Purpose: Surgical destabilization of the medial meniscus (DMM) in the mouse knee results in slowly progressive osteoarthritis (OA), characterized by mild-to-moderate joint damage by week 8 and severe damage by week 16 after surgery. Progressive joint damage is associated with pain-related behaviors. Using NaV1.8-tdTomato reporter mice, which express a bright red fluorescent tdTomato reporter in >90% of C-nociceptors (pain-sensing neurons), we recently reported that DMM surgery led to changes in the anatomical distribution of nociceptors in the medial compartment of the knee. Specifically, in association with severe structural joint damage 16 weeks after DMM, the medial compartment of OA knees showed increased NaV1.8+ innervation in the medial synovium and meniscus, and NaV1.8+ nociceptors in subchondral bone channels. Here, we analyzed the nociceptive innervation of the knee in the early stages of experimental OA, 4 and 8 weeks after DMM.
Methods: DMM or sham surgery was performed in the right knee of 10-week old male C57BL/6 NaV1.8-tdTomato mice. Four and eight weeks after surgery, n=3 mice/group mice were perfused transcardially with paraformaldehyde, and the right knees collected, post fixed and decalcified. Twenty-μm thick coronal frozen sections were collected at mid-joint level, and imaged using a confocal microscope. NaV1.8-tdTomato signal of the medial synovium was quantified using ImageJ. Channels observed in the subchondral bone of the medial femoral condyles and tibial plateaux that contained NaV1.8+ nerves were quantified as follows: two mid-joint sections (80 μm apart) per knee were used to count NaV1.8+ channels; the counts were averaged for each knee.
Results: As previously reported, 4 and 8 weeks after DMM surgery, cartilage damage in the femur and tibia was very mild and limited to slight loss of proteoglycans. In addition, DMM mice had maximal subchondral bone sclerosis in the medial compartment by week 4. Despite the limited cartilage damage at this stage, analysis of the NaV1.8+ signal showed striking changes in the nociceptive innervation after DMM surgery, compared to controls. Firstly, we detected an increase in NaV1.8 innervation of the medial synovium, as early as 4 weeks after DMM, and no further increase weeks 8-16 (Fig. 1). Secondly, NaV1.8+ nociceptors were observed in the subchondral bone pointing toward calcified cartilage, and this as early as week 4.
Conclusions: These findings suggest that the NaV1.8 nociceptive innervation of the mouse knee changes very rapidly after DMM surgery, and this before the onset of significant joint damage. While the biological significance of this observation needs to be established, it suggests that neuroplasticity of sensory nerves is an early feature of OA joint damage, which may contribute to joint disease.
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