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Type 2 diabetes and obesity are associated with back pain in juveniles and adults and are implicated in intervertebral disc (IVD) degeneration. Hypercaloric Western diets are associated with both obesity and type 2 diabetes. The objective of this study was to determine if obesity and type 2 diabetes result in spinal pathology in a sex-specific manner using in vivo diabetic and dietary mouse models. Leptin is an appetite-regulating hormone, and its deficiency leads to polyphagia, resulting in obesity and diabetes. Leptin is also associated with IVD degeneration, and increased expression of its receptor was identified in degenerated IVDs. We used young, leptin receptor deficient (Db/Db) mice to mimic the effect of diet and diabetes on adolescents. Db/Db and Control mice were fed either Western or Control diets, and were sacrificed at 3 months of age. Db/Db mice were obese, while only female mice developed diabetes. Female Db/Db mice displayed altered IVD morphology, with increased intradiscal notochordal band area, suggesting delayed IVD cell proliferation and differentiation, rather than IVD degeneration. Motion segments from Db/Db mice exhibited increased failure risk with decreased torsional failure strength. Db/Db mice also had inferior bone quality, which was most prominent in females. We conclude that obesity and diabetes due to impaired leptin signaling contribute to pathological changes in vertebrae, as well as an immature IVD phenotype, particularly of females, suggesting a sex-dependent role of leptin in the spine.

Background Rats are a widely accepted preclinical model for evaluating intervertebral disc (IVD) degeneration and regeneration. IVD morphology is commonly assessed using histology, which forms the foundation for quantifying the state of IVD degeneration. IVD degeneration severity is evaluated using different grading systems that focus on distinct degenerative features. A standard grading system would facilitate more accurate comparison across laboratories and more robust comparisons of different models and interventions. Aims This study aimed to develop a histology grading system to quantify IVD degeneration for different rat models. Materials & Methods This study involved a literature review, a survey of experts in the field, and a validation study using 25 slides that were scored by 15 graders from different international institutes to determine inter‐ and intra‐rater reliability. Results A new IVD degeneration grading system was established and it consists of eight significant degenerative features, including nucleus pulposus (NP) shape, NP area, NP cell number, NP cell morphology, annulus fibrosus (AF) lamellar organization, AF tears/fissures/disruptions, NP‐AF border appearance, as well as endplate disruptions/microfractures and osteophyte/ossification. The validation study indicated this system was easily adopted, and able to discern different severities of degenerative changes from different rat IVD degeneration models with high reproducibility for both experienced and inexperienced graders. In addition, a widely‐accepted protocol for histological preparation of rat IVD samples based on the survey findings include paraffin embedding, sagittal orientation, section thickness < 10 μm, and staining using H&E and/or SO/FG to facilitate comparison across laboratories. Conclusion The proposed histological preparation protocol and grading system provide a platform for more precise comparisons and more robust evaluation of rat IVD degeneration models and interventions across laboratories. Standardized histopathology scoring system with different categories and features for quantifying intervertebral disc degeneration in rat models.

Pentosan polysulfate (PPS) is an FDA-approved, oral medication with anti-inflammatory and pro-chondrogenic properties. We have previously shown that animal models of the mucopolysaccharidoses (MPS) exhibit significant inflammatory disease, contributing to cartilage degeneration. Enzyme replacement therapy (ERT) only partly reduced inflammation, and anti-TNF-alpha antibody therapy significantly enhanced clinical and pathological outcomes. Here we describe the use of PPS for the treatment of MPS type VI rats. Treatment began during prenatal development and at 1 and 6 months of age. All animals were treated until they were 9 months old. Significant reductions in the serum and tissue levels of several inflammatory markers (e.g., TNF-alpha, MIP-1alpha and RANTES/CCL5) were observed, as was reduced expression of inflammatory markers in cultured articular chondrocytes. ADAMTS-5/aggrecanase-2 levels also were reduced in chondrocytes, consistent with an elevation of serum tissue inhibitor of metalloproteinase 1. Marked improvements in motility and grooming behavior occurred, along with a reduction in eye and nasal secretions and a lessening of the tracheal deformities. MicroCT and radiographic analyses further revealed that the treated MPS skulls were longer and thinner, and that the teeth malocclusions, misalignments and mineral densities were improved. MicroCT analysis of the femurs and vertebrae revealed improvements in trabecular bone mineral densities, number and spacing in a subset of treated MPS animals. Biomechanical assessments of PPS-treated spines showed partially restored torsional behaviors, suggesting increased spinal stability. No improvements were observed in cortical bone or femur length. The positive changes in the PPS-treated MPS VI rats occurred despite glycosaminoglycan accumulation in their tissues. Based on these findings we conclude that PPS could be a simple and effective therapy for MPS that might provide significant clinical benefits alone and in combination with other therapies.

Developing effective therapies for back pain associated with intervertebral disc (IVD) degeneration is a research priority since it is a major socioeconomic burden and current conservative and surgical treatments have limited success. Polyphenols are naturally occurring compounds in plant-derived foods and beverages, and evidence suggests dietary supplementation with select polyphenol preparations can modulate diverse neurological and painful disorders. This study tested whether supplementation with a select standardized Bioactive-Dietary-Polyphenol-Preparation (BDPP) may alleviate pain symptoms associated with IVD degeneration. Painful IVD degeneration was surgically induced in skeletally-mature rats by intradiscal saline injection into three consecutive lumbar IVDs. Injured rats were given normal or BDPP-supplemented drinking water. In-vivo hindpaw mechanical allodynia and IVD height were assessed weekly for 6 weeks following injury. Spinal column, dorsal-root-ganglion (DRG) and serum were collected at 1 and 6 weeks post-operative (post-op) for analyses of IVD-related mechanical and biological pathogenic processes. Dietary BDPP significantly alleviated the typical behavioral sensitivity associated with surgical procedures and IVD degeneration, but did not modulate IVD degeneration nor changes of pro-inflammatory cytokine levels in IVD. Gene expression analyses suggested BDPP might have an immunomodulatory effect in attenuating the expression of pro-inflammatory cytokines in DRGs. This study supports the idea that dietary supplementation with BDPP has potential to alleviate IVD degeneration-related pain, and further investigations are warranted to identify the mechanisms of action of dietary BDPP.

We previously demonstrated the benefits of daily, oral pentosan polysulfate (PPS) treatment in a rat model of mucopolysaccharidosis (MPS) type VI. Herein we compare these effects to once weekly, subcutaneous (s.c.) injection. The bioavailability of injected PPS is greater than oral, suggesting better delivery to difficult tissues such as bone and cartilage. Injected PPS also effectively treats osteoarthritis in animals, and has shown success in osteoarthritis patients. One-month-old MPS VI rats were given once weekly s.c. injections of PPS (1, 2 and 4 mg/kg, human equivalent dose (HED)), or daily oral PPS (4 mg/kg HED) for 6 months. Serum inflammatory markers and total glycosaminoglycans (GAGs) were measured, as were several histological, morphological and functional endpoints. Overall, weekly s.c. PPS injections led to similar or greater therapeutic effects as daily oral administration. Common findings between the two treatment approaches included reduced serum inflammatory markers, improved dentition and skull lengths, reduced tracheal deformities, and improved mobility. Enhanced effects of s.c. treatment included GAG reduction in urine and tissues, greater endurance on a rotarod, and better improvements in articular cartilage and bone in some dose groups. Optimal therapeutic effects were observed at 2 mg/kg, s.c.. No drug-related increases in liver enzymes, coagulation factor abnormalities or other adverse effects were identified following 6 months of s.c. PPS administration. Once weekly s.c. administration of PPS in MPS VI rats led to equal or better therapeutic effects than daily oral administration, including a surprising reduction in urine and tissue GAGs. No adverse effects from s.c. PPS administration were observed over the 6-month study period.

Background Intervertebral disc (IVD) degeneration (IVDD) is a major cause of global disability. Three papers on puncture models of IVDD were published 20 years ago, transforming the application of preclinical animal models for pathophysiology and therapeutic screening studies. Methods Narrative review describing historic and current usage of preclinical puncture models of IVDD, documenting their introduction to induce slow, progressive IVDD and evolution to include many injury types broadly called “puncture models.” IVDD puncture models were reviewed for variability in species, needle gauge, puncture depth, IVD compartment, injectates, angle of puncture, motion of needle, and IVDD phenotype mimicked. Results IVD puncture models gained prominence following seminal 2005 publications describing needle puncture to induce slow, progressive IVDD for screening therapies. Specific details of puncture methods were described for controlling injury severity to induce IVDD phenotypes, including slow progressive IVDD, severe IVDD, chronic IVDD, disc herniation, and Modic‐like changes. Common measurements for characterizing IVDD were also described. Conclusions Surgically induced IVD puncture injury animal models have evolved over decades to include many variations simulating distinct clinical phenotypes of IVDD. To facilitate cross‐study comparisons, we recommend reporting a common set of injury features including needle gauge, puncture depth, injectates, puncture angle changes, needle motion, involvement of endplate and surrounding tissues, and phenotypes of IVDD mimicked. Surgically induced “outside‐in” puncture injury models are valuable tools to test specific hypotheses and screening therapies. This review of surgically induced IVD puncture injury animal models presents an evolution over decades to include many variations simulating distinct clinical phenotypes of IVDD, and recommends reporting a common set of injury features to facilitate cross‐study comparison.

[This corrects the article DOI: 10.1371/journal.pone.0223435.].

To determine the role of tumor necrosis factor‐alpha (TNFα) on initiating painful intervertebral disc (IVD) degeneration, rat lumbar IVDs were punctured and injected with TNFα or anti‐TNFα, and the resulting pain behavior, IVD structural degeneration, and intradiscal pro‐inflammatory cytokine expressions were determined. TNFα injection increased pain and IVD degeneration, whereas anti‐TNFα decreased both pain and IVD degeneration to control levels, and pain was predicted by IVD degeneration and TNFα expression using a multivariate stepwise linear regression. We conclude TNFα is an initiator of painful IVD degeneration and its early inhibition can mitigate pain and degeneration. Background Painful intervertebral disc (IVD) degeneration has tremendous societal costs and few effective therapies. Intradiscal tumor necrosis factor‐alpha (TNFα) is commonly associated with low back pain, but the direct relationship remains unclear. Purpose Treatment strategies for low back pain require improved understanding of the complex relationships between pain, intradiscal pro‐inflammatory cytokines, and structural IVD degeneration. A rat in vivo lumbar IVD puncture model was used to 1) determine the role of TNFα in initiating painful IVD degeneration, and 2) identify statistical relationships between painful behavior, IVD degeneration, and intradiscal pro‐inflammatory cytokine expression. Methods Lumbar IVDs were punctured anteriorly and injected with TNFα, anti‐TNFα, or saline and compared with sham and naive controls. Hindpaw mechanical hyperalgesia was assayed weekly to determine pain over time. 6‐weeks post‐surgery, animals were sacrificed, and IVD degeneration, IVD height, and intradiscal TNFα and interleukin‐1 beta (IL‐1β) expressions were assayed. Results Intradiscal TNFα injection increased pain and IVD degeneration whereas anti‐TNFα alleviated pain to sham level. Multivariate step‐wise linear regression identified pain threshold was predicted by IVD degeneration and intradiscal TNFα expression. Pain threshold was also linearly associated with IVD height loss and IL‐1β. Discussion The significant associations between IVD degeneration, height loss, inflammation, and painful behavior highlight the multifactorial nature of painful IVD degeneration and the challenges to diagnose and treat a specific underlying factor. We concluded that TNFα is an initiator of painful IVD degeneration and its early inhibition can mitigate pain and degeneration. Intradiscal TNFα inhibition following IVD injury may warrant investigation for its potential to alter downstream painful IVD degeneration processes.

Background The rabbit lumbar spine is a commonly utilized model for studying intervertebral disc degeneration and for the pre‐clinical evaluation of regenerative therapies. Histopathology is the foundation for which alterations to disc morphology and cellularity with degeneration, or following repair or treatment are assessed. Despite this, no standardized histology grading scale has yet been established for the spine field for any of the frequently utilized animal models. Aims The purpose of this study was to establish a new standardized scoring system to assess disc degeneration and regeneration in the rabbit model. Materials and Methods The scoring system was formulated following a review of the literature and a survey of spine researchers. Validation of the scoring system was carried out using images provided by 4 independent laboratories, which were graded by 12 independent graders of varying experience levels. Reliability testing was performed via the computation of intra‐class correlation coefficients (ICC) for each category and the total score. The scoring system was then further refined based on the results of the ICC analysis and discussions amongst the authors. Results The final general scoring system involves scoring 7 features (nucleus pulposus shape, area, cellularity and matrix condensation, annulus fibrosus/nucleus pulposus border appearance, annulus fibrosus morphology, and endplate sclerosis/thickening) on a 0 (healthy) to 2 (severe degeneration) scale. ICCs demonstrated overall moderate to good agreement across graders. An addendum to the main scoring system is also included for use in studies evaluating regenerative therapeutics, which involves scoring cell cloning and morphology within the nucleus pulposus and inner annulus fibrosus. Discussion Overall, this new scoring system provides an avenue to improve standardization, allow a more accurate comparison between labs and more robust evaluation of pathophysiology and regenerative treatments across the field. Conclusion This study developed a histopathology scoring system for degeneration and regeneration in the rabbit model based on reported practice in the literature, a survey of spine researchers, and validation testing. The rabbit lumbar spine is a commonly utilized model for studying intervertebral disc degeneration and for the pre‐clinical evaluation of regenerative therapies, and histopathology is the foundation for which alterations to disc morphology and cellularity with degeneration, or following repair or treatment are assessed. Despite this, no standardized histology grading scale has yet been established for the spine field for any of the frequently utilized animal models. Therefore, the purpose of this study was to establish a new standardized scoring system to assess disc degeneration and regeneration in the rabbit model.

Yet, to date no commonly accepted histology scoring systems exist in the spine field; in contrast in the cartilage field, the OARSI and ICRS scoring systems are utilized for evaluating cartilage degeneration and repair. 1,2 In June 2019, the editors of JOR Spine in collaboration with the ORS Spine Section tasked the community to generate a series of histopathology scoring systems to improve cross-species comparisons of animal or human features characteristic of disc degeneration and regeneration where relevant and available. 3 Volunteer leaders reviewed literature, organized conference calls with spine scientists across the globe and developed recommendations for scoring systems specific for mouse, rat, rabbit, large animal models, or human intervertebral discs. [...]the manuscript focused on human disc tissues provides a contemporary system for characterizing the features of human disc degeneration that will allow consistent and reproducible linkages to clinical information and imaging to establish relevance and provide a reference standard against which animal data should be evaluated to address applicability to the human situation. In large animal models, complementary outcomes studying disc degeneration/regeneration in a single disc are possible but not yet widely used. [...]the team focused on bringing first available expertise and experiences to create a comprehensive toolbox for anatomical and functional outcomes. [...]mock” human discs were compiled utilizing images submitted by the spine community to represent whole disc images and high magnification regions representative of features which could be identified in such human and large animal discs to enable testing of the scoring system.