# Notch Signaling in the Regulation of TMJ Osteoarthritis

> **NIH NIH R03** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2022 · $1

## Abstract

Osteoarthritis (OA) of mandibular condylar cartilage (MCC) of the Temporomandibular Joint (TMJ) is a growing
epidemic that afflicts men and women not only in United States but across the globe. OA is primarily
characterized by cartilage degeneration, subchondral bone sclerosis and joint pain. It is well established that
altered expression and activation of catabolic enzymes underlies the joint cartilage destruction observed in OA,
however the precise molecular mechanisms responsible for promoting joint cartilage catabolism is not well
understood, nor is there a defined understanding of the molecular mediators of OA.
Notch signaling pathway has been identified as a potential regulator of both catabolic and anabolic mediators
of OA. In our preliminary experiments, the lineage specific over expression of Notch Intracellular Domain 1
(NICD1) in mice developed accelerated OA like signs in the MCC of TMJ. We further observed that with NICD1
over expression there is upregulation of bone morphogenetic protein 2 (BMP2), Indian hedgehog (Ihh), MMP13
and ADAMTS5 and down regulation of proteoglycan 4 (PRG4). Based on these observations, we hypothesize
that NICD1 over expression in mature chondrocytes will modulate the BMP2 signaling pathways and will
subsequently lead altered expression of Ihh and increased expression of degradative enzymes, which will
result in cartilage breakdown. To test this hypothesis, we will: (1) Determine the effects and mechanism of
lineage-specific over expression of NICD1 on the osteochondral tissue of the TMJ. Using a transgenic mice
model of lineage specific over expression of NICD1, we will examine the effects and the mechanism by which
NICD1 over expression stimulates the catabolic responses in the MCC of TMJ. (2) Determine the effects of
blocking the notch signaling pathway in preventing the progression of osteochondral tissue degeneration and;
(3) Define the molecular mechanism by which notch signaling regulates the BMP2 and the degradative
enzymes. Utilizing in vitro and in vivo experimental study models and inhibitors of different pathways, we will
focus on deciphering the role of altered BMP2 and Ihh signaling due to increase over expression of NICD1 in
the development of OA.
The proposed project will establish proof of principle that the altered expression of NICD1 is early and decisive
event in the development of OA. The proposed studies have the potential to reveal important new regulatory
pathways that controls homeostasis of the MCC of TMJ and open new insight on disease mechanisms and
therapeutic interventions.

## Key facts

- **NIH application ID:** 10468792
- **Project number:** 5R03DE030226-02
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Sumit Yadav
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1
- **Award type:** 5
- **Project period:** 2021-09-01 → 2023-03-05

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468792

## Citation

> US National Institutes of Health, RePORTER application 10468792, Notch Signaling in the Regulation of TMJ Osteoarthritis (5R03DE030226-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10468792. Licensed CC0.

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