Pann Patrick, Kalke Paul, Maier Verena, Schäfer Nicole, Clausen-Schaumann Hauke, Schilling Arndt F, Grässel Susanne
Dept. of Orthopaedic Surgery, Experimental Orthopaedics, Center for Medical Biotechnology, University of Regensburg, ZMB im Biopark 1 Am Biopark 9, 93053, Regensburg, Germany.
Department of Trauma Surgery, Orthopedics and Plastic Surgery, University Medicine Göttingen, Göttingen, Germany.
Arthritis Res Ther. 2025 Jun 21;27(1):129. doi: 10.1186/s13075-025-03589-6.
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.
骨关节炎（OA）是一种慢性退行性关节疾病，其特征为软骨破坏、软骨下骨重塑和炎症。机械应力，如运动，可影响OA的进展，根据强度的不同，它既可以作为一种治疗干预措施，也可以作为一种风险因素。感觉神经肽αCGRP在调节软骨、骨骼和炎症反应中发挥作用，使其成为运动对OA影响的潜在介质。本研究在创伤后小鼠模型中探究了αCGRP缺乏和运动强度对OA进展的影响。
通过内侧半月板失稳（DMM）在雄性αCGRP基因敲除（KO）小鼠和野生型（C57Bl/6J）小鼠中诱导OA。小鼠进行长达6周（术后8周）的中度或高强度跑步机运动。进行组织学分析以评估软骨降解。分别通过纳米计算机断层扫描（nanoCT）和原子力显微镜（AFM）评估软骨下和干骺端骨形态以及软骨硬度。使用多重免疫测定法分析血清炎症标志物。
αCGRP缺乏的小鼠血清促炎标志物水平升高，特别是在高强度运动后，与OA进展无关。DMM手术导致显著的软骨降解。大体软骨形态不受运动强度或αCGRP缺乏的影响，但αCGRP缺乏可防止DMM和高强度运动后关节软骨细胞外基质硬化。αCGRP缺乏和DMM诱导软骨下骨硬化，但高强度运动可减轻这种硬化。在干骺端骨中，高强度运动导致αCGRP缺乏的小鼠小梁骨丢失。
本研究强调αCGRP是OA期间关节和骨骼对机械负荷反应的内在调节因子。虽然DMM和跑步机运动后的软骨降解不受αCGRP缺乏的影响，但其缺乏改变了细胞外基质硬度、骨重塑和炎症反应。这些发现表明αCGRP是关节稳态的关键调节因子，特别是对于跑步运动期间的骨骼健康和OA进展而言。
