gms | German Medical Science

Objectives: The ongoing degenerative processes in subchondral bone in osteoarthritis (OA) might be associated with changes in innervation pattern of sensory nerves. The sensory neuropeptide substance P (SP) is a known regulator of bone homeostasis by affecting metabolism of bone cells like osteoblasts and osteoclasts. SP effects on bone are ambivalent and can be either catabolic or anabolic. Physiological concentrations of SP are critical for proper bone quality what has been shown in a fracture healing model. We aimed to analyze the influence of an altered sensory neuropeptide microenvironment on subchondral bone changes in a murine OA model.

Methods: OA was induced in wildtype (WT) and SP-knockout (Tachykinin (Tac) 1-/-) mice by surgical destabilization of the medial meniscus (DMM model). Structural alterations of bone were analyzed by µCT and morphometrical analysis of paraffin-embedded knee sections. TRAP-staining was applied for analysis of osteoclastogenesis.

Results and Conclusion: Evaluation of OA progression on paraffin sections by a modified OARSI histopathology score showed a reduced articular cartilage OA pathology in Tac1-/- joints compared to WT joints at 4 weeks after surgery. OARSI scoring of knee joint articular cartilage sections from aged WT and Tac1-/- mice revealed no difference in 12 months old animals but the score was reduced for Tac1-/- joint cartilage compared to WT in 16 months old mice. µCT analysis revealed DMM induced changes in the trabecular subchondral bone compartment. DMM surgery lead to a reduced BV/TV ratio in the lateral subchondral bone compartment compared to WT Sham controls but not in Tac1-/-Sham controls. Both mice strains have reduced trabecular numbers 4 weeks after OA induction compared to their Sham controls. Comparison of trabecular numbers between DMM operated WT and Tac1-/- mice revealed significantly higher trabecular numbers in Tac1-/- mice. Trabecular space was larger in DMM WT subchondral bone compared to Sham WT mice and DMM Tac1-/- subchondral bone had less trabecular space compared to DMM WT. In the medial subchondral bone compartment, trabecular numbers and space were unaltered after DMM in WT mice. DMM Tac1-/- mice instead showed a decrease in medial trabecular numbers and an increase in space compared to Sham operated animals. DMM Tac1-/- mice developed a thicker subchondral bone plate in the medial compartment in relation to DMM WT mice. Osteophyte development 4 weeks after DMM was comparable in WT and Tac1-/- mice. In vitro, osteoclastogenesis of bone marrow-derived macrophages from WT mice was reduced 4 weeks after DMM and increased 8 weeks after surgery compared to Sham mice.

Absence of SP in Tac1-/- mice ameliorates OA progression in cartilage and bone in a surgical OA model as well as in spontaneously occurring OA related to aging. Mediators of bone structural changes might be osteoclasts, which show an altered differentiation pattern after DMM surgery.