# Pro-resolving Annexin A1-derived peptide Ac2-26 reduces nociception and mitigates joint damage in experimental osteoarthritis

## TL;DR

A peptide derived from Annexin A1 reduces joint pain and damage in a mouse model of osteoarthritis.

## Contribution

The study demonstrates that Ac2-26, a peptide from Annexin A1, mitigates OA-related nociception and joint damage in mice.

## Key findings

- AnxA1-deficient mice showed increased joint pain and inflammation compared to wild-type mice.
- Ac2-26 treatment reduced mechanical nociception, tissue damage, and metalloproteinase-3 expression in OA-affected joints.
- Ac2-26 normalized the increased number of synoviocytes expressing RANKL induced by collagenase.

## Abstract

We investigated whether treatment with Annexin A1 (AnxA1) ameliorated joint nociception and tissue damage in an experimental osteoarthritis (OA) model.

OA was induced by injection of collagenase into the tibiofemoral joint of wild-type (WT) and AnxA1-deficient male Balb/c mice. The control group received saline. Groups of WT mice were treated weekly with Ac2-26, an active peptide corresponding to the N-terminal region of AnxA1, in the affected joint. Mechanical nociception was analyzed weekly, and samples were collected 6 weeks after OA induction to analyze histopathology and markers of joint damage by qPCR and flow cytometry.

The expression of Anxa1 is upregulated in the joints at the 1st and 3rd week and returned to the basal level at the 6th week after OA induction. AnxA1-deficient mice had persistent nociception and increased joint inflammation when compared to WT mice, although both groups had comparable cartilage damage. In WT mice, the treatment with Ac2-26 decreased joint nociception, tissue damage, and the expression of metalloproteinase-3 in the joint tissue. The collagenase injection increased the number of FAP+CD90− fibroblast-like and CX3CR1+macrophage-like synoviocytes expressing RANKL when compared to saline-injected mice. Treatment with Ac2-26 normalized the latter parameters.

AnxA1 and Ac2-26 are promising molecules that regulate key processes in OA, effectively mitigating tissue damage and dysfunction in a model of OA in mice.

The online version contains supplementary material available at 10.1007/s00011-026-02191-z.

We wanted to find out if a treatment with the pro-resolving molecules called Annexin A1 (AnxA1) could reduce joint pain and damage in a mouse model of osteoarthritis (OA).

Osteoarthritis was induced in mice by injecting a chemical called collagenase into their knee joints. We used mice that lacked the AnxA1 protein, and others without gene modification. A group of normal mice was treated weekly with a piece of the AnxA1 protein called Ac2-26, which was injected into their affected joints. Pain was measured every week after the induction of this model up to 6 weeks. The joints were collected at the end for the analysis of signs of tissue damage and inflammation.

The level of AnxA1 in the joints increased in the first few weeks after OA induction but returned to normal at the later time point. Mice without AnxA1 had more joint pain and inflammation than normal mice, although both groups showed similar cartilage damage. The Ac2-26 treatment reduced joint pain, tissue damage, and enzymes related to cartilage damage. This model of OA increased the number and activation of important cells present into the joint, but Ac2-26 treatment reduced these levels back to normal.

AnxA1 and its active portion, Ac2-26, could be useful for treating OA by reducing joint damage and pain.

The online version contains supplementary material available at 10.1007/s00011-026-02191-z.