Prognostic Factors in Canine Acute Intervertebral Disc Disease.
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ABSTRACT:
SUBMITTER: Olby NJ
PROVIDER: S-EPMC7725764 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
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Prognostic Factors in Canine Acute Intervertebral Disc Disease.
Olby Natasha J NJ da Costa Ronaldo C RC Levine Jon M JM Stein Veronika M VM
Frontiers in veterinary science 20201126
Knowledge of the prognosis of acute spinal cord injury is critical to provide appropriate information for clients and make the best treatment choices. Acute intervertebral disc extrusions (IVDE) are a common cause of pain and paralysis in dogs with several types of IVDE occurring. Important prognostic considerations are recovery of ambulation, return of urinary and fecal continence, resolution of pain and, on the negative side, development of progressive myelomalacia. Initial injury severity aff ...[more]
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Project description:Background: Canine intervertebral disc disease (IVDD) represents a significant clinical problem in veterinary medicine, with similarities to the human pathology. Host-derived damage-associated molecular patterns like fibronectin fragments (FnF) that develop during tissue dysfunction may be of specific relevance to IVD pathologies by inducing an inflammatory response in resident cells. Aim: This project aimed to determine the presence and pathobiological role of FnF during IVD herniation in dogs, with a focus on inflammation. Methods: Herniated nucleus pulposus (NP) material from five dogs as well as non-herniated adjacent NP material from three dogs was collected during spinal surgery required due to acute IVD herniation. The presence of different types of FnF were determined by Western blot analysis. NP cells isolated from six herniated canine IVDs were then exposed to 30 kDa FnF. NP cell inflammation and catabolism was examined by investigating the expression of IL-1β, IL-6, IL-8, and COX-2, as well as MMP-1 and MMP-3 by qPCR (all targets) and ELISA (IL-6, PGE2). Results: Amongst multiple sized FnF (30, 35, 45, and >170kDa), N-terminal fragments at a size of ~30 kDa were most consistently expressed in all five herniated IVDs. Importantly, these fragments were exclusively present in herniated, but not in non-herniated IVDs. Exposure of canine NP cells to 500 nM 30 kDa FnF caused a significant upregulation of IL-6 (62.5 ± 79.9, p = 0.032) and IL-8 (53.0 ± 75.7, p = 0.031) on the gene level, whereas IL-6 protein analysis was inconclusive. Donor-donor variation was observed in response to FnF treatment, whereby this phenomenon was most evident for COX-2, with three donors demonstrating a significant downregulation (0.67 ± 0.03, p = 0.003) and three donors showing upregulation (6.9 ± 5.5, p = 0.21). Co-treatment with Sparstolonin B, a TRL-2/TRL-4 antagonist, showed no statistical difference to FnF treatment alone in all tested target genes. Conclusion: Given the presence of the 30 kDa FnF in canine herniated IVDs and the proinflammatory effect of 30 kDa FnF on NP cells, we concluded that the accumulation of FnF may be involved in the pathogenesis of canine IVDD. These results correspond to the findings in humans with IVDD.
| S-EPMC7701143 | biostudies-literature
Project description:Intervertebral disc herniation (IVDH) is an important pathology in humans and also in dogs. While the molecular disease mechanisms are well investigated in humans, little is known about the inflammatory mediators in naturally occurring canine IVDH. The objective of this study was to investigate whether the involved proinflammatory cytokines in human IVDH are also key cytokines in canine IVDH and thus to elucidate the suitability of the dog as a model for human trials. 59 samples from 25 dogs with surgically confirmed thoracolumbar IVDH were collected and classified in three subgroups: herniated (H), affected non-herniated (NH) disc, and adjacent non-affected (NA) disc. Discs from 11 healthy dogs acted as controls (C). Samples were analyzed for IL-1, IL-6, IL-8, and TNF-? expression (qPCR/ELISA) as well as cell infiltration and activation of the MAP kinase pathways (immunohistochemistry). Gene and protein expression of all key cytokines could be detected in IVDH affected dogs. Canine IVDH was significantly associated with a higher gene expression of IL-6 (H?>?C, NH?>?C) and TNF-? (H?>?C, NH?>?C, NA?>?C) and a significant down-regulation of IL-1? (H?<?C). Dogs with spontaneous pain had significantly higher IL-6 mRNA compared to those with pain arising only upon palpation. An inter-donor comparison (H and HN relative to NA) revealed a significant increase of IL-6 gene expression (H?>?NA, NH?>?NA). IL-8 (H?>?C, NA?>?C) and TNF-? (NH?>?C) protein levels were significantly increased in diseased dogs while inversely, IL-6 protein levels were significantly higher in patients with better clinical outcome. Aside from resident IVD cells, mostly monocytes and macrophages were found in extruded material, with concomitant activation of extracellular signal-regulated kinase p38 in the majority of samples. Dogs with spontaneous IVDH might provide a useful model for human disc diseases. Although the expression of key cytokines found in human IVDH was also demonstrated in canine tissue, the inflammatory mechanisms accompanying canine IVDH diverges partially from humans, which will require further investigations in the future. In dogs, IL-6 seems to play an important pathological role and may represent a new potential therapeutic target for canine patients.
| S-EPMC5723024 | biostudies-literature
Project description:Low back pain (LBP) is a major cause of disability and imposes huge economic burdens on human society worldwide. Among many factors responsible for LBP, intervertebral disc degeneration (IDD) is the most common disorder and is a target for intervention. The etiology of IDD is complex and its mechanism is still not completely understood. Many factors such as aging, spine deformities and diseases, spine injuries, and genetic factors are involved in the pathogenesis of IDD. In this review, we will focus on the recent advances in studies on the most promising and extensively examined genetic factors associated with IDD in humans. A number of genetic defects have been correlated with structural and functional changes within the intervertebral disc (IVD), which may compromise the disc's mechanical properties and metabolic activities. These genetic and proteomic studies have begun to shed light on the molecular basis of IDD, suggesting that genetic factors are important contributors to the onset and progression of IDD. By continuing to improve our understanding of the molecular mechanisms of IDD, specific early diagnosis and more effective treatments for this disabling disease will be possible in the future.
| S-EPMC5016799 | biostudies-literature
Project description:Intervertebral disc disease (IVDD) has been recognized in dogs since the 1800s, when the first descriptions of extruded disc material within the vertebral canal were published. In the intervening time our understanding of intervertebral disc pathology in dogs and cats has increased dramatically, with many variations of IVDD described. Whilst the volume of literature and collective understanding of IVDD has expanded, there has also been scope for confusion as the definition of intervertebral disc disease, with its myriad different manifestations, becomes more complicated. A large volume of literature has aimed to combine the use of histopathology, diagnostic imaging and clinical findings to better understand the various ways in which IVDD can be classified. Much of this research has focused on the classification of mechanisms of intervertebral disc degeneration, centering around the differences between, and overlaps in, IVDD in chondrodystrophic and non-chondrodystrophic dog breeds. However, with the increasing availability of advanced imaging modalities allowing more accurate antemortem diagnosis, the concept of IVDD has expanded to include other clinical presentations that may not fit into traditional models of classification of IVDD. This review aims to provide an up to date overview of both historical and current systems of IVDD classification, highlighting the important findings and controversies underpinning them.
| S-EPMC7572860 | biostudies-literature
Project description:BackgroundIntervertebral disc degeneration (IVDD) is considered a multifactorial disease that is influenced by both environmental and genetic factors. The last two decades of research strongly demonstrate that genetic factors contribute about 75% of the IVDD etiology. Recent total genome sequencing studies have shed light on the various single-nucleotide polymorphisms (SNPs) that are associated with IVDD.AimThis review presents comprehensive and updated information about the diversity of genetic factors in the inflammatory, degradative, homeostatic, and structural systems involved in the IVDD. An organized collection of information is provided regarding genetic polymorphisms that have been identified to influence the risk of developing IVDD. Understanding the proteins and signaling systems involved in IVDD can lead to improved understanding and targeting of therapeutics.Materials and methodsAn electronic literature search was performed using the National Library of Medicine for publications using the keywords genetics of IVDD, lumbar disc degeneration, degenerative disc disease, polymorphisms, SNPs, and disc disease. The articles were then screened based on inclusion criteria that included topics that covered the correlation of SNPs with developing IVDD. Sixty-five articles were identified as containing relevant information. Articles were excluded if they investigated lower back pain or just disc herniation without an analysis of disc degeneration. This study focuses on the chronic degeneration of IVDs.ResultsVarious genes were identified to contain SNPs that influenced the risk of developing IVDD. Among these are genes contributing to structural proteins, such as COL1A1, COL9A3, COL9A3, COL11A1, and COL11A2, ACAN, and CHST3. Furthermore, various SNPs found in the vitamin-D receptor gene are also associated with IVDD. SNPs related to inflammatory cytokine imbalance are associated with IVDD, although some effects are limited by sex and certain populations. SNPs in genes that code for extracellular matrix-degrading enzymes, such as MMP-1, MMP-2, MMP-3, MMP-9, MMP-14, ADAMTS-4, and ADAMTS-5 are also associated with IVDD. Apoptosis-mediating genes, such as caspase 9 gene (CASP9), TRAIL, and death receptor 4 (DR4), as well as those for growth factors, such as growth differentiation factor 5 and VEGF, are identified to have polymorphisms that influence the risk of developing IVDD.ConclusionWithin the last 10 years, countless new SNPs have been identified in genes previously unknown to be associated with IVDD. Furthermore, the last decade has also revealed new SNPs identified in genes already known to be involved with increased risk of developing IVDD. Improved understanding of the numerous genetic variants behind various pathophysiological elements of IVDD could help advance personalized care and pharmacotherapeutic strategies for patients suffering from IVDD in the future.
| S-EPMC5116693 | biostudies-literature
Project description:Introduction: Canine interverterbral disc (IVD), although physiologically acellular, displays an inflammatory cell population consisting almost exclusively of macrophages (M?) when acutely herniated. M? encompass a heterogenous cell population, roughly divided into classically (M1) or alternatively activated (M2)M?. Polarization into M1 M? leads to strong antimicrobial activity and pro-inflammatory response. In contrast, M2M? exibit anti-inflammatory function and regulate wound healing. The purpose of this study was to characterize the phenotype of the M? population present in naturally occurring IVD herniation. Materials and Methods: IVD material of dogs with IVD disease was collected during standard decompressive surgery. A negative control consisting of IVD material of dogs without IVD degeneration and a positive control consisting of canine liver and lymph node samples were also included. All samples were embedded in OCT and shock frozen. Eight micrometer cryostat sections were prepared, air dried and immunostained without prefixation or permeabilization. CD14 was used as marker M?, MHCII for M1M? and CD206 for M2M?. Results: Fifteen samples of dogs with IVD herniation, 10 negative, and 5 positive control samples were obtained. No positive cell was found in the negative control group. The positive control group displayed several MHCII and CD206 positive cells, all of them being simultaneously positive to CD14. All herniated samples displayed a mixed population of M1M? and M2M?, and some sparse M? displaying markers for both M1 and M2M? simultaneously. Conclusion: The mixed phenotype encountered shows the plasticity and dynamism of M? and evidences the chronic component of IVD disease despite its acute clinical presentation.
| S-EPMC7005589 | biostudies-literature
Project description:Objective:Possible regenerative treatments for lumbar intervertebral disc degeneration (DD) are rapidly emerging. There is consensus that the patient that would benefit most has early-stage DD, with a predicted deterioration in the near future. To identify this patient, the aim of this study was to identify prognostic factors for progression of DD. Study design:Systematic review. Methods:A systematic search was performed on studies evaluating one or more prognostic factor(s) in the progression of DD. The criteria for inclusion were (a) patients diagnosed with DD on MRI, (b) progression of DD at follow-up, and (c) reporting of one or more prognostic factor(s) in progression of DD. Two authors independently assessed the methodological quality of the included studies. Due to heterogeneity in DD determinants and outcomes, only a best-evidence synthesis could be conducted. Results:The search generated 3165 references, of which 16 studies met our inclusion criteria, involving 2.423 patients. Within these, a total of 23 clinical and environmental and 12 imaging factors were identified. There was strong evidence that disc herniation at baseline is associated with progression of DD at follow-up. There is limited evidence that IL6 rs1800795 genotype G/C male was associated with no progression of DD. Some clinical or environmental factors such as BMI, occupation and smoking were not associated with progression. Conclusions:Disc herniation is strongly associated with the progression of DD. Surprisingly, there was strong evidence that smoking, occupation, and several other factors were not associated with the progression of DD. Only one genetic variant may have a protective effect on progression, otherwise there was conflicting or only limited evidence for most prognostic factors. Future research into these prognostic factors with conflicting and limited evidence is not only needed to determine which patients should be targeted by regenerative therapies, but will also contribute to spinal phenotyping.
| S-EPMC6764790 | biostudies-literature
Project description:The most common reason that adults in the United States see their physician is lower back or neck pain secondary to degenerative disc disease. To date, approaches to treat degenerative disc disease are confined to purely mechanical devices designed to either eliminate or enable flexibility of the diseased motion segment. Tissue engineered intervertebral discs (TE-IVDs) have been proposed as an alternative approach and have shown promise in replacing native IVD in the rodent tail spine. Here we demonstrate the efficacy of our TE-IVDs in the canine cervical spine. TE-IVD components were constructed using adult canine annulus fibrosis and nucleus pulposus cells seeded into collagen and alginate hydrogels, respectively. Seeded gels were formed into a single disc unit using molds designed from the geometry of the canine spine. Skeletally mature beagles underwent discectomy with whole IVD resection at levels between C3/4 and C6/7, and were then divided into two groups that received only discectomy or discectomy followed by implantation of TE-IVD. Stably implanted TE-IVDs demonstrated significant retention of disc height and physiological hydration compared to discectomy control. Both 4-week and 16-week histological assessments demonstrated chondrocytic cells surrounded by proteoglycan-rich matrices in the NP and by fibrocartilaginous matrices in the AF portions of implanted TE-IVDs. Integration into host tissue was confirmed over 16 weeks without any signs of immune reaction. Despite the significant biomechanical demands of the beagle cervical spine, our stably implanted TE-IVDs maintained their position, structure and hydration as well as disc height over 16 weeks in vivo.
| S-EPMC5650136 | biostudies-literature
Project description:The intervertebral disc (IVD) is a highly hydrated tissue, the rich proteoglycan matrix imbibes water, enabling the disc to withstand compressive loads. During aging and degeneration increased matrix degradation leads to dehydration and loss of function. Aquaporins (AQP) are a family of transmembrane channel proteins that selectively allow the passage of water in and out of cells and are responsible for maintaining water homeostasis in many tissues. Here, the expression of all 13 AQPs at gene and protein level was investigated in human and canine nondegenerate and degenerate IVDs to develop an understanding of the role of AQPs during degeneration. Furthermore, in order to explore the transition of notochordal cells (NCs) towards nucleus pulposus (NP) cells, AQP expression was investigated in canine IVDs enriched in NCs to understand the role of AQPs in IVD maturation. AQP0, 1, 2, 3, 4, 5, 6, 7, and 9 were expressed at gene and protein level in both nondegenerate and degenerate human NP tissue. AQP2 and 7 immunopositivity increased with degeneration in human NP tissue, whereas AQP4 expression decreased with degeneration in a similar way to AQP1 and 5 shown previously. All AQP proteins that were identified in human NP tissue were also expressed in canine NP tissue. AQP2, 5, 6, and 9 were found to localize to vacuole-like membranes and cell membranes in NC cells. In conclusion, AQPs were abundantly expressed in human and canine IVDs. The expression of many AQP isotypes potentially alludes to multifaceted functions related to adaption of NP cells to the conditions they encounter within their microenvironment in health and degeneration. The presence of AQPs within the IVD may suggest an adaptive role for these water channels during the development and maintenance of the healthy, mature IVD.
| S-EPMC6686802 | biostudies-literature
Project description:Whether disc aging is influenced by factors beyond its local environment is an important unresolved question. Here we performed heterochronic parabiosis in mice to study the effects of circulating factors in young and old blood on age-associated intervertebral disc degeneration. Compared to young isochronic pairs (Y-Y), young mice paired with old mice (Y-O) showed significant increases in levels of disc MMP-13 and ADAMTS4, aggrecan fragmentation, and histologic tissue degeneration, but negligible changes in cellular senescence markers (p16INK4a, p21Cip1). Compared to old isochronic pairs (O-O), old mice paired with young mice (O-Y) exhibited a significant decrease in expression of cellular senescence markers (p16, p21, p53), but only marginal decreases in the levels of disc MMP-13 and ADAMTS4, aggrecan fragmentation, and histologic degeneration. Thus, exposing old mice to young blood circulation greatly suppressed disc cellular senescence, but only slightly decreased disc matrix imbalance and degeneration. Conversely, exposing young mice to old blood accelerated their disc matrix imbalance and tissue degeneration, with little effects on disc cellular senescence. Thus, non-cell autonomous effects of circulating factors on disc cellular senescence and matrix homeostasis are complex and suggest that disc matrix homeostasis is modulated by systemic factors and not solely through local disc cellular senescence.
| S-EPMC7343497 | biostudies-literature