# Pathogenic mechanisms of TMJ osteophyte formation

> **NIH NIH R21** · CHILDREN'S HOSP OF PHILADELPHIA · 2024 · $222,500

## Abstract

Abstract
 The temporomandibular joint (TMJ) controls the movement of the jaw but is susceptible to acquired
diseases, including osteoarthritis (OA). Osteophytes, referred to as fibrocartilage-capped bony spurs, are one
of the radiographic hallmarks of TMJ degenerative disease and cause skeletal deformities, chronic pain, and
limited condyle movement. Current treatments are limited, and patients may undergo reparative surgical
procedures, which are not always remedial. The etiology and pathogenesis of osteophyte formation in TMJ
OA remain unresolved and interfere with basic, translational, and clinical progress toward new effective
treatments. Recently, arthropathy, including in the TMJ, was reported for the first time in a patient with
compound heterozygous mutations in the PRG4 gene. Our preliminary studies show that Prg4-mutant mice
reproduce some key phenotypes in TMJ OA patients, including synovial hyperplasia and osteophytes.
Whereas heterozygous Prg4-deficient (Prg4+/-) mice did not exhibit a strong TMJ phenotype, osteophytes
did form in homozygous Prg4-null (Prg4-/-) mice, initiating ectopic chondrogenesis. The latter data indicate
that local normal anti-chondrogenic mechanisms had been deranged, possibly causing greater availability of
chondrogenic factors and leading to osteophyte onset. We tested this novel thesis and found that before
osteophyte formation, the expression of the heparan sulfate (HS) synthesizing gene EXT1 was downregulated
in the TMJ fibrocartilage. In addition, we found that the local levels of heparanase (HSPE), the primary
enzyme responsible for extracellular HS degradation, were markedly increased in osteophyte-forming regions
of TMJs. These preliminary data suggest that local decreases in HS and increases in HSPE cause a significant
drop in HS levels and create a robust prochondrogenic-inducing environment. In support of this thesis, BMP
signaling was more greatly distributed within the mutant condyles and developing osteophytes. These and
other data lead to our central hypothesis that a steep local loss of HS triggers osteophyte formation. Aim 1
will test whether conditional Ext1 ablation causes osteophyte formation or worsens the TMJ phenotype in
Prg4+/- mice. We will conduct single-cell RNAseq studies to assess cellular phenotypic characteristics,
developmental trajectories, signaling pathways, and networks during osteophyte formation. Aim 2 will test
whether Bmpr1a ablation will inhibit osteophyte formation in Prg4-null and other mutant mice above. To
expand treatment options and make them clinically relevant, we will test whether administering a BMP
signaling antagonist LDN-193189 prevents or inhibits osteophyte development. This project is based on new
data and insights into the mechanisms of osteophyte formation in the TMJ and will test the efficacy of drug
therapy. Given its novelty, the project is in its early stages but will undoubtedly have major and broadly
relevant implications for basic research and t...

## Key facts

- **NIH application ID:** 10983587
- **Project number:** 1R21DE033505-01A1
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** EIKI KOYAMA
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $222,500
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10983587

## Citation

> US National Institutes of Health, RePORTER application 10983587, Pathogenic mechanisms of TMJ osteophyte formation (1R21DE033505-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10983587. Licensed CC0.

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