# Impact of mast cell heterogeneity on Osteoarthritis

> **NIH NIH R21** · TUFTS UNIVERSITY BOSTON · 2024 · $452,437

## Abstract

SUMMARY
Osteoarthritis (OA) is a highly prevalent and debilitating disease, affecting over 27 million people in the US. Its
risk factors include aging, joint injury, obesity, and the female sex.
It is characterized by the degeneration of
weightbearing joints, which is exacerbated by localized and persistent inflammation. However, there is not a
single FDA-approved disease-modifying treatment for OA, posing an urgent need for designing new treatment
options. Typical anti-inflammatory therapies have not successfully halted OA progression in clinical trials,
suggesting that perhaps OA has an inflammatory signature different from other types of arthritis and requires a
strategy to specifically target this signature. In this grant, we will address this critical need for the understanding
the inflammatory milieu unique to OA.
One of the predominant types of immune cells increased in human OA joints is the mast cell (MC). Mice deficient
in MCs had diminished joint damage in injury-induced OA, suggesting that MCs are required for OA progression.
This notion is further supported by our gain-of-function data showing that promoting MC activity exacerbated
joint damage, thus warranting mechanistic investigation of MCs in OA. One special feature of MCs is their
capacity to store inflammatory mediators in their numerous granules. When stimulated, MCs release them over
time; and since MCs are long-lived, they also replenish these inflammatory mediators for future use. Thus, the
MC is a strong candidate for sustaining chronic inflammation in OA. Another intriguing property of the MC is it
demonstrates a level of heterogeneity that is altered under disease conditions and in a tissue-specific way. In
the synovium, there are two known subtypes, based on histological analysis of the two key proteases: (i) MCTC
that expresses both chymase and tryptase and (ii) MCT that expresses only tryptase. While these two enzymes
have their own substrates, the two subtypes also likely to differ in the expression of other genes. However, little
is known about the nature of MC heterogeneity in OA joints. Our central hypothesis is that MC heterogeneity
constitutes a unique inflammatory signature of OA to promote OA pathogenesis. The objective of this grant is to
investigate the genetic basis and functions of MCTC and MCT subtypes in the OA synovium, through performing
advanced proteomics and single cell RNAseq technologies as well as testing them in the mouse model of
Anterior Cruciate Ligament Transection (ACLT).
From this investigation, we will uncover a new level of regulation that may elucidate a key aspect of OA-specific
inflammatory microenvironment and inspire the design of more effective strategies to target OA. Thus, this study
has the potential of being highly impactful and paradigm-changing for combating OA in our ever-aging society.

## Key facts

- **NIH application ID:** 10995974
- **Project number:** 1R21AG089881-01
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Li Zeng
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $452,437
- **Award type:** 1
- **Project period:** 2024-08-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995974

## Citation

> US National Institutes of Health, RePORTER application 10995974, Impact of mast cell heterogeneity on Osteoarthritis (1R21AG089881-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10995974. Licensed CC0.

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