Molecular Mechanisms That Contribute to Bone Marrow Pain

Ivanusic, Jason J.

doi:10.3389/fneur.2017.00458

Cited by 34 publications

(25 citation statements)

References 138 publications

(127 reference statements)

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“…One advantage of studying the mouse knee is that it is small enough to be sectioned intact, thereby giving an overview of the entire knee. In 10-week old mice, we found that Na V 1.8 neurons densely innervated bone marrow cavities, which confirms reports in the literature that bone marrow is densely innervated by both Adand C-fiber sensory neurons 30 . It receives the greatest total number of sensory and sympathetic neurons when compared to mineralized bone and periosteum 31,32 .…”

Section: Discussionsupporting

confidence: 91%

The nociceptive innervation of the normal and osteoarthritic mouse knee

Obeidat

Miller

et al. 2019

Osteoarthritis and Cartilage

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Objectives: To document the nociceptive innervation of the normal and osteoarthritic murine knee. Methods: Knees were collected from naïve male C57BL/6 Na V 1.8-tdTomato reporter mice aged 10, 26, and 52 weeks (n ¼ 5/group). Destabilization of the medial meniscus (DMM) or sham surgeries (n ¼ 5/ group) were performed in the right knee of 10-week old male Na V 1.8-tdTomato mice, and knees were harvested 16 weeks later. Twenty 20-mm frozen sections from a 400-mm 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 ¼ 5/group) and protein gene product 9.5 (PGP9.5) immunostaining of C57BL/6 wild type (WT) mice (n ¼ 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 Na V 1.8þ 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.

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Section: Discussionsupporting

confidence: 91%

The nociceptive innervation of the normal and osteoarthritic mouse knee

Obeidat

Miller

et al. 2019

Osteoarthritis and Cartilage

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“…Another possibility is that peripheral sensitization contributes to movement-related pain in bone cancer. Bone cancer causes inflammation that activates peripheral bone marrow nociceptors through the release of inflammatory mediators, 34 which may cause a decreased threshold and increased responsiveness of nociceptors in bone marrow. TRPV2 is activated by local insulin-like growth factor I produced by activated osteoblasts in bone cancer progression.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of TRPV2 channels in sensory neurons increases limb use and weight bearing but does not affect spontaneous flinching behavior in a mouse model of bone cancer

et al. 2018

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Bone cancer pain is a complex pain state involving ongoing pain and movement-related pain, which are thought to be caused by different mechanisms. Transient receptor potential vanilloid subfamily 1 (TRPV1) is involved in ongoing pain but not movement-related pain. The purpose of this study was to investigate the role of transient receptor potential vanilloid subfamily 2 (TRPV2) in bone cancer pain. Proportions of TRPV1- and TRPV2-immunoreactive neurons in lumbar dorsal root ganglia innervating the femurs of male mice were examined by using Fluoro-Gold. Mice were intrathecally injected with small interfering RNA (siRNA) against TRPV2 or scrambled siRNA for three consecutive days from day 14 after sarcoma injection into the left femur. In the mice with bone cancer, the number of spontaneous flinches was quantified for assessment of ongoing pain, and limb use and weight bearing were assessed as indications of movement-related pain. Changes in TRPV2 protein levels in dorsal root ganglion were evaluated by Western blotting. We also examined the effects of intrathecal administration of siRNA against TRPV2 or scrambled siRNA on thermal and mechanical sensitivities in normal mice without tumors. The proportions of TRPV1-immunoreactive and TRPV2-immunoreactive neurons were 21% and 22% of neurons in dorsal root ganglia innervating the femur, respectively. Tumor-bearing mice exhibited an increased number of spontaneous flinches and impaired limb use and weight bearing at day 13 after sarcoma injection. TRPV2 protein level in dorsal root ganglia at day 13 was comparable to that at baseline. siRNA against TRPV2 significantly improved limb use and weight bearing but did not affect the number of spontaneous flinches compared to those in the group treated with scrambled siRNA. siRNA against TRPV2 did not affect thermal or mechanical sensitivity in normal mice. The results suggest that TRPV2 is involved in movement-related pain but not ongoing pain in mice with bone cancer.

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“…The inflammation eventually causes both the peripheral and central sensitization of neurons, leading to spontaneous joint pain at rest and hyperalgesia. Despite progress on the exact mechanism leading to the pain sensation [ 71 ], our detailed mechanistic understanding remains sketchy. However, it seems reasonable to assume that release of sensory neuropeptides such as substance P, calcitonin gene-related peptide (CGRP), and neurokinin A, contributes to the pain sensation in OA [ 62 , 72 ].…”

Section: Novel Indicationsmentioning

confidence: 99%

The Expanding Therapeutic Utility of Botulinum Neurotoxins

Fonfría

Maignel

Lezmi

et al. 2018

Toxins

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Botulinum neurotoxin (BoNT) is a major therapeutic agent that is licensed in neurological indications, such as dystonia and spasticity. The BoNT family, which is produced in nature by clostridial bacteria, comprises several pharmacologically distinct proteins with distinct properties. In this review, we present an overview of the current therapeutic landscape and explore the diversity of BoNT proteins as future therapeutics. In recent years, novel indications have emerged in the fields of pain, migraine, overactive bladder, osteoarthritis, and wound healing. The study of biological effects distal to the injection site could provide future opportunities for disease-tailored BoNT therapies. However, there are some challenges in the pharmaceutical development of BoNTs, such as liquid and slow-release BoNT formulations; and, transdermal, transurothelial, and transepithelial delivery. Innovative approaches in the areas of formulation and delivery, together with highly sensitive analytical tools, will be key for the success of next generation BoNT clinical products.

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Molecular Mechanisms That Contribute to Bone Marrow Pain

Cited by 34 publications

References 138 publications

The nociceptive innervation of the normal and osteoarthritic mouse knee

The nociceptive innervation of the normal and osteoarthritic mouse knee

Knockdown of TRPV2 channels in sensory neurons increases limb use and weight bearing but does not affect spontaneous flinching behavior in a mouse model of bone cancer

The Expanding Therapeutic Utility of Botulinum Neurotoxins

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