Nociceptive Sensory Fibers Drive Interleukin-23 Production in a Murine Model of Psoriasis via Calcitonin Gene-Related Peptide

Neuroimmunity is involved in the pathogenesis of psoriasis, but the mechanism underlying the interaction between the nervous system and the interleukin (IL)-23/IL-17 immune axis is yet unclear. This study reveals the essential role of the sensory neuron-derived calcitonin gene-related peptide (CGRP) in imiquimod (IMQ)-induced expression of IL-23. First, we show that the increased nociceptive behavior was consistent with the development of psoriasiform dermatitis, which requires intact sensory innervation. Systemic ultrapotent Transient receptor potential vanilloid 1 (TRPV1) agonist (resiniferatoxin, RTX) treatment-induced sensory denervation resulted in a significant decrease in IL-23 expression in this model, while the recombinant IL-23 treatment induced IL-17A expression was intact after RTX treatment. In addition, IMQ exposure induced a transient increase in CGRP expression in the dorsal root ganglion. The neuron-derived CGRP expression was completely abolished by sensory denervation, thereby downregulating IL-23 expression, which could be reversed through the introduction of CGRP into the denervated dorsal skin. Our results suggest that nociceptive sensory neurons may drive the production of IL-23, resulting in IL-17A production from γδ T cells via the neuropeptide CGRP in the pathology of psoriasis.

Divalent Metal Cations Stimulate Skeleton Interoception to Promote Bone Formation

Bone formation induced by divalent metal cations has been widely reported; however, the underlying mechanism is unclear. Here we report that these cations stimulate skeleton interoception by promoting prostaglandin E2 (PGE2) secretion from macrophages. This imune response is accompanied by the sprouting and arborization of calcitonin gene-related polypeptide-α+ nerve fibers, which sense the inflammatory cue with PGE2 receptor 4 (EP4) and convey the interoceptive signals to the central nervous system. Activating skeleton interoception downregulates sympathetic tone for new bone formation. Moreover, either macrophage depletion or knockout of cyclooxygenase-2 in the macrophage abolishes divalent cation–induced skeleton interoception. Furthermore, sensory denervation or knockout of EP4 in the sensory nerves eliminates the osteogenic effects of divalent cations. Thus, our study reveals that divalent cations promote bone formation through the skeleton interoception circuit, a finding which could prompt the development of novel biomaterials to elicit the therapeutic power of these divalent cations.

Percutaneous Radiofrequency Hip Joint Denervation

With an aging population, chronic osteoarthritic hip joint pain is becoming a major issue. Most patients with hip pain can control their pain with conservative measures but with a gradual reduction in their quality of life. When gradually reduced ambulation and pain become recalcitrant, total hip arthroplasty is the next step. For most patients, this is a good way to improve pain control and to recover some quality of life, but for a few this aggressive surgical procedure is not possible. Sometimes co-morbidities make total hip arthroplasties undesirable. At other times, the age of the patients recommends to wait for a while. In these cases, other options have to be explored. Percutaneous partial hip joint sensory denervation has become a notable option as it can provide acceptable rates of pain relief with minimal surgical aggressiveness. There are three modalities to perform it: thermal, cooled and pulsed radiofrequency.

Validation of a new protocol for ultrasound-guided genicular nerve radiofrequency ablation with accurate anatomical targets: cadaveric study

IntroductionUltrasound (US)-guided radiofrequency ablation (RFA) of genicular nerves (GNs) is increasingly performed to manage chronic knee pain. The anatomical foundations supporting the choice of original targets for US-guided GN-RFA have been thoroughly improved by recent anatomical studies. Therefore, this study aimed to provide a new protocol with revised anatomical targets for US-guided GN-RFA and to assess their accuracy in a cadaveric model.Materials and methodsFourteen fresh-frozen cadaveric knees were used. After a pilot study with 4 knees, five consistent nerves were targeted in the other 10 knees with revised anatomical landmarks: superior medial genicular nerve (SMGN), superior lateral genicular nerve (SLGN), inferior medial genicular nerve (IMGN), recurrent fibular nerve (RFN) and the infrapatellar branch of the saphenous nerve (IPBSN). For each nerve, the lumen of radiofrequency (RF) cannula was prefilled with non-diffusible black paint, and then the cannula was inserted at the target site under US guidance. After US verification of correct placement, the stylet was introduced in the cannula to create a limited black mark on the tissues at the top of the active tip. Anatomical dissection was performed to assess for accuracy.ResultsThe proportion of nerves directly found in contact with the black mark was 7/10, 8/10, 10/10 and 9/10 for the SMGN, SLGN, IMGN and RFN, respectively. The proportions of nerve captured by the theoretical largest monopolar RF lesions were 100% for the SMGN, IMGN and RFN, and IPBSN and 95% for SLGN. The mean distances from the center of the black mark to the targeted nerve were 2.1±2.2 mm, 1.0±1.4 mm, 0.75±1.1 mm and 2.4±4.5 mm for the SMGN, SLGN, IMGN and RFN, respectively.ConclusionUS-guided GN-RFA with revised anatomical targets resulted in accurate capture of the five targeted nerves. This protocol provides precise sensory denervation of a larger panel of nerves, targeting those whose constancy regarding anatomical location has been clearly demonstrated. It is expected to improve the clinical outcomes.

A Novel Technical Protocol for Improved Capture of the Genicular Nerves by Radiofrequency Ablation

Background Fluoroscopically guided cooled genicular nerve radiofrequency ablation (RFA) is an increasingly performed procedure for chronic, refractory knee pain due to osteoarthritis. Traditionally, partial sensory denervation has been accomplished through ablation of the superomedial, superolateral, and inferomedial genicular nerves. However, recent cadaveric studies have demonstrated additional sensory nerves and significant anatomic variation that impact current protocols. Objective We describe an updated cooled genicular nerve radiofrequency ablation protocol that accounts for varied nerve location of the superomedial, superolateral, and inferomedial genicular nerves, as well as capture of the terminal articular branches of the nerves to the vastus intermedius, vastus lateralis, and vastus medialis. Furthermore, we describe an adjusted technique for inferomedial genicular nerve capture that mitigates the risk of pes anserine tendon injury. Design Technical report and brief literature review. Methods Cadaveric studies relating to the sensory innervation of the anterior knee joint were reviewed, and a more accurate and comprehensive cooled genicular nerve radiofrequency ablation (CRFA) protocol is proposed. Conclusions Based on recent, rigorous anatomic dissections of the knee, the proposed genicular nerve CRFA protocol will provide more complete sensory denervation and potentially improve clinical outcomes. Prospective studies will be needed to confirm the hypothesis that this protocol will result in improved effectiveness and safety of genicular nerve RFA.

Effects of capsaicin-induced sensory denervation on early implant osseointegration in adult rats

The presence of nerve endings around implants is well-known, but the interaction between the peripheral nervous system and the osseointegration of implants has not been thoroughly elucidated to date. The purpose of this study was to test the effects of selective sensory denervation on early implant osseointegration. Forty male Sprague-Dawley rats were divided randomly into two groups, group A and group B, and they were treated with capsaicin and normal saline, respectively. One week later, titanium implants were placed in the bilateral femurs of the rats. Three and six weeks after implantation, histological examination, microcomputed tomography and biomechanical testing were performed to observe the effect of sensory denervation on implant osseointegration. At three weeks and six weeks, bone area, trabecular bone volume/total bone volume and bone density were significantly lower in group A than in group B. Similarly, the bone–implant contact rate, trabecular number and trabecular thickness were clearly lower in group A than in group B at three weeks. However, the trabecular separation spacing in group A was greater than that in group B at both time points. Biomechanical testing revealed that the implant-bone binding ability of group A was significantly lower than that in group B. The research demonstrated that sensory innervation played an important role in the formation of osseointegration. Selective-sensory denervation could reduce osseointegration and lower the binding force of the bone and the implant.

Array profiling reveals contribution of Cthrc1 to growth of the denervated rat urinary bladder

Bladder denervation and bladder outlet obstruction are urological conditions that cause bladder growth. Transcriptomic surveys in outlet obstruction have identified differentially expressed genes, but similar studies following denervation have not been done. This was addressed using a rat model in which the pelvic ganglia were cryo-ablated followed by bladder microarray analyses. At 10 days following denervation, bladder weight had increased 5.6-fold, and 2,890 mRNAs and 135 micro-RNAs (miRNAs) were differentially expressed. Comparison with array data from obstructed bladders demonstrated overlap between the conditions, and 10% of mRNAs changed significantly and in the same direction. Many mRNAs, including collagen triple helix repeat containing 1 ( Cthrc1), Prc1, Plod2, and Dkk3, and miRNAs, such as miR-212 and miR-29, resided in the shared signature. Discordantly regulated transcripts in the two models were rare, making up for <0.07% of all changes, and the gene products in this category localized to the urothelium of normal bladders. These transcripts may potentially be used to diagnose sensory denervation. Western blotting demonstrated directionally consistent changes at the protein level, with increases of, e.g., Cthrc1, Prc1, Plod2, and Dkk3. We chose Cthrc1 for further studies and found that Cthrc1 was induced in the smooth muscle cell (SMC) layer following denervation. TGF-β1 stimulation and miR-30d-5p inhibition increased Cthrc1 in bladder SMCs, and knockdown and overexpression of Cthrc1 reduced and increased SMC proliferation. This work defines common and distinguishing features of bladder denervation and obstruction and suggests a role for Cthrc1 in bladder growth following denervation.