Name: Prof. Dr. Susanne Grässel
The joints are innervated by calcitonin gene-related peptide (aCGRP)- and substance P (SP) positive sensory nerve fibers and there is accumulating evidence that sensory neurotransmitters have crucial trophic effects which are essential for proper bone metabolism and bone remodeling. Alteration of sensory joint innervation might be partly responsible for degenerative changes which contribute to development of osteoarthritis. Underlying molecular mechanisms which contribute to abnormal subchondral bone remodeling and osteophyte formation during the pathogenesis of OA due to changes in sensory joint innervation and their respective neurotransmitter milieu are mostly unknown. We hypothesize that the profile of sensory nerve fibers in subchondral bone is altered already early in OA and this alteration affects osteoclast number/activity during OA progression. We propose that inhibition of osteoclasts improves subchondral bone pathophysiology and ameliorate OA pathogenesis (WP1). Likely, sensory neurotransmitters modulate joint repair processes in response to aberrant mechanical loading (WP2) and thus mechanical stress may modulate neurotransmitter effects on osteoclast/BMM metabolism in cell culture (WP3). We further assume that the profile of neurotransmitter-receptor (neurokinin-1- receptor and CGRP-receptor) regulatory miRs is altered in synovial- and bone marrow derived macrophages during pathogenesis of OA (WP4).
Comparison of spontaneous and surgical induced OA-pathogenesis between Tac-1-deficient and WT mice.
We did not observe differences in spontaneous OA-scoring in the 12 month old group (A, B, E), however after 16 months WT-mice develop significant more severe spontaneous OA scores compared to Tac1-deficient mice (C, D, E).
4 weeks after induction of OA by DMM, WT mice obtained a significant higher OA-score compared to Tac1-deficient mice (F, G, H). 12 months old group N=6, 16 months old group N=8, 4 weeks after DMM group N=7, bars = 200 µm.
CGRP-receptor and NK1R localization in osteoclasts/BMM from WT mice
A) Immunofluorescence staining of osteoclast/BMM cultures for NK1R (red) = upper panel
B) Immunofluorescence staining of osteoclast/BMM cultures for CGRP-receptor (red) = upper panel
Cell nuclei are stained with DAPI (blue). Arrows indicate multi-nuclear osteoclasts.
Lower panel: respective light microscopic images. Magnification for all images = 400x.
Induction of murine osteoarthritis by destabilization of the medial meniscus (DMM).
A) µCT analysis of sham-operated knees from C57BL/6J mice shows normal localization of the medial meniscus (red circle) in the weight bearing region between femoral condyle and tibial plateau.
B) Transection of the medial meniscotibial ligament provokes translocation of the medial meniscus (red circle) leading to instability and progressive osteoarthritis in mice.