# Understanding synovial macrophage inflamm-aging within osteoarthritis

> **NIH NIH P20** · UNIVERSITY OF DELAWARE · 2021 · $182,404

## Abstract

PROJECT SUMMARY
Patient age is the predominant risk factor in the incidence of osteoarthritis (OA), a degenerative joint disease
that is thought to result from persistent low-grade inflammation, i.e., “inflamm-aging.” Macrophages (MΦ),
immune cells that line the synovial membrane, contribute to cartilage degradation through the secretion of
inflammatory cytokines and matrix metalloproteinases (MMPs), adding to the proinflammatory feedback loop
and progression of OA symptoms. MΦ functions are highly dependent on environmental cues, such as tissue
stiffness, extracellular matrix (ECM) composition, and damage-associated molecular patterns (DAMPs);
however, there are conflicting hypotheses as to whether environmental cues directly cause synovial MΦ-
inflamm-aging or if aged MΦs inherently obtain intrinsic defects. This knowledge gap has limited our ability to
determine and prevent the contribution of MΦ inflamm-aging in OA. However, there are currently no robust
in vitro or in vivo models to study the mechanism of MΦ inflamm-aging. Cell lines or short-lived primary
synovial MΦs cultures are not useful for elucidating age-specific drivers in vitro, while established murine OA in
vivo models, such as destabilization of medial meniscus (DMM) surgery, have not been applied to the study of
MΦ-specific inflamm-aging. The dearth of studies in suitable model systems prevents the mechanistic
determination of factors driving MΦ inflamm-aging and ultimately hinders development of curative therapeutics.
There remains a fundamental need to identify the underlying causes of MΦ inflamm-aging in OA and to develop
meaningful preclinical tools that can model them. Utilizing synthetic nanoparticle (NP) systems that can directly
interface with synovial MΦ (SMΦs), the objective of this proposal is to establish in vivo and in vitro tools that
address our central question: how is SMΦ function impacted specifically by age? Our work will advance
knowledge of MΦ inflamm-aging mechanisms in two aims; we will 1) detail SMΦ phenotype and behavior as a
function of subject age using SMΦ-selective NP probes in a murine OA model that captures the full complexity
of disease to elucidate intrinsic aging effects in SMΦ function, and 2) develop a dynamic hydrogel culture model
that recreates in vivo responses in vitro to identify the role of extrinsic environmental cues in MΦ inflamm-aging.
Our in vitro approach will be the first attempt in recreating MΦ inflamm-aging through microenvironment mimicry
and validated with in vivo findings in an accepted OA model. These combined studies will assess our central
hypothesis—that the SMΦ inflamm-aging phenotype is directly regulated by both age (intrinsic) and
microenvironment (extrinsic) cues. The overall scientific impact of this project will be generation of new evidence
of intrinsic age effects on MΦ response to isolated extrinsic environmental cues and a novel in vitro tool to study
MΦ inflamm-aging. Both outcomes will directly support fut...

## Key facts

- **NIH application ID:** 10091024
- **Project number:** 1P20GM139760-01
- **Recipient organization:** UNIVERSITY OF DELAWARE
- **Principal Investigator:** Catherine A Fromen
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $182,404
- **Award type:** 1
- **Project period:** 2021-02-15 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10091024

## Citation

> US National Institutes of Health, RePORTER application 10091024, Understanding synovial macrophage inflamm-aging within osteoarthritis (1P20GM139760-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10091024. Licensed CC0.

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