Pathobiology of Modic changes Dudli, Stefan; Fields, Aaron J.; Samartzis, Dino ...
European Spine Journal,
11/2016, Letnik:
25, Številka:
11
Journal Article, Book Review
Recenzirano
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Purpose
Low back pain (LBP) is the most disabling condition worldwide. Although LBP relates to different spinal pathologies, vertebral bone marrow lesions visualized as Modic changes on MRI have a ...high specificity for discogenic LBP. This review summarizes the pathobiology of Modic changes and suggests a disease model.
Methods
Non-systematic literature review.
Results
Chemical and mechanical stimulation of nociceptors adjacent to damaged endplates are likely a source of pain. Modic changes are adjacent to a degenerated intervertebral disc and have three generally interconvertible types suggesting that the different Modic change types represent different stages of the same pathological process, which is characterized by inflammation, high bone turnover, and fibrosis. A disease model is suggested where disc/endplate damage and the persistence of an inflammatory stimulus (i.e., occult discitis or autoimmune response against disc material) create predisposing conditions. The risk to develop Modic changes likely depends on the inflammatory potential of the disc and the capacity of the bone marrow to respond to it. Bone marrow lesions in osteoarthritic knee joints share many characteristics with Modic changes adjacent to degenerated discs and suggest that damage-associated molecular patterns and marrow fat metabolism are important pathogenetic factors. There is no consensus on the ideal therapy. Non-surgical treatment approaches including intradiscal steroid injections, anti-TNF-α antibody, antibiotics, and bisphosphonates have some demonstrated efficacy in mostly non-replicated clinical studies in reducing Modic changes in the short term, but with unknown long-term benefits. New diagnostic tools and animal models are required to improve painful Modic change identification and classification, and to clarify the pathogenesis.
Conclusion
Modic changes are likely to be more than just a coincidental imaging finding in LBP patients and rather represent an underlying pathology that should be a target for therapy.
Poor solute transport through the cartilage endplate (CEP) impairs disc nutrition and could be a key factor that limits the success of intradiscal biologic therapies. Here we demonstrate that ...treating the CEP with matrix metalloproteinase-8 (MMP-8) reduces the matrix constituents that impede solute uptake and thereby improves nutrient diffusion. Human CEP tissues harvested from four fresh cadaveric lumbar spines (age range: 38-66 years old) were treated with MMP-8. Treatment caused a dose-dependent reduction in sGAG, localized reductions to the amount of collagen, and alterations to collagen structure. These matrix modifications corresponded with 16-24% increases in the uptake of a small solute (376 Da). Interestingly, the effects of MMP-8 treatment depended on the extent of non-enzymatic glycation: treated CEPs with high concentrations of advanced glycation end products (AGEs) exhibited the lowest uptake compared to treated CEPs with low concentrations of AGEs. Moreover, AGE concentrations were donor-specific, and the donor tissues with the highest AGE concentrations appeared to have lower uptake than would be expected based on the initial amounts of collagen and sGAG. Finally, increasing solute uptake in the CEP improved cell viability inside diffusion chambers, which supports the nutritional relevance of enhancing the transport properties of the CEP. Taken together, our results provide new insights and in vitro proof-of-concept for a treatment approach that could improve disc nutrition for biologic therapy: specifically, matrix reduction by MMP-8 can enhance solute uptake and nutrient diffusion through the CEP, and AGE concentration appears to be an important, patient-specific factor that influences the efficacy of this approach.
Abstract Background context Magnetic 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. Purpose To 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/setting A cross-sectional histology and imaging study of vertebral end plates and intervertebral discs harvested from human cadaver spines. Methods We 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. Results Nerves 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). Conclusions These 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.
Abstract The microstructure of trabecular bone is usually perceived as a collection of plate-like and rod-like trabeculae, which can be determined from the emerging high-resolution skeletal imaging ...modalities such as micro-computed tomography (μCT) or clinical high-resolution peripheral quantitative CT (HR-pQCT) using the individual trabecula segmentation (ITS) technique. It has been shown that the ITS-based plate and rod parameters are highly correlated with elastic modulus and yield strength of human trabecular bone. In the current study, plate–rod (PR) finite element (FE) models were constructed completely based on ITS-identified individual trabecular plates and rods. We hypothesized that PR FE can accurately and efficiently predict elastic modulus and yield strength of human trabecular bone. Human trabecular bone cores from proximal tibia (PT), femoral neck (FN) and greater trochanter (GT) were scanned by μCT. Specimen-specific ITS-based PR FE models were generated for each μCT image and corresponding voxel-based FE models were also generated in comparison. Both types of specimen-specific models were subjected to nonlinear FE analysis to predict the apparent elastic modulus and yield strength using the same trabecular bone tissue properties. Then, mechanical tests were performed to experimentally measure the apparent modulus and yield strength. Strong linear correlations for both elastic modulus (r2 = 0.97) and yield strength (r2 = 0.96) were found between the PR FE model predictions and experimental measures, suggesting that trabecular plate and rod morphology adequately captures three-dimensional (3D) microarchitecture of human trabecular bone. In addition, the PR FE model predictions in both elastic modulus and yield strength were highly correlated with the voxel-based FE models (r2 = 0.99, r2 = 0.98, respectively), resulted from the original 3D images without the PR segmentation. In conclusion, the ITS-based PR models predicted accurately both elastic modulus and yield strength determined experimentally across three distinct anatomic sites. Trabecular plates and rods accurately determine elastic modulus and yield strength of human trabecular bone.
Nutrient and metabolite transport through the cartilage endplate (CEP) is important for maintaining proper disc nutrition, but the mechanisms of solute transport remain unclear. One unresolved issue ...is the role of dynamic loading. In comparison to static loading, dynamic loading is thought to enhance transport by increasing convection. However, the CEP has a high resistance to fluid flow, which could limit solute convection. Here we measure solute transport through site-matched cadaveric human lumbar CEP tissues under static vs. dynamic loading, and we determine how the degree of transport enhancement from dynamic loading depends on CEP porosity and solute size. We found that dynamic loading significantly increased small and large solute transport through the CEP: on average, dynamic loading increased the transport of sodium fluorescein (376 Da) by a factor of 1.85 ± 0.64 and the transport of a large dextran (4000 Da) by a factor of 4.97 ± 3.05. Importantly, CEP porosity (0.65 ± 0.07; range: 0.47–0.76) strongly influenced the degree of transport enhancement. Specifically, for both solutes, transport enhancement was greater for CEPs with low porosity than for CEPs with high porosity. This is because the CEPs with low porosity were susceptible to larger improvements in fluid flow under dynamic loading. The CEP becomes less porous and less hydrated with aging and as disc degeneration progresses. Together, these findings suggest that as those changes occur, dynamic loading has a greater effect on solute transport through the CEP compared to static loading, and thus may play a larger role in disc nutrition.
Cross-sectional cohort study of chronic low back pain (CLBP) patients and matched controls.
To explore the interplay between vertebral endplate damage and adjacent paraspinal muscle (PSM) quality, ...and to test their association in a cohort of patients with CLBP and matched controls.
Nonspecific CLBP is challenging to diagnose, in part, due to uncertainty regarding the source of pain. Delineating interactions among potential CLBP mechanisms may enhance diagnosis and treatment customization.
We collected advanced MRI imaging on 52 adult subjects, including 38 CLBP patients and 14 age- and sex-matched asymptomatic control subjects. Mean multifidus and erector spinae fat fraction (FF) was measured throughout the spine using an IDEAL MRI sequence. Presence of cartilage endplate (CEP) defects was determined at each disc level using UTE MRI. Logistic regression was used to test association of PSM FF, CEP defects, modic changes (MC), disc degeneration, and their interplay.
We observed that CEP defects were the strongest predictor of nonspecific CLBP (OR: 14.1, P < 0.01) even after adjusting for MC and disc degeneration (OR: 26.1, P = 0.04). PSM quality did not independently distinguish patient and control groups, except for patients with high self-reported disability.At specifically L4L5, CEP damage was most prevalent and CEP damage was significantly associated with CLBP (OR: 3.7, 95% CI: 1.2-21.5, P = 0.03). CEP damage at L4L5 was predictive of CLBP when adjacent to PSMs with greater FF (MF, OR 14.7, P = 0.04; ES, OR: 17.3, P = 0.03), but not when PSM FF was lower and comparable to values in control, asymptomatic subjects.
These results demonstrate the clinically important reciprocity between passive and dynamic spinal stabilizers, and support the notion that therapies targeting the PSMs may provide clinical benefit even in the presence of other spinal pathologies.
4.
To measure the T2* of the human cartilaginous end plate by using magnetic resonance (MR) imaging with very short echo times and to determine the effect of the orientation of the end plate on T2* and ...on relationships between T2* and biochemical composition.
This study was exempt from institutional review board approval, and informed consent was not required. Thirty-four samples of three cadaveric lumbar spines (from subjects who died at ages 51, 57, and 66 years) containing cartilaginous end plates and subchondral bone were prepared. Samples were imaged with a 3-T imager for T2* quantification by using a three-dimensional very short echo time sequence (repetition time msec/echo times msec, 30/0.075, 2, 5, 12, 18). Samples were imaged with the end plate at three orientations with respect to the constant magnetic induction field: 0°, 54.7°, and 90°. After imaging, the cartilage was assayed for its water, glycosaminoglycan, and collagen content. Pearson correlations were used to investigate the effect of orientation on the relationships between T2* and biochemical composition.
T2* was significantly longer when measured at an orientation of 54.7° (21.8 msec ± 2.8 ± standard error of the mean) than at 0° (10.0 msec ± 0.7, P < .001) or 90° (9.9 msec ± 0.4, P < .001). At 54.7°, T2* was highly correlated with glycosaminoglycan content (r = 0.85, P < .001), the collagen-to-glycosaminoglycan ratio (r = -0.79, P < .001), and water content (r = 0.62, P = .02); at 0° and 90°, there were no significant differences in these relationships, with a minimum P value of .19.
T2* evaluation can allow noninvasive estimation of the degeneration of the cartilaginous end plate; however, the accuracy of T2*-based estimates of biochemical composition depends on the orientation of the end plate.
Cartilage endplate (CEP) biochemical composition may influence disc degeneration and regeneration. However, evaluating CEP composition in patients remains a challenge. We used T2* mapping from ...ultrashort echo‐time (UTE) magnetic resonance imaging (MRI), which is sensitive to CEP hydration, to investigate spatial variations in CEP T2* values and to determine how CEP T2* values correlate with adjacent disc degeneration. Thirteen human cadavers (56.4 ± 12.7 years) and seven volunteers (36.9 ± 10.9 years) underwent 3T MRI, including UTE and T1ρ mapping sequences. Spatial mappings of T2* values in L4‐S1 CEPs were generated from UTE images and compared between subregions. In the abutting discs, mean T1ρ values in the nucleus pulposus were compared between CEPs with high vs low T2* values. To assess in vivo repeatability, precision errors in mean T2* values, and intraclass correlation coefficients (ICC) were measured from repeat scans. Results showed that CEP T2* values were highest centrally and lowest posteriorly. In the youngest individuals (<50 years), who had mild‐to‐moderately degenerated Pfirrmann grade II‐III discs, low CEP T2* values associated with severer disc degeneration: T1ρ values were 26.7% lower in subjects with low CEP T2* values (P = .025). In older individuals, CEP T2* values did not associate with disc degeneration (P = .39‐.62). Precision errors in T2* ranged from 1.7 to 2.6 ms, and reliability was good‐to‐excellent (ICC = 0.89‐0.94). These findings suggest that deficits in CEP composition, as indicated by low T2* values, associate with severer disc degeneration during the mild‐to‐moderate stages. Measuring CEP T2* values with UTE MRI may clarify the role of CEP composition in patients with mild‐to‐moderate disc degeneration.
Osteoarthritis (OA), long considered a primary disorder of articular cartilage, is commonly associated with subchondral bone sclerosis. However, the cellular mechanisms responsible for changes to ...subchondral bone in OA, and the extent to which these changes are drivers of or a secondary reaction to cartilage degeneration, remain unclear. In knee joints from human patients with end-stage OA, we found evidence of profound defects in osteocyte function. Suppression of osteocyte perilacunar/canalicular remodeling (PLR) was most severe in the medial compartment of OA subchondral bone, with lower protease expression, diminished canalicular networks, and disorganized and hypermineralized extracellular matrix. As a step toward evaluating the causality of PLR suppression in OA, we ablated the PLR enzyme MMP13 in osteocytes while leaving chondrocytic MMP13 intact, using Cre recombinase driven by the 9.6-kb DMP1 promoter. Not only did osteocytic MMP13 deficiency suppress PLR in cortical and subchondral bone, but it also compromised cartilage. Even in the absence of injury, osteocytic MMP13 deficiency was sufficient to reduce cartilage proteoglycan content, change chondrocyte production of collagen II, aggrecan, and MMP13, and increase the incidence of cartilage lesions, consistent with early OA. Thus, in humans and mice, defects in PLR coincide with cartilage defects. Osteocyte-derived MMP13 emerges as a critical regulator of cartilage homeostasis, likely via its effects on PLR. Together, these findings implicate osteocytes in bone-cartilage crosstalk in the joint and suggest a causal role for suppressed perilacunar/canalicular remodeling in osteoarthritis.
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