gms | German Medical Science

Objectives: Osteoarthritis (OA) is characterized by degenerative changes of the articular cartilage and the underlying bone of the affected joint. As a result, patients suffer from pain and stiffness up to loss of function. Exercise can improve joint mobility and stability while relieving pain. Excessive training, however, might favor OA progression. Furthermore, the joint is innervated by sensitive nerve fibers, which might influence joint tissue metabolism by secreting sensitive neuropeptides like substance P (SP) and alpha-calcitonin gene-related peptide (alpha-CGRP). The aim of this study is to elucidate the role of SP and alpha-CGRP during OA pathogenesis in the context of different exercise programs.

Methods: OA was induced via surgical destabilization of the medial meniscus (DMM) in male SP- and alpha-CGRP KO mice as well as in C57Bl/6J WT mice at 12 weeks of age (N=6 per group). Sham surgery was performed in control mice groups in which the meniscotibial ligament was exposed but not transected. Starting 2 weeks after DMM/Sham surgery, forced exercise experiments were performed using a treadmill for 30 minutes 5 days a week for 2 and 6 weeks. Mice were split in intense and moderate exercise groups. The moderate exercise program involved running at 10 m per minute at 5° incline, while the intense exercise was carried out at 16 m per minute at 15° incline. Histomorphometric assessment of articular cartilage degradation (according to OARSI scoring system) was performed. Serum samples were analyzed for inflammatory cytokines via Multiplex Immunoassays. Immunohistochemistry, atomic force microscopy, and nanoCT analysis are in progress.

Results and conclusion: OARSI scoring confirmed OA induction 4 weeks after DMM surgery by increased medial cartilage degradation. Two weeks of forced exercise amplified this effect irrespective of program intensity. No significant genotype-dependent differences were observed 4 weeks after DMM surgery. Serum analysis revealed increased levels of cytokines associated with OA and general inflammation in alpha-CGRP KO mice, namely VEGF-A, MCP-1, MIP1-alpha, MIP1-beta, and RANKL. The increase in cytokine levels was induced by intense exercise after DMM or Sham surgery. However, DMM surgery amplified the observed effects. SP KO mice showed similar trends in serum cytokine levels, although not significantly.

Our results suggest a negative effect of exercise on the progression of OA in early disease stages, independent of exercise intensity. Furthermore, intense exercise induced inflammatory processes correlated to increased cytokine levels in the serum that might exacerbate OA pathogenesis in later stages. The neuropeptides alpha-CGRP and, to some extent, SP may play a role in protecting against these adverse effects.