¹Dept. of Orthopaedic Surgery, University Medical Center Regensburg (UKR), Regensburg, Deutschland
²Department of Trauma Surgery, University Medicine Göttingen, Göttingen, Deutschland
³Center for Applied Tissue Engineering and Regenerative Medicine (CANTER), University of Applied Sciences Munich, Munich, Deutschland

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Objectives and questions: Osteoarthritis (OA) is a prevalent degenerative joint disease marked by cartilage deterioration, subchondral bone alterations, and inflammation. Mechanical stress through exercise has a dual role in OA, offering both therapeutic and harmful effects depending on the intensity. The sensory neuropeptide α-calcitonin gene-related peptide (αCGRP) is known to influence cartilage integrity, bone remodeling, and inflammatory responses, suggesting a role in exercise-related changes in OA. This study aimed to examine the interplay between αCGRP deficiency and exercise intensity in OA progression using a post-traumatic murine model.

Material and methods: OA was induced in male αCGRP knockout (KO) and wild type (C57Bl/6J) mice via destabilization of the medial meniscus (DMM). Following surgery, mice were subjected to either moderate or high-intensity treadmill exercise for up to eight weeks. Histological assessments evaluated cartilage degradation. Osteophyte formation as well as subchondral and subarticular bone changes were analyzed using nanoCT. Cartilage stiffness was measured through atomic force microscopy (AFM), and serum inflammatory markers were quantified via multiplex immunoassays.

Results: Proinflammatory serum markers were elevated in αCGRP knockout mice, particularly following high-intensity exercise, independent of OA progression. DMM surgery led to significant cartilage degradation. However, gross cartilage morphology was not influenced by exercise intensity or αCGRP deficiency. αCGRP deficiency inhibited the stiffening of the articular cartilage extracellular matrix after DMM and intense exercise. Subchondral bone sclerosis was more pronounced in αCGRP-deficient mice after DMM and moderate exercise, whereas intense exercise reduced these sclerotic changes. In contrast, αCGRP-deficient mice experienced trabecular bone loss in subarticular regions after intense exercise.

Discussion and conclusions: Our findings highlight αCGRP as a modulator of joint and bone responses to mechanical loading in OA. While cartilage degradation was not influenced by αCGRP deficiency, changes in extracellular matrix stiffness, bone remodeling, and systemic inflammation were significantly affected. These results suggest that targeting αCGRP signaling may offer new avenues for managing mechanical stress-related joint degeneration in OA.