# Investigating the IL-4/13 Axis in Osteoarthritis

> **NIH VA I01** · VETERANS ADMIN PALO ALTO HEALTH CARE SYS · 2020 · —

## Abstract

Many Veterans and civilians sustain traumatic joint injuries, which frequently lead to joint dysfunction and
development of osteoarthritis (OA). Existing treatments for joint injury and OA only alleviate symptoms, and are
ineffective in promoting healing or preventing OA. Increasing evidence implicates “low-grade” inflammation
following joint injury in development of OA. A better understanding of the underlying inflammatory mechanisms
and identification of pharmacologic agents that target these mechanisms could transform care for military
personnel, Veterans, and civilians with traumatic joint injuries and/or that are developing OA. Our preliminary
studies suggest that Type II immunity and the IL-4/IL-13 inflammatory axis are dysregulated in OA. In this
proposal, we aim to elucidate the roles of Type II immunity and the IL-4/IL-13 axis in the development of OA.
Type II immunity and the IL-4/IL-13 inflammatory axis have been widely implicated in atopic diseases, such as
asthma, but have not been extensively studied in the context of OA. We found that IL-4 is downregulated, while
IL-13 levels are elevated, in the synovial fluids of individuals with OA. Our findings showed that genetic
deficiency in IL-4 leads to more severe OA in mice after destabilization of the medial meniscus (DMM), while
IL-13 may promote OA and thereby play an opposing role. Our in vitro studies showed IL-13 induces
pathogenic activation of osteoblasts and fibroblasts; while IL-4 promotes protective M2 macrophage
phagocytosis of pro-inflammatory cartilage debris and inhibits activation of osteoclasts. We found that
pharmacologic inhibition of mast cells, which are major producers of IL-13, prevented OA in mice.
Nevertheless, important questions remain about the mechanisms through which the IL-4/IL-13 axis mediates
inflammatory responses following joint injury and in OA. We hypothesize that IL-4 and IL-13 mediate distinct
responses in different cell types by signaling through the type-I or type-II cellular receptors, respectively. We
hypothesize that following joint injury dysregulated activation of mast cells, basophils, ILC2 cells, and/or Th2
cells results in the production of IL-13. Further, we hypothesize that dysregulated IL-4/IL-13 expression leads
to activation of osteoblasts and fibroblasts, loss of osteoclast inhibition, and dysregulated macrophage
polarization. Finally, we hypothesize that, together, these changes disrupt homeostasis following joint injury or
other insult and lead to development of OA.
To test these hypotheses, Aim 1 will characterize the role of Type II immunity in the development of OA
through analysis of the IL-4 and IL-13-producing cell types in OA synovial and infrapatellar fat pad tissues, and
by analyzing in vivo the contributions of these cell types to OA development. Aim 2 will investigate the
molecular mechanisms by which IL-4 and IL-13 regulate protective and pathogenic cellular responses in
macrophages, osteoclasts, osteoblasts, synovial f...

## Key facts

- **NIH application ID:** 9891690
- **Project number:** 1I01BX004713-01A1
- **Recipient organization:** VETERANS ADMIN PALO ALTO HEALTH CARE SYS
- **Principal Investigator:** William H Robinson
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2020-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891690

## Citation

> US National Institutes of Health, RePORTER application 9891690, Investigating the IL-4/13 Axis in Osteoarthritis (1I01BX004713-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9891690. Licensed CC0.

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