# Roles of soluble CD13 and its receptor in angiogenesis, monocyte recruitment, and joint inflammation

> **NIH NIH R56** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $446,881

## Abstract

Abstract
Aminopeptidase N/CD13, is a transmembrane, cytokine-inducible ectopeptidase, highly expressed by
rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS), monocytes (MNs), and endothelial cells (ECs).
CD13 is shed from the FLS surface and high levels of soluble (s)CD13 are found in RA synovial fluid (SF).
sCD13 is a potent chemoattractant for activated T cells, MNs, and ECs, and depletion of sCD13 from RA SF
decreased T cell and MN migration. We have recently published that sCD13 is also a potent angiogenic factor
and mediates its actions through engagement of a G-protein-coupled receptor (GPCR). We have identified
the receptor for sCD13 as the bradykinin B1 receptor (B1R), a GPCR. A B1R antagonist inhibited K/BxN
serum transfer arthritis, zymosan induced arthritis in mice, MN migration, and phosphorylation of signaling
molecules in RA FLS. We have found, using an enzymatically inactive mutant, that most of the effects of
sCD13, are independent of its enzymatic activity. Moreover, Cd13 knockout mice are resistant to acute
arthritis development when injected with tumor necrosis factor-α.
 This proposal will determine the roles of CD13 and B1R in RA angiogenesis, MN ingress, and murine
models of arthritis. The role of sCD13 and B1R in acute inflammatory arthritis will be evaluated by injecting
pro-inflammatory factors into knees of Cd13-/-, B1R-/-, and wild type (wt) mice. The RA model, collagen induced
arthritis (CIA), will be performed in Cd13-/-, B1R-/-, and DBA/1J wt mice. We will compare arthritis severity, bone
destruction, leukocyte recruitment, angiogenesis, and production of cytokines in these groups of mice.
 To further examine the roles of CD13 and B1R in angiogenesis, the dermal punch wound, and sponge
granuloma models will be studied in Cd13-/-, B1R-/-, and wt mice. These models represent various aspects of
the angiogenic processes involved in RA pathogenesis. B1R antagonists will be used to determine the role of
B1R in sCD13-mediated angiogenesis, MN migration, and phosphorylation of signaling molecules. Subsets of
RA FLS will be sorted by flow cytometry and the role of sCD13 and its receptor will be assessed in these FLS
subpopulations. The contribution of sCD13 in RA angiogenesis will be examined by performing EC tube
formation and Matrigel plug assays with CD13-depleted or sham depleted RA SFs. Sponge granuloma assays
will be performed using sCD13 as a stimulus to evaluate whether defective angiogenesis can be restored in
Cd13-/- mice. We will perform these assays using mutant and WT CD13 +/- B1R antagonists to demonstrate
whether its enzymatic activity contributes to sCD13-mediated functions. To assess the interaction between
sCD13 and B1R, an RA synovial tissue-severe combined immunodeficient mouse chimera will be performed
using sCD13 +/- B1R antagonists. After accomplishing these studies, we will be able to demonstrate the
contribution of sCD13 and its receptor in angiogenesis- and leukocyte-dependent diseases. sCD...

## Key facts

- **NIH application ID:** 10239581
- **Project number:** 1R56AR076384-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** David Alan Fox
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $446,881
- **Award type:** 1
- **Project period:** 2020-09-10 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10239581

## Citation

> US National Institutes of Health, RePORTER application 10239581, Roles of soluble CD13 and its receptor in angiogenesis, monocyte recruitment, and joint inflammation (1R56AR076384-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10239581. Licensed CC0.

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