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

Aso, Koji; Izumi, Masashi; Sugimura, Natsuki; Okanoue, Yusuke; Ushida, Takahiro; Ikeuchi, Masahiko

doi:10.1016/j.joca.2016.04.009

Cited by 46 publications

(36 citation statements)

References 38 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%

“…Microarray analysis of BMLs in OA demonstrated up‐regulation of genes implicated in neurogenesis, osteochondral turnover, and inflammation that might contribute to OA pain . In animals, OA caused up‐regulation of nociceptive markers (calcitonin gene‐related peptide and tropomyosin receptor kinase A [TrkA]) in subchondral bone afferents . However, the mechanisms by which subchondral pathology contributes to OA pain are incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Introductionmentioning

confidence: 99%

Associations of Symptomatic Knee Osteoarthritis With Histopathologic Features in Subchondral Bone

Aso

Shahtaheri

Hill

et al. 2019

Arthritis & Rheumatology

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“…In light of the side effect profile of NSAIDs and opiates, new mechanism‐based analgesics that relieve bone pain with a lower side effect profile are clearly needed. To develop such analgesics, rodent models of malignant and nonmalignant bone pain were developed . These models of bone pain were then utilized to define the mechanisms that drive bone pain, test whether new mechanism‐based therapies could relieve bone pain and translate promising candidates into human clinical trials .…”

Section: Introductionmentioning

confidence: 99%

Mechanisms that drive bone pain across the lifespan

Mantyh

2018

Brit J Clinical Pharma

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Disorders of the skeleton are frequently accompanied by bone pain and a decline in the functional status of the patient. Bone pain occurs following a variety of injuries and diseases including bone fracture, osteoarthritis, low back pain, orthopedic surgery, fibrous dysplasia, rare bone diseases, sickle cell disease and bone cancer. In the past 2 decades, significant progress has been made in understanding the unique population of sensory and sympathetic nerves that innervate bone and the mechanisms that drive bone pain. Following physical injury of bone, mechanotranducers expressed by sensory nerve fibres that innervate bone are activated and sensitized so that even normally non-noxious loading or movement of bone is now being perceived as noxious. Injury of the bone also causes release of factors that; directly excite and sensitize sensory nerve fibres, upregulate proalgesic neurotransmitters, receptors and ion channels expressed by sensory neurons, induce ectopic sprouting of sensory and sympathetic nerve fibres resulting in a hyper-innervation of bone, and central sensitization in the brain that amplifies pain. Many of these mechanisms appear to be involved in driving both nonmalignant and malignant bone pain. Results from human clinical trials suggest that mechanism-based therapies that attenuate one type of bone pain are often effective in attenuating pain in other seemingly unrelated bone diseases. Understanding the specific mechanisms that drive bone pain in different diseases and developing mechanism-based therapies to control this pain has the potential to fundamentally change the quality of life and functional status of patients suffering from bone pain.

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“…This is in line with accelerated subchondral bone loss, but so far no such observations have been reported for other OA joints [50]. The subchondral bone of rat knee joints with monoiodacetate-induced OA showed clear sprouting of CGRP- and tropomyosin receptor kinase A (TrkA)-immunoreactive fibers and this phenomenon was associated with increased pain [51] (Figure 1). Interestingly, Ghilardi et al demonstrated that in a mouse model of chronic arthritic pain induced by Complete Freund Adjuvant (CFA) injection into the knee joint, the sprouting of CGRP-positive sensory fibers in the synovium is accompanied by sprouting of TH-positive sympathetic fibers in close proximity [52].…”

Section: Sensory and Sympathetic Nerve Fibers In Osteoarthritic Jomentioning

confidence: 57%

Peripheral Nerve Fibers and Their Neurotransmitters in Osteoarthritis Pathology

Grässel

Muschter

2017

IJMS

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The importance of the nociceptive nervous system for maintaining tissue homeostasis has been known for some time, and it has also been suggested that organogenesis and tissue repair are under neuronal control. Changes in peripheral joint innervation are supposed to be partly responsible for degenerative alterations in joint tissues which contribute to development of osteoarthritis. Various resident cell types of the musculoskeletal system express receptors for sensory and sympathetic neurotransmitters, allowing response to peripheral neuronal stimuli. Among them are mesenchymal stem cells, synovial fibroblasts, bone cells and chondrocytes of different origin, which express distinct subtypes of adrenoceptors (AR), receptors for vasoactive intestinal peptide (VIP), substance P (SP) and calcitonin gene-related peptide (CGRP). Some of these cell types synthesize and secrete neuropeptides such as SP, and they are positive for tyrosine-hydroxylase (TH), the rate limiting enzyme for biosynthesis of catecholamines. Sensory and sympathetic neurotransmitters are involved in the pathology of inflammatory diseases such as rheumatoid arthritis (RA) which manifests mainly in the joints. In addition, they seem to play a role in pathogenesis of priori degenerative joint disorders such as osteoarthritis (OA). Altogether it is evident that sensory and sympathetic neurotransmitters have crucial trophic effects which are critical for joint tissue and bone homeostasis. They modulate articular cartilage, subchondral bone and synovial tissue properties in physiological and pathophysiological conditions, in addition to their classical neurological features.

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

Cited by 46 publications

References 38 publications

Associations of Symptomatic Knee Osteoarthritis With Histopathologic Features in Subchondral Bone

Associations of Symptomatic Knee Osteoarthritis With Histopathologic Features in Subchondral Bone

Mechanisms that drive bone pain across the lifespan

Peripheral Nerve Fibers and Their Neurotransmitters in Osteoarthritis Pathology

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