The nociceptive innervation of the normal and osteoarthritic mouse knee

Osteoarthritis Cartilage. 2019 Nov;27(11):1669-1679. doi: 10.1016/j.joca.2019.07.012. Epub 2019 Jul 25.


Objectives: To document the nociceptive innervation of the normal and osteoarthritic murine knee.

Methods: Knees were collected from naïve male C57BL/6 NaV1.8-tdTomato reporter mice aged 10, 26, and 52 weeks (n = 5/group). Destabilization of the medial meniscus (DMM) or sham surgeries (n = 5/group) were performed in the right knee of 10-week old male NaV1.8-tdTomato mice, and knees were harvested 16 weeks later. Twenty 20-μm frozen sections from a 400-μm mid-joint region were collected for confocal microscopy. Integrated density of the tdTomato signal was calculated using Image J by two independent observers blinded to the groups. Consecutive sections were stained with hematoxylin & eosin. C57BL/6-Pirt-GCaMP3 mice (n = 5/group) and protein gene product 9.5 (PGP9.5) immunostaining of C57BL/6 wild type (WT) mice (n = 5/group) were used to confirm innervation patterns.

Results: In naive 10-week old mice, nociceptive innervation was most dense in bone marrow cavities, lateral synovium and at the insertions of the cruciate ligaments. By age 26 weeks, unoperated knees showed a marked decline in nociceptors in the lateral synovium and cruciate ligament insertions. No further decline was observed by age 1 year. Sixteen weeks after DMM, the medial compartment of OA knees exhibited striking changes in NaV1.8+ innervation, including increased innervation of the medial synovium and meniscus, and nociceptors in subchondral bone channels. All results were confirmed through quantification, also in Pirt-GCaMP3 and PGP9.5-immunostained WT mice.

Conclusions: Nociceptive innervation of the mouse knee markedly declines by age 26 weeks, before onset of spontaneous OA. Late-stage surgically induced OA is associated with striking plasticity of joint afferents in the medial compartment of the knee.

Keywords: Innervation; Knee joint; Mouse; Na(V)1.8; Nociceptors; Osteoarthritis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Disease Models, Animal
  • Knee Joint / innervation*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nociception / physiology*
  • Nociceptors / physiology*
  • Osteoarthritis, Knee / physiopathology*
  • Range of Motion, Articular / physiology*