartilage-specific Wnt16 knockout mice exhibit
enhanced hip OA compared to control mice. We will measure OA severity, synovitis, and bone remodeling. We
will also quantify behavioral changes and pain responses, as well as determine the association of these
measurements with hip OA severity. We will use human hip primary chondrocytes with WNT16 modulation to
investigate its effects on hypertrophy.
Specific Aim 3: To elucidate altered chondrocyte cell-cell crosstalk in hip healthy/FAI/OA cartilage and to
determine if WNT16 mRNA delivery can mitigate hip OA by restoring normal WNT signaling among
chondrocyte crosstalk. We will fully characterize distinct chondrocyte phenotypes in human healthy, FAI, and
OA hip cartilage by integrating scRNA/Spatial-seq datasets. We will determine if WNT16 mRNA delivery using
nanoparticles to hip FAI/OA cartilage explants is sufficient to mitigate hip OA progression.
Impact: A mechanistic understanding of the role of WNT16 in hip cartilage homeostasis and FAI/OA will
provide insights into the development of therapeutic interventions for hip OA by targeting WNT16 signaling.

## Key facts

- **NIH application ID:** 10808343
- **Project number:** 1R01AR082403-01A1
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Chia-Lung Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $644,887
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10808343

## Citation

> US National Institutes of Health, RePORTER application 10808343, WNT signaling in chondrocyte biology and osteoarthritis (1R01AR082403-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10808343. Licensed CC0.

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