23 research outputs found
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Innervation of pathologies in the lumbar vertebral end plate and intervertebral disc
Background contextMagnetic resonance imaging (MRI) has limited diagnostic value for chronic low back pain because of the unclear relationship between any anatomic abnormalities on MRI and pain reported by the patient. Assessing the innervation of end plate and disc pathologies-and determining the relationship between these pathologies and any abnormalities seen on MRI-could clarify the sources of back pain and help identify abnormalities with enhanced diagnostic value.PurposeTo quantify innervation in the vertebral end plate and intervertebral disc and to relate variation in innervation to the presence of pathologic features observed by histology and conventional MRI.Study design/settingA cross-sectional histology and imaging study of vertebral end plates and intervertebral discs harvested from human cadaver spines.MethodsWe collected 92 end plates and 46 intervertebral discs from seven cadaver spines (ages 51-67 years). Before dissection, the spines were scanned with MRI to grade for Modic changes and high-intensity zones (HIZ). Standard immunohistochemical techniques were used to localize the general nerve marker protein gene product 9.5. We quantified innervation in the following pathologies: fibrovascular end-plate marrow, fatty end-plate marrow, end-plate defects, and annular tears.ResultsNerves were present in the majority of end plates with fibrovascular marrow, fatty marrow, and defects. Nerve density was significantly higher in fibrovascular end-plate marrow than in normal end-plate marrow (p<.001). Of the end plates with fibrovascular and fatty marrow, less than 40% were Modic on MRI. Innervated marrow pathologies collocated with more than 75% of the end plate defects; hence, innervation was significantly higher in end plate defects than in normal end plates (p<.0001). In the disc, nerves were observed in only 35% of the annular tears; in particular, innervation in radial tears tended to be higher than in normal discs (p=.07). Of the discs with radial tears, less than 13% had HIZ on T2 MRI. Innervation was significantly less in radial tears than in fibrovascular end-plate marrow (p=.05) and end-plate defects (p=.02).ConclusionsThese findings indicate that vertebral end-plate pathologies are more innervated than intervertebral disc pathologies and that many innervated end-plate pathologies are not detectable on MRI. Taken together, these findings suggest that improved visualization of end-plate pathologies could enhance the diagnostic value of MRI for chronic low back pain
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Contribution of the Endplates to Disc Degeneration
Purpose of reviewThe endplates form the interface between the rigid vertebral bodies and compliant intervertebral discs. Proper endplate function involves a balance between conflicting biomechanical and nutritional demands. This review summarizes recent data that highlight the importance of proper endplate function and the relationships between endplate dysfunction, adjacent disc degeneration, and axial low back pain.Recent findingsChanges to endplate morphology and composition that impair its permeability associate with disc degeneration. Endplate damage also associates with disc degeneration, and the progression of degeneration may be accelerated and the chronicity of symptoms heightened when damage coincides with evidence of adjacent bone marrow lesions.SummaryThe endplate plays a key role in the development of disc degeneration and low back pain. Clarification of the mechanisms governing endplate degeneration and developments in clinical imaging that enable precise evaluation of endplate function and dysfunction will distinguish the correlative vs. causative nature of endplate damage and motivate new treatments that target pathologic endplate function
Modic type 1 change is an autoimmune response that requires a proinflammatory milieu provided by the "Modic disc"
BACKGROUND CONTEXT: Modic changes (MCs) are magnetic resonance imaging (MRI) evidence of inflammatory and fibrotic vertebral bone marrow lesions that associate with adjacent disc degeneration and end plate damage. Although MC etiology is uncertain, historical data suggest a linkage to an autoimmune response of bone marrow triggered by the nucleus pulposus (NP).
PURPOSE: The aim of this study was to test whether bone marrow has an autoimmune response to NP cells that is amplified by an inflammatory milieu and ultimately leads to MC development in vivo. We hypothesized that an inflammatory co-stimulus is required for bone marrow/NP crosstalk to stimulate MC.
STUDY DESIGN: This is an in-vitro cell co-culture study plus in-vivo experiments in rat caudal vertebrae.
METHODS: In in-vitro study, bone marrow mononuclear cells (BMNCs) and NP cells (NPCs) from rats were co-cultured with and without interleukin (IL)-1α stimulation. Cell viability (n=3) of BMNCs and NPCs and gene expression (n=7) were analyzed. In in-vivo study, proinflammatory lipopolysaccharide (LPS) and control disc nucleus surrogates (NP micromass pellets) were generated in vitro from rat NPCs and implanted into rat tail vertebrae, and the response was compared with sham surgery (n=12 each). Tissue changes were investigated with T1w and T2w MRI (7T), histology, and immunohistochemistry (tumor necrosis factor, CD3) 1 (n=6) and 2 weeks (n=6) after implantation.
RESULTS: BMNC/NPC co-culture significantly increased lymphocyte viability (42%-69%, p<.05) and reduced NPC viability (96%-88%, p<.001), indicating immunogenicity of NPC. However, IL-1α was required to cause significant transcriptional upregulation of IL-1, IL-6, IL-10, and tropomyosin receptor kinase A. Therefore, an inflammatory activation is required to amplify the immune response. Immunogenicity of the NP was corroborated in vivo by CD3 cell accumulation around LPS and control disc surrogates at Day 7. However, only the LPS disc surrogate group demonstrated infiltration of CD3 cells at Day 14. Furthermore, end plate defects (p<.05, LPS: n=4/6, Ctrl: n=0/6, sham: n=0/6) and MC1-like MRI changes (T2w hyperintensity, p<.05) were only seen with LPS disc surrogates.
CONCLUSIONS: NPCs are immunogenic but cannot trigger MC without an additional proinflammatory stimulus. Our data suggest that MC requires end plate defects that allow marrow/NPC co-mingling plus an adjacent inflammatory "MC disc" that can amplify the immune response
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Structure-function relationships at the human spinal disc-vertebra interface.
Damage at the intervertebral disc-vertebra interface associates with back pain and disc herniation. However, the structural and biomechanical properties of the disc-vertebra interface remain underexplored. We sought to measure mechanical properties and failure mechanisms, quantify architectural features, and assess structure-function relationships at this vulnerable location. Vertebra-disc-vertebra specimens from human cadaver thoracic spines were scanned with micro-computed tomography (μCT), surface speckle-coated, and loaded to failure in uniaxial tension. Digital image correlation (DIC) was used to calculate local surface strains. Failure surfaces were scanned using scanning electron microscopy (SEM), and adjacent sagittal slices were analyzed with histology and SEM. Seventy-one percent of specimens failed initially at the cartilage endplate-bone interface of the inner annulus region. Histology and SEM both indicated a lack of structural integration between the cartilage endplate (CEP) and bone. The interface failure strength was increased in samples with higher trabecular bone volume fraction in the vertebral endplates. Furthermore, failure strength decreased with degeneration, and in discs with thicker CEPs. Our findings indicate that poor structural connectivity between the CEP and vertebra may explain the structural weakness at this region, and provide insight into structural features that may contribute to risk for disc-vertebra interface injury. The disc-vertebra interface is the site of failure in the majority of herniation injuries. Here we show new structure-function relationships at this interface that may motivate the development of diagnostics, prevention strategies, and treatments to improve the prognosis for many low back pain patients with disc-vertebra interface injuries. © 2017 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 36:192-201, 2018
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Microstructural abnormalities are evident by histology but not HR-pQCT at the periosteal cortex of the human tibia under CVD and T2D conditions
Cortical bone microstructure deficits may increase fracture risk in individuals with cardiovascular disease and diabetes. High resolution peripheral quantitative computed tomography (HR-pQCT) enables in vivo microstructure characterization but is limited in its ability to visualize important biological features. We conducted histological analyses and HR-pQCT imaging of distal tibia bone samples from 6 donors with cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D). Histology but not HR-pQCT identified previously undocumented morphopathological deficits that may contribute to cortical bone fragility. These observations may provide guidance for improved HR-pQCT microstructural characterization as well as insight into mechanisms of cortical bone degradation
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Tidemark Avulsions are a Predominant Form of Endplate Irregularity
Study designDescriptive histologic and magnetic resonance imaging study of human cadaveric spines.ObjectiveTo identify and characterize common endplate pathologies to form a histologic foundation for an etiology-based classification system.Summary of background dataIrregularities at the spinal disc-vertebra interface are associated with back pain and intervertebral disc herniation injuries. However, there is currently a lack of consensus regarding terminology for classification. This limits the potential for advancing understanding of back pain mechanisms, and prohibits meaningful comparisons for identifying priorities for prevention and treatment. Prior classification systems largely rely on observations from clinical imaging, which may miss subtle pathologic features.MethodsFifteen cadaveric spines with moderate to severe disc degeneration were obtained and scanned with MRI in the sagittal plane using two-dimensional T1-weighted and T2-weighted fast spin-echo sequences. Eighty-nine lumbar and lower thoracic bone-disc-bone motion segments were extracted, fixed, sectioned, and stained for histologic evaluation. Focal endplate irregularities were identified and categorized based on features that inferred causation. The presence, type, and anatomic location were recorded. A classification system with three major categories of focal endplate irregularities was created.ResultsDisc-vertebra avulsion and vertebral rim degeneration were more common than subchondral nodes: 50% of irregularities were classified as rim degeneration (75/150), 35% were classified as avulsions (52/150), and 15% were classified as nodes (23/150). Ninety percent of avulsions were subclassified as "tidemark avulsions," a highly prevalent form of endplate irregularity in which the outer annulus separates from the vertebra at the tidemark. These tidemark avulsions have not been previously described, yet are visible on T2-weighted MRI as high-intensity regions.ConclusionThis study provides histologic basis for a system to classify focal endplate irregularities. Included is a previously unidentified but prevalent finding of tidemark avulsions, which are visible with both histology and magnetic resonance imaging. These observations will help clinicians better organize patients into meaningful groups to facilitate diagnosis, treatment, and clinical research.Level of evidence3
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A modular approach to creating large engineered cartilage surfaces.
Native articular cartilage has limited capacity to repair itself from focal defects or osteoarthritis. Tissue engineering has provided a promising biological treatment strategy that is currently being evaluated in clinical trials. However, current approaches in translating these techniques to developing large engineered tissues remains a significant challenge. In this study, we present a method for developing large-scale engineered cartilage surfaces through modular fabrication. Modular Engineered Tissue Surfaces (METS) uses the well-known, but largely under-utilized self-adhesion properties of de novo tissue to create large scaffolds with nutrient channels. Compressive mechanical properties were evaluated throughout METS specimens, and the tensile mechanical strength of the bonds between attached constructs was evaluated over time. Raman spectroscopy, biochemical assays, and histology were performed to investigate matrix distribution. Results showed that by Day 14, stable connections had formed between the constructs in the METS samples. By Day 21, bonds were robust enough to form a rigid sheet and continued to increase in size and strength over time. Compressive mechanical properties and glycosaminoglycan (GAG) content of METS and individual constructs increased significantly over time. The METS technique builds on established tissue engineering accomplishments of developing constructs with GAG composition and compressive properties approaching native cartilage. This study demonstrated that modular fabrication is a viable technique for creating large-scale engineered cartilage, which can be broadly applied to many tissue engineering applications and construct geometries
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Pulsed electromagnetic fields reduce acute inflammation in the injured rat-tail intervertebral disc.
Pro-inflammatory cytokines are recognized contributors to intervertebral disc (IVD) degeneration and discogenic pain. We have recently reported the anti-inflammatory effect of pulsed electromagnetic fields (PEMF) on IVD cells in vitro. Whether these potentially therapeutic effects are sufficiently potent to influence disc health in vivo has not been demonstrated. We report here the effect of PEMF on acute inflammation arising from a rat-tail IVD injury model. Disc degeneration was induced by percutaneously stabbing the Co6-7, Co7-8, and Co8-9 levels using a 20-gauge needle. Seventy-two (72) rats were divided into three groups: sham control, needle stab, needle stab+PEMF. Treated rats were exposed to PEMF immediately following surgery and for either 4 or 7 days (4 hr/d). Stab and PEMF effects were evaluated by measuring inflammatory cytokine gene expression (RT-PCR) and protein levels (ELISA assay), anabolic and catabolic gene expression (RT-PCR), and histologic changes. We observed in untreated animals that at day 7 after injury, inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor α, and IL-1β) were significantly increased at both gene and protein levels (P < .05). Similarly, catabolic factors (MMP [metalloproteinases]-2, MMP-13 and the transcriptional factor NF-kβ gene expression) were significantly increased (P < .05). At day 7, PEMF treatment significantly inhibited inflammatory cytokine gene and protein expression induced by needle stab injury (P < .05). At day 4, PEMF downregulated FGF-1 and upregulated MMP-2 compared to the stab-only group. These data demonstrate that previously reported anti-inflammatory effects of PEMF on disc cells carry over to the in vivo situation, suggesting potential therapeutic benefits. Though we observed an inhibitory effect of PEMF on acute inflammatory cytokine expression, a consistent effect was not observed for acute changes in disc histology and anabolic and catabolic factor expression. Therefore, these findings should be further investigated in studies of longer duration following needle-stab injury
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Cartilage Endplate Thickness Variation Measured by Ultrashort Echo-Time MRI Is Associated With Adjacent Disc Degeneration.
Study designA magnetic resonance imaging study of human cadaver spines.ObjectiveTo investigate associations between cartilage endplate (CEP) thickness and disc degeneration.Summary of background dataDamage to the CEP is associated with spinal injury and back pain. However, CEP morphology and its association with disc degeneration have not been well characterized.MethodsTen lumbar motion segments with varying degrees of disc degeneration were harvested from six cadaveric spines and scanned with magnetic resonance imaging in the sagittal plane using a T2-weighted two-dimensional (2D) sequence, a three-dimensional (3D) ultrashort echo-time (UTE) imaging sequence, and a 3D T1ρ mapping sequence. CEP thicknesses were calculated from 3D UTE image data using a custom, automated algorithm, and these values were validated against histology measurements. Pfirrmann grades and T1ρ values in the disc were assessed and correlated with CEP thickness.ResultsThe mean CEP thickness calculated from UTE images was 0.74 ± 0.04 mm. Statistical comparisons between histology and UTE-derived measurements of CEP thickness showed significant agreement, with the mean difference not significantly different from zero (P = 0.32). Within-disc variation of T1ρ (standard deviation) was significantly lower for Pfirrmann grade 4 than Pfirrmann grade 3 (P < 0.05). Within-disc variation of T1ρ and adjacent CEP thickness heterogeneity (coefficient of variation) had a significant negative correlation (r = -0.65, P = 0.04). The standard deviation of T1ρand the mean CEP thickness showed a moderate positive correlation (r = 0.40, P = 0.26).ConclusionThis study demonstrates that quantitative measurements of CEP thickness measured from UTE magnetic resonance imaging are associated with disc degeneration. Our results suggest that variability in CEP thickness and T1ρ, rather than their mean values, may serve as valuable diagnostic markers for disc degeneration.Level of evidenceN/A
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Parallel mechanisms suppress cochlear bone remodeling to protect hearing.
Bone remodeling, a combination of bone resorption and formation, requires precise regulation of cellular and molecular signaling to maintain proper bone quality. Whereas osteoblasts deposit and osteoclasts resorb bone matrix, osteocytes both dynamically resorb and replace perilacunar bone matrix. Osteocytes secrete proteases like matrix metalloproteinase-13 (MMP13) to maintain the material quality of bone matrix through perilacunar remodeling (PLR). Deregulated bone remodeling impairs bone quality and can compromise hearing since the auditory transduction mechanism is within bone. Understanding the mechanisms regulating cochlear bone provides unique ways to assess bone quality independent of other aspects that contribute to bone mechanical behavior. Cochlear bone is singular in its regulation of remodeling by expressing high levels of osteoprotegerin. Since cochlear bone expresses a key PLR enzyme, MMP13, we examined whether cochlear bone relies on, or is protected from, osteocyte-mediated PLR to maintain hearing and bone quality using a mouse model lacking MMP13 (MMP13(-/-)). We investigated the canalicular network, collagen organization, lacunar volume via micro-computed tomography, and dynamic histomorphometry. Despite finding defects in these hallmarks of PLR in MMP13(-/-) long bones, cochlear bone revealed no differences in these markers, nor hearing loss as measured by auditory brainstem response (ABR) or distortion product oto-acoustic emissions (DPOAEs), between wild type and MMP13(-/-) mice. Dynamic histomorphometry revealed abundant PLR by tibial osteocytes, but near absence in cochlear bone. Cochlear suppression of PLR corresponds to repression of several key PLR genes in the cochlea relative to long bones. These data suggest that cochlear bone uniquely maintains bone quality and hearing independent of MMP13-mediated osteocytic PLR. Furthermore, the cochlea employs parallel mechanisms to inhibit remodeling by osteoclasts and osteoblasts, and by osteocytes, to protect hearing. Understanding the cellular and molecular mechanisms that confer site-specific control of bone remodeling has the potential to elucidate new pathways that are deregulated in skeletal disease