# Decoding the impact of exercise and αCGRP signaling on murine post-traumatic osteoarthritis progression

## TL;DR

This study explores how exercise and a neuropeptide called αCGRP affect the progression of osteoarthritis in mice, revealing αCGRP's role in regulating joint and bone health.

## Contribution

The study identifies αCGRP as a novel intrinsic regulator of joint and bone responses to mechanical loading during osteoarthritis.

## Key findings

- αCGRP deficiency altered cartilage extracellular matrix stiffness and inflammatory responses after intense exercise.
- Intense exercise mitigated subchondral bone sclerosis caused by αCGRP deficiency and DMM surgery.
- Metaphyseal bone trabecular loss occurred in αCGRP-deficient mice after intense exercise.

## Abstract

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by cartilage breakdown, subchondral bone remodeling, and inflammation. Mechanical stress, such as exercise, can influence OA progression, acting as either a therapeutic intervention or a risk factor depending on intensity. The sensory neuropeptide αCGRP plays a role in modulating cartilage, bone, and inflammatory responses, making it a potential mediator of exercise effects on OA. This study investigated the impact of αCGRP deficiency and exercise intensity on OA progression in a post-traumatic murine model.

OA was induced in male αCGRP knockout (KO) and wild type (C57Bl/6J) mice via destabilization of the medial meniscus (DMM). Mice underwent moderate or intense treadmill exercise for up to 6 weeks (8 weeks post-surgery). Histological analyses were performed to assess cartilage degradation. Subchondral and metaphyseal bone morphology as well as cartilage stiffness were evaluated by nanoCT and atomic force microscopy (AFM), respectively. Serum inflammatory markers were analyzed using multiplex immunoassays.

Serum levels of proinflammatory markers were elevated in αCGRP-deficient mice, particularly after intense exercise, independent of OA progression. DMM surgery induced significant cartilage degradation. Gross cartilage morphology was not influenced by exercise intensity or αCGRP deficiency, but αCGRP deficiency prevented articular cartilage extracellular matrix stiffening after DMM and intense exercise. Subchondral bone sclerosis was induced by αCGRP deficiency and DMM but mitigated by intense exercise. In metaphyseal bone, intense exercise induced trabecular loss in αCGRP-deficient mice.

This study highlights αCGRP as an intrinsic regulator of joint and bone responses to mechanical loading during OA. While cartilage degradation after DMM and treadmill exercise was unaffected by lack of αCGRP, its deficiency altered ECM stiffness, bone remodeling, and inflammatory responses. These findings position αCGRP as a critical regulator of joint homeostasis, particularly for bone health during running exercise and OA progression.

The online version contains supplementary material available at 10.1186/s13075-025-03589-6.