Intra-articular collagenase in the spinal facet joint induces pain, DRG neuron dysregulation and increased MMP-1 absent evidence of joint destruction
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ABSTRACT:
SUBMITTER: Ita M
PROVIDER: S-EPMC7738551 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
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Project description:This study aimed to demonstrate the effect of intra-articular (IA) lumbar facet joint (LFJ) pulsed radiofrequency (PRF) for the management of LFJ pain, and to compare the effect of IA LFJ PRF to IA corticosteroid injection (ICI). Pathology in the LFJ is a common source of lower back pain (LBP). It is responsible for chronic LBP in approximately 15% to 45% of patients. It has been reported that PRF stimulation can effectively reduce refractory joint pain.Sixty patients with LFJ pain were recruited and randomly assigned to 1 of 2 groups: the IA PRF group and the ICI group. There were 30 patients in each group. At pretreatment, 2 weeks, 1, 3, and 6 months after treatment, we assessed the severity of LBP using a numeric rating scale (NRS).Compared with the pretreatment NRS scores, patients in both groups showed a significant decrease in NRS scores at 2 weeks, and 1, 3, and 6 months after each treatment. Between groups, changes in the NRS scores were significantly different over time. At 2 weeks and 1 month after each procedure, the NRS score after ICI was significantly lower than that after the PRF stimulation. However, at 3 and 6 months after the procedures, the decrements of NRS scores were not significantly different between the 2 groups. Six months after treatment, about half of patients in both groups reported successful pain relief (pain relief of ?50%).In the current study, both IA PRF stimulation and ICI into the LFJ significantly relieved LFJ pain. Their effects persisted for at least 6 months after the procedure. Thus, IA PRF is a useful therapeutic option for the management of LFJ pain.
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Project description:Facet joint osteoarthritis (FJOA) is a common degenerative joint disorder with high prevalence in the elderly. FJOA causes lower back pain and lower extremity pain, and thus severely impacts the quality of life of affected patients. Emerging studies have focused on the histomorphological and histomorphometric changes in FJOA. However, the dynamic genetic changes in FJOA have remained to be clearly determined. In the present study, previously obtained RNA deep sequencing data were subjected to an ingenuity pathway analysis (IPA) and canonical signaling pathways of differentially expressed genes (DEGs) in FJOA were studied. The top 25 enriched canonical signaling pathways were identified and canonical signaling pathways with high absolute values of z-scores, specifically leukocyte extravasation signaling, Tec kinase signaling and osteoarthritis pathway, were investigated in detail. DEGs were further categorized by disease, biological function and toxicity (tox) function. The genetic networks between DEGs as well as hub genes in these functional networks were also investigated. It was demonstrated that C-X-C motif chemokine ligand 8, elastase, neutrophil expressed, growth factor independent 1 transcriptional repressor, Spi-1 proto-oncogene, CCAAT enhancer binding protein epsilon, GATA binding protein 1, TAL bHLH transcription factor 1, erythroid differentiation factor, minichromosome maintenance complex component 4, BTG anti-proliferation factor 2, BRCA1 DNA repair-associated, cyclin D1, chromatin assembly factor 1 subunit A, triggering receptor expressed on myeloid cells 1 and tumor protein p63 were hub genes in the top 5 IPA networks (with a score >30). The present study provides insight into the pathological processes of FJOA from a genetic perspective and may thus benefit the clinical treatment of FJOA.
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Project description:Previously we showed that MMP-1 (collagenase-1) and MMP-13 (collagenase-3) differentially regulate the expression of osteoblastic markers in a heterogenous population of primary human periodontal ligament cells. The mechanisms for these differential responses are not known, but may result from divergence in regulation of early osteogenic transcription factors. The purpose of this study was to elucidate where in the hierarchy of osteoblast-specific transcription factors and markers the differences in MMP-1- and -13-mediated regulation of osteoblastic differentiation arise. We found that the overexpression of MMP-1 resulted in significant decreases in BMP-2, Dlx5, AP, OP and BSP and increases in TGF-?1 and MSX2. In contrast, MMP-13 overexpression resulted in significant decreases in Runx2, OP and BSP, and increases in TGF-?1, MSX2 and OC. The knockdown of MMP-1 caused significant increases in all osteoblastic markers. MMP-13 knockdown produced significant increases only in TGF-?1, MSX2 and Osx, but decreases in Runx2 and OC. Suppression of both MMPs together resulted in significant increases of all osteoblastic markers except Runx2. MMP-1 had a more robust and generalized effect in regulating osteoblast transcription factors and markers than MMP-13. Finally, of the markers and transcription factors assayed, Runx2 is the most early stage transcription factor induced by suppression of MMP-1, while Osx and MSX2 are the most early stage transcription factors regulated by MMP-13. These data show that MMP-1's and -13's differential regulation of osteoblastic markers in MG63 cells likely results from their modulation of divergent signaling pathways involved in osteoblastic differentiation.
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Project description:Lumbar zygapophyseal joints act as primary pain generators in at least 10-15% of patients with chronic low back pain.Diagnostic nerve blocks are the most reliable way to diagnose lumbar zygapophyseal joint pain.IASP recommends either controlled or comparative blocks for diagnosis of zygapophyseal joint pain as there is a significant incidence of false positives with single blocks.Management should be multimodal comprising education, exercises, analgesics and procedural interventions to achieve functional restoration.There is a need for further RCTs with standardised diagnostic criteria and outcome measures as well as long-term data to determine the efficacy of radiofrequency denervation.
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Project description:Osteoarthritis is a degenerative joint disease whose molecular mechanism is currently unknown. Wnt/beta-catenin signaling has been demonstrated to play a critical role in the development and function of articular chondrocytes. To determine the role of beta-catenin signaling in articular chondrocyte function, we generated Col2a1-ICAT-transgenic mice to inhibit beta-catenin signaling in chondrocytes.The expression of the ICAT transgene was determined by immunostaining and Western blot analysis. Histologic analyses were performed to determine changes in articular cartilage structure and morphology. Cell apoptosis was determined by TUNEL staining and the immunostaining of cleaved caspase 3 and poly(ADP-ribose) polymerase (PARP) proteins. Expression of Bcl-2, Bcl-x(L), and Bax proteins and caspase 9 and caspase 3/7 activities were examined in primary sternal chondrocytes isolated from 3-day-old neonatal Col2a1-ICAT-transgenic mice and their wild-type littermates and in primary chicken and porcine articular chondrocytes.Expression of the ICAT transgene was detected in articular chondrocytes of the transgenic mice. Associated with this, age-dependent articular cartilage destruction was observed in Col2a1-ICAT-transgenic mice. A significant increase in cell apoptosis in articular chondrocytes was identified by TUNEL staining and the immunostaining of cleaved caspase 3 and PARP proteins in these transgenic mice. Consistent with this, Bcl-2 and Bcl-x(L) expression were decreased and caspase 9 and caspase 3/7 activity were increased, suggesting that increased cell apoptosis may contribute significantly to the articular cartilage destruction observed in Col2a1-ICAT-transgenic mice.Inhibition of beta-catenin signaling in articular chondrocytes causes increased cell apoptosis and articular cartilage destruction in Col2a1-ICAT- transgenic mice.
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Project description:IntroductionLumbar pain of facet origin is a common problem worldwide. For those patients not responding to traditional treatment, one approach may be intra-articular infiltration of corticoid and anaesthetic. However, despite the increasing demand for this procedure, no consensus exists regarding its therapeutic value. The selection of eligible participants may be a determining factor since only those with an inflammatory process will benefit from the use of corticosteroids. This study aims to identify differences in disability, pain and quality of life scores in individuals with and without facet joint inflammation who were diagnosed using MRI.Method and analysisThis prospective cohort will include individuals older than 18 years with a clinical diagnosis of facet syndrome who underwent intra-articular infiltration. Changes in scores of pain, disability and quality of life questionnaires at 1, 3, 6 and 12 months of follow-up compared with baseline will be analysed. An MRI examination performed before infiltration will help to distinguish between exposed (with inflammation) and non-exposed (non-inflammation) groups with facet syndrome. The primary outcome will be the disability questionnaire (Roland Morris), and the secondary outcomes will be the score questionnaires for pain (Visual Analogue Scale), quality of life (EuroQol Quality of Life Questionnaire) and disability (Oswestry).Ethics and disseminationThe Internal Review Board approved this study, which started only after the approval number (5291417.0.0000.0071) was received. All recruited participants will receive a verbal explanation about the purpose of the study, and their decision to participate will be free and voluntary. All participants enrolled in the study will provide a signed informed consent form including confidentiality terms. The results obtained in this study will be presented at national and international conferences and published in peer-reviewed scientific journals to disseminate the knowledge.Trials registration numberNCT03304730; Pre-results.
| S-EPMC6624116 | biostudies-literature
Project description:BACKGROUND:This study was performed to investigate the association between lumbar disc herniation (LDH) and facet joint osteoarthritis (FJOA) using magnetic resonance imaging (MRI). METHODS:Between March 2012 and September 2018, a total of 441 segments from 394 patients with LDH were included in the study. LDH was classified according to the Michigan State University (MSU) classification, in which the degree of LDH is divided into 3 levels (expressed as 1, 2, and 3) and the location of LDH is divided into 4 zones (described as A, AB, B, and C). Bilateral FJOA was graded from 0 to 3 using the criteria introduced by Weishaupt et al., and bilateral facet orientations were measured on axial MRI slices. A mixed-effects ordinal logistic regression model was utilized to determine the potential factors that may be associated with FJOA, including sex, age, body mass index (BMI), segment, facet orientation and tropism, and the degree and location of LDH. RESULTS:In general, the prevalence of FJOA (grade???2) was 66.2% in LDH segments. For both the left and right sides, the degree of LDH was associated with the severity of FJOA (p?<?0.01). Age and BMI were also associated with the severity of left and right FJOA (p?=?0.002 and p <?0.001 for age, p <?0.001 and p?=?0.003 for BMI, respectively), while segment, facet orientation, and facet tropism were not (p?>?0.05 for all). Notably, MSU-B LDH was associated with greater odds of having more severe FJOA on the herniation side (left: p <?0.001, odds ratio (OR)?=?2.714, 95% confidence interval (CI)?=?1.583~4.650; right: p?=?0.003, OR?=?2.615, 95% CI?=?1.405~4.870). However, other locations of LDH were not associated with the severity of FJOA (p?>?0.05 for all). CONCLUSIONS:Both the degree of LDH and MSU-B LDH are associated with the severity of FJOA. The association between LDH and FJOA highlights the complexity of the etiology of FJOA.
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Project description:Bladder small DRG neurons, which are putative nociceptors pivotal to urinary bladder function, express more than a dozen different ionic membrane mechanisms: ion channels, pumps and exchangers. Small-conductance Ca2+-activated K+ (SKCa) channels which were earlier thought to be gated solely by intracellular Ca2+ concentration ([Ca]i) have recently been shown to exhibit inward rectification with respect to membrane potential. The effect of SKCa inward rectification on the excitability of these neurons is unknown. Furthermore, studies on the role of KCa channels in repetitive firing and their contributions to different types of afterhyperpolarization (AHP) in these neurons are lacking. In order to study these phenomena, we first constructed and validated a biophysically detailed single compartment model of bladder small DRG neuron soma constrained by physiological data. The model includes twenty-two major known membrane mechanisms along with intracellular Ca2+ dynamics comprising Ca2+ diffusion, cytoplasmic buffering, and endoplasmic reticulum (ER) and mitochondrial mechanisms. Using modelling studies, we show that inward rectification of SKCa is an important parameter regulating neuronal repetitive firing and that its absence reduces action potential (AP) firing frequency. We also show that SKCa is more potent in reducing AP spiking than the large-conductance KCa channel (BKCa) in these neurons. Moreover, BKCa was found to contribute to the fast AHP (fAHP) and SKCa to the medium-duration (mAHP) and slow AHP (sAHP). We also report that the slow inactivating A-type K+ channel (slow KA) current in these neurons is composed of 2 components: an initial fast inactivating (time constant ? 25-100 ms) and a slow inactivating (time constant ? 200-800 ms) current. We discuss the implications of our findings, and how our detailed model can help further our understanding of the role of C-fibre afferents in the physiology of urinary bladder as well as in certain disorders.
| S-EPMC6066259 | biostudies-literature
Project description:Dysfunction of the fast-inactivating Kv3.4 potassium current in dorsal root ganglion (DRG) neurons contributes to the hyperexcitability associated with persistent pain induced by spinal cord injury (SCI). However, the underlying mechanism is not known. In light of our previous work demonstrating modulation of the Kv3.4 channel by phosphorylation, we investigated the role of the phosphatase calcineurin (CaN) using electrophysiological, molecular, and imaging approaches in adult female Sprague Dawley rats. Pharmacological inhibition of CaN in small-diameter DRG neurons slowed repolarization of the somatic action potential (AP) and attenuated the Kv3.4 current. Attenuated Kv3.4 currents also exhibited slowed inactivation. We observed similar effects on the recombinant Kv3.4 channel heterologously expressed in Chinese hamster ovary cells, supporting our findings in DRG neurons. Elucidating the molecular basis of these effects, mutation of four previously characterized serines within the Kv3.4 N-terminal inactivation domain eliminated the effects of CaN inhibition on the Kv3.4 current. SCI similarly induced concurrent Kv3.4 current attenuation and slowing of inactivation. Although there was little change in CaN expression and localization after injury, SCI induced upregulation of the native regulator of CaN 1 (RCAN1) in the DRG at the transcript and protein levels. Consistent with CaN inhibition resulting from RCAN1 upregulation, overexpression of RCAN1 in naive DRG neurons recapitulated the effects of pharmacological CaN inhibition on the Kv3.4 current and the AP. Overall, these results demonstrate a novel regulatory pathway that links CaN, RCAN1, and Kv3.4 in DRG neurons. Dysregulation of this pathway might underlie a peripheral mechanism of pain sensitization induced by SCI.SIGNIFICANCE STATEMENT Pain sensitization associated with spinal cord injury (SCI) involves poorly understood maladaptive modulation of neuronal excitability. Although central mechanisms have received significant attention, recent studies have identified peripheral nerve hyperexcitability as a driver of persistent pain signaling after SCI. However, the ion channels and signaling molecules responsible for this change in primary sensory neuron excitability are still not well defined. To address this problem, this study used complementary electrophysiological and molecular methods to determine how Kv3.4, a voltage-gated K+ channel robustly expressed in dorsal root ganglion neurons, becomes dysfunctional upon calcineurin (CaN) inhibition. The results strongly suggest that CaN inhibition underlies SCI-induced dysfunction of Kv3.4 and the associated excitability changes through upregulation of the native regulator of CaN 1 (RCAN1).
| S-EPMC5566871 | biostudies-literature
Project description:Low back pain (LBP) is the most common pain syndrome, and is an enormous burden and cost generator for society. Lumbar facet joints (FJ) constitute a common source of pain, accounting for 15-45% of LBP. Facet joint degenerative osteoarthritis is the most frequent form of facet joint pain. History and physical examination may suggest but not confirm facet joint syndrome. Although imaging (radiographs, MRI, CT, SPECT) for back pain syndrome is very commonly performed, there are no effective correlations between clinical symptoms and degenerative spinal changes. Diagnostic positive facet joint block can indicate facet joints as the source of chronic spinal pain. These patients may benefit from specific interventions to eliminate facet joint pain such as neurolysis, by radiofrequency or cryoablation. The purpose of this review is to describe the anatomy, epidemiology, clinical presentation, and radiologic findings of facet joint syndrome. Specific interventional facet joint management will also be described in detail. TEACHING POINTS: • Lumbar facet joints constitute a common source of pain accounting of 15-45%. • Facet arthrosis is the most frequent form of facet pathology. • There are no effective correlations between clinical symptoms, physical examination and degenerative spinal changes. • Diagnostic positive facet joint block can indicate facet joints as the source of pain. • After selection processing, patients may benefit from facet joint neurolysis, notably by radiofrequency or cryoablation.
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