Nociceptive phenotype of dorsal root ganglia neurons innervating the subchondral bone in rat knee joints

Aso, Koji; Ikeuchi, Masahiko; Izumi, Masashi; Sugimura, Natsuki; Kato, Tomonari; Ushida, Takahiro; Tani, Tohru

doi:10.1002/j.1532-2149.2013.00360.x

Cited by 33 publications

(31 citation statements)

References 40 publications

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“…NGF‐immunoreactive cells were colocalized with sensory nerve fibers within osteochondral channels in human subchondral bone . Indeed, most sensory neurons innervating the subchondral bone in rat knee joints were found to be TrkA‐immunoreactive , and TrkA expression in subchondral bone afferents was further increased during mono‐iodoacetate–induced OA in rats .…”

Section: Discussionmentioning

confidence: 97%

Associations of Symptomatic Knee Osteoarthritis With Histopathologic Features in Subchondral Bone

Aso

Shahtaheri

Hill

et al. 2019

Arthritis & Rheumatology

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Objective. Subchondral bone and the osteochondral junction are thought to contribute to osteoarthritis (OA) knee pain. We undertook this study to identify osteochondral pathologies specifically associated with symptomatic human knee OA.Methods. Medial tibial plateau samples from 2 groups of subjects (n = 31 per group) were matched for macroscopic chondropathy scores. The symptomatic chondropathy group had undergone total knee replacement for OA knee pain, at which time specimens of the medial tibial plateau were obtained. The asymptomatic chondropathy group included subjects who died of unrelated illness (specimens were obtained at postmortem examination) and who had not previously sought help for knee pain. OA histopathology, immunoreactivity for nerve growth factor (NGF) and CD68 (macrophages), tartrate-resistant acid phosphatase-positive subchondral osteoclasts, and synovitis were compared between groups.Results. Mankin scores, subchondral bone density, and subchondral CD68-immunoreactive macrophage infiltration were similar between the 2 groups. NGF-like immunoreactivity was found in subchondral mononuclear cells and osteoclasts, as well as in chondrocytes. NGF in osteochondral channels and osteoclast densities in subchondral bone were higher in the symptomatic chondropathy group than in the asymptomatic chondropathy group (P < 0.01 and P = 0.02, respectively), as were synovitis scores (P < 0.01). Osteochondral pathology was not significantly associated with synovitis score. The differences in NGF expression and in osteoclast density remained significant after adjustment for age and synovitis score (P = 0.01 and P = 0.04, respectively). Osteochondral NGF and osteoclast densities, together with synovitis scores, explained ~28% of sample allocation to symptomatic or asymptomatic groups.Conclusion. Subchondral pathology was associated with symptomatic knee OA, independent of chondropathy and synovitis. Increased NGF expression in osteochondral channels and increased osteoclast density appear to be key features associated with bone pain in knee OA.

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Section: Discussionmentioning

confidence: 97%

Associations of Symptomatic Knee Osteoarthritis With Histopathologic Features in Subchondral Bone

Aso

Shahtaheri

Hill

et al. 2019

Arthritis & Rheumatology

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“…A similar proportion is reported for sensory neurons supplying subchondral bone of the rat femur. 40 Whether this reflects species differences, or the different methodologies used, remains to be determined. However, what is clear is that the proportions of TrkA+ sensory neurons that innervate bone are significantly greater than published reports of TrkA+ sensory neurons that innervate skin, muscle and joints, 40,56,57 suggesting that NGF-signaling may be more important in bone pain compared to pain from other somatic tissues.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of nerve growth factor signaling in bone nociceptors and in an animal model of inflammatory bone pain

et al. 2017

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Sequestration of nerve growth factor has been used successfully in the management of pain in animal models of bone disease and in human osteoarthritis. However, the mechanisms of nerve growth factor-induced bone pain and its role in modulating inflammatory bone pain remain to be determined. In this study, we show that nerve growth factor receptors (TrkA and p75) and some other nerve growth factor-signaling molecules (TRPV1 and Nav1.8, but not Nav1.9) are expressed in substantial proportions of rat bone nociceptors. We demonstrate that nerve growth factor injected directly into rat tibia rapidly activates and sensitizes bone nociceptors and produces acute behavioral responses with a similar time course. The nerve growth factor-induced changes in the activity and sensitivity of bone nociceptors we report are dependent on signaling through the TrkA receptor, but are not affected by mast cell stabilization. We failed to show evidence for longer term changes in expression of TrkA, TRPV1, Nav1.8 or Nav1.9 in the soma of bone nociceptors in a rat model of inflammatory bone pain. Thus, retrograde transport of NGF/TrkA and increased expression of some of the common nerve growth factor signaling molecules do not appear to be important for the maintenance of inflammatory bone pain. The findings are relevant to understand the basis of nerve growth factor sequestration and other therapies directed at nerve growth factor signaling, in managing pain in bone disease.

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“…Functionally, the specificity of innervation in the skeleton suggests that a deep tissue like bone requires less nociceptor “redundancy” for the detection of injury. Although naïve bone and joint tissues appear to be innervated by the same subpopulations of nociceptive nerve fibers, the density, pattern, and morphology of nerve fibers in each tissue is remarkably different [4,14,53,62]. Thus, in the young, healthy skeleton, there are no sensory nerve fibers in the articular cartilage, a very low density in mineralized bone, low to moderate density in bone marrow, and a very high density in the periosteum [14].…”

Section: Discussionmentioning

confidence: 99%

Exuberant sprouting of sensory and sympathetic nerve fibers in nonhealed bone fractures and the generation and maintenance of chronic skeletal pain

Chartier

Thompson

Longo

et al. 2014

Pain

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Skeletal injury is a leading cause of chronic pain and long-term disability worldwide. While most acute skeletal pain can be effectively managed with nonsteroidal anti-inflammatory drugs and opiates, chronic skeletal pain is more difficult to control using these same therapy regimens. One possibility as to why chronic skeletal pain is more difficult to manage over time is that there may be nerve sprouting in non-healed areas of the skeleton that normally receive little (mineralized bone) to no (articular cartilage) innervation. If such ectopic sprouting did occur, it could result in normally nonnoxious loading of the skeleton being perceived as noxious and/or the generation of a neuropathic pain state. To explore this possibility, a mouse model of skeletal pain was generated by inducing a closed fracture of the femur. Examined animals had comminuted fractures and did not fully heal even at 90+ days post fracture. In all mice with nonhealed fractures, exuberant sensory and sympathetic nerve sprouting, an increase in the density of nerve fibers, and the formation of neuroma-like structures near the fracture site were observed. Additionally, all of these animals exhibited significant pain behaviors upon palpation of the nonhealed fracture site. In contrast, sprouting of sensory and sympathetic nerve fibers or significant palpation-induced pain behaviors was never observed in naïve animals. Understanding what drives this ectopic nerve sprouting and the role it plays in skeletal pain may allow a better understanding and treatment of this currently difficult-to-control pain state.

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Nociceptive phenotype of dorsal root ganglia neurons innervating the subchondral bone in rat knee joints

Cited by 33 publications

References 40 publications

Associations of Symptomatic Knee Osteoarthritis With Histopathologic Features in Subchondral Bone

Associations of Symptomatic Knee Osteoarthritis With Histopathologic Features in Subchondral Bone

Mechanisms of nerve growth factor signaling in bone nociceptors and in an animal model of inflammatory bone pain

Exuberant sprouting of sensory and sympathetic nerve fibers in nonhealed bone fractures and the generation and maintenance of chronic skeletal pain

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