abstract: Introduction. Intervertebral disc degeneration (DD) is one of the most common diagnoses in patients with neck pain and contributes to worldwide disability. Despite the advances in diagnostic imaging today, little is known about functional status of cervical DD. The purpose of this research was to 1) develop and validate an ovine model of cervical spine DD, 2) to quantify and compare the effect of disc lesions on dynamic spinal stiffness, and 3) study the effect of disc lesions on spinal accelerations and displacements during two types of spinal manipulative therapy (SMT). Methods. Fifteen sheep received surgically induced disc injury to the mid-cervical spine via scalpel wound a minimum of five months earlier and 15 sheep served as controls. All animals were biomechanically assessed at the level of the lesion using swept-sine mechanical loads from 0-20 Hz under load control to quantify dynamic dorsoventral (DV) spine stiffness (load/deformation, N/mm). The effect of disc lesion on stiffness was assessed using a one-factor repeated measures ANOVA comparing 32 mechanical excitation frequencies. Tri-axial accelerometers rigidly attached to adjacent vertebrae across the target level further evaluated the effect of disc lesion on spinal motion response during two types of SMTs. A 2x6x2 repeated measures ANOVA examined the effect of disc lesion and SMT force-time profile on spine motion response. Postmortem histological analysis graded specimens at the target site and comparison was made with descriptive statistics. Results. Annular disc tears were only observed in the disc lesion group and the mild degeneration identified was localized to the injured annular tissue that did not progress to affect other areas of the disc. No difference in overall DD grading was found among the groups. DV stiffness was significantly increased in the disc lesion group by approximately 34% at 31 of 32 frequencies examined (p<.05). SMTs resulted in decreased displacements in the disc lesion group (p<.05), and SMT type significantly influenced spinal accelerations for both the DV and axial planes. Conclusion. Disc lesions in the ovine cervical spine produce localized annular degenerative changes that increase the cervical spine dynamic stiffness and reduce its spinal motion response during manual examination and treatment that is further augmented by the force-time profile administered by the clinician. / Dissertation/Thesis / Doctoral Dissertation Kinesiology 2015

abstract: Intervertebral Disc Degeneration (IVDD) is a complex phenomenon characterizing the desiccation and structural compromise of the primary joint in the human spine. The intervertebral disc (IVD) serves to connect vertebral bodies, cushion shock, and allow for flexion and extension of the vertebral column. Often presenting in the 4th or 5th decades of life as low back pain, this disease was originally believed to be the result of natural “wear and tear” coupled with repetitive mechanical insult, and as such most studies focus on patients between 40 and 50 years of age. Research over the past two decades, however, has demonstrated that environmental factors have only a modest effect on disc degeneration, with genetic influences playing a much more substantial role. Extensive research has focused on this process, though definitive risk factors and a clear pathophysiology have proven elusive. The aim of this study was to assemble a cohort of patients exhibiting definitive signs of degeneration who were well below the average age of presentation, with minimal or no exposure to suspected environmental risk factors and to conduct a targeted genome analysis in an attempt to elucidate a common genetic component. Through whole genome sequencing and analysis, the results corroborated findings in a previous study, as well as demonstrated a potential connection and influence between mutations found in IVD structural or functional genes, and the provocation of IVDD. Though the sample size was limited in scale and age, these findings suggest that further IVDD research into the association of variants in collagen, aggrecan and the insulin-like growth factor receptor genes of young patients with an early presentation of disc degeneration and minimal exposure to suspected risk factors is merited. / Dissertation/Thesis / Masters Thesis Biology 2016

Abstract Low back pain (LBP) is a truly enervating condition, presenting with considerable negative socioeconomic and health impacts on many levels. Although LBP may be attributed to many factors, there is increasing evidence that disc degeneration (DD) of the lumbar spine is a strong contributing factor, especially among young individuals. Understanding the aetiopathogenesis of DD has changed over the past few decades as numerous studies have indicated that inherited factors are largely responsible for the development of DD. Despite the many genetic associations in DD that have been reported, these associations have proven difficult to validate. The genetic component of DD is still unexplained for the most part. Previous studies have focused on adults, who have been exposed to environmental risk factors of DD, which may mask genetic associations. Thus, investigations among young individuals are well justified. The purpose of this study was to validate the associations between DD defined by magnetic resonance imaging (MRI) and genetic polymorphisms in two study populations of Finnish and Danish young individuals. New polymorphisms that have not been associated with DD were also included in the study. Associations with progression of DD were also investigated among Danish individuals. Furthermore, this study aimed to clarify the level of evidence of previously identified associations. Among Finnish individuals, polymorphisms in IL6, SKT and CILP were associated with moderate DD, but the association in CILP was significant only in women. Among Danish individuals, polymorphisms in IL6 and IL1A were associated with early DD and progression of DD. The genetic associations among the Danish teenagers were gender-specific as they were mainly observed in girls. Among both populations, the individuals with DD were significantly taller than individuals without DD. In the systematic analysis of previous reports, polymorphisms in GDF5, THBS2, MMP9, COL11A1, SKT and ASPN were found to have a moderate level of association evidence. The results mostly support earlier findings in adults. However, unexpected differences between genders were observed. In conclusion, this study increased the knowledge of genetics in DD but more investigations are needed to draw any solid conclusions. / Tiivistelmä Alaselkäkipu on yksi merkittävimmistä toimintakykyyn vaikuttavista sairauksista. Alaselkäkivun riskitekijöitä tunnetaan useita, mutta näyttö siitä, että selän välilevyrappeuma on yksi tärkeimmistä riskitekijöistä, erityisesti nuorilla henkilöillä, lisääntyy jatkuvasti. Aiemmat tutkimukset ovat osoittaneet, että perintötekijöillä on merkittävä osuus välilevyjen rappeutumisessa. Useiden geenien on raportoitu vaikuttavan välilevyrappeumaan. Positiivisten tulosten toistaminen on kuitenkin osoittautunut vaikeaksi, ja kokonaiskuva on vielä suurelta osin epäselvä. Aikaisemmat tutkimukset aiheesta ovat keskittyneet aikuisiin, joilla nuoria pidempi altistus ympäristötekijöille saattaa peittää geneettisten tekijöiden yhteyttä. Tämän tutkimuksen tavoitteena oli varmentaa yhteyksiä magneettikuvauksella (MRI) määritetyn välilevyrappeuman ja geneettisten monimuotoisuuskohtien (polymorfioiden) välillä käyttäen yhtä suomalaisista ja yhtä tanskalaisista nuorista koostuvaa aineistoa. Työssä analysoitiin myös polymorfioita, joita ei ole aiemmin yhdistetty välilevyrappeumaan. Yhteyttä polymorfioiden ja välilevyrappeuman etenemisen välillä tutkittiin tanskalaisessa aineistossa. Lisäksi tutkimuksen tavoitteena oli selvittää aiemmin tunnistettujen geneettisten yhteyksien näytön aste. Suomalaisten nuorten aineistossa polymorfiat IL6-, SKT- ja CILP-geeneissä olivat yhteydessä kohtalaista astetta olevaan välilevyrappeumaan. Tanskalaisten nuorten aineistossa polymorfiat IL6- ja IL1A-geeneissä olivat yhteydessä varhaiseen välilevyrappeumaan ja sen etenemiseen. Tanskalaisten nuorten aineistossa nämä yhteydet olivat sukupuolesta riippuvaisia, koska yhteyksiä havaittiin pääasiassa tytöillä. Suomalaisten nuoren aineistossa yhteys CILP-geenissä havaittiin ainoastaan nuorilla naisilla. Kummassakin tutkimusaineistossa nuoret, joilla oli välilevyrappeuma, olivat pidempiä, kuin nuoret, joilla ei ollut välilevyrappeumaa. Aikaisempien tutkimusten systemaattinen analyysi osoitti, että tunnistetun geneettisen yhteyden näytön aste on kohtalainen GDF5-, THBS2-, MMP9-, COL11A1-, SKT- ja ASPN-geenien polymorfioissa. Tutkimusten tulokset ovat pääosin samansuuntaisia aiempien tutkimuksien kanssa, mutta nyt nähty eroavaisuus sukupuolten välillä on uusi havainto. Kokonaisuudessaan tämä väitöstutkimus kasvattaa ymmärtämystä välilevyrappeumasta, mutta lisätutkimuksia aiheesta tarvitaan.

Back pain is a highly prevalent condition whose pathogenesis is associated with intervertebral disc (IVD) degeneration. Degeneration is driven by abnormal cell biology, particularly within the IVD’s inner core, the nucleus pulposus (NP). In recent years, there has been an ever-increasing search for cell-based therapies aimed at correcting the cell biology and thus repairing/regenerating the degenerate IVD. The success of these novel therapies, however, requires a thorough understanding of IVD development and of the phenotype of its cells. The embryonic, foetal and juvenile NP is populated by large vacuolated notochordal cells that with skeletal maturity are replaced by smaller NP cells. Since notochordal cells have been shown to display protective and anabolic roles in the IVD their loss in humans has often been suggested to initiate the degenerative process. As such, a detailed understanding of notochordal cells and their regulatory pathways may help identify factors involved in IVD homeostasis and aid the development of novel cell-based therapies targeting IVD degeneration. The study of human notochordal cells has, however, been hindered by ethical, logistical and technical difficulties in obtaining suitable samples and, as such, the human notochordal cell phenotype is, to date, unknown, constituting a major limitation in the field. The work presented here was conducted with the objective of developing a methodology to isolate human developing notochordal cells (NP progenitors) from adjacent sclerotomal cells (annulus fibrosus and vertebral body progenitors), to characterise the notochordal cell phenotype and identify potential factors involved in notochordal cell biology. Initially, human embryonic and foetal spines were characterised to assess their suitability as a source of notochordal cells and to identify a notochord-specific marker that could be used to isolate notochordal cells for microarray studies. The human developing spine contained large vacuolated notochordal cells in all stages analysed (3.5-18 weeks post-conception (WPC)) that specifically expressed KRT8, KRT18 and KRT19 at all stages and CD24 between 5.5-18 WPC. KRT18 and CD24 were independently used to label notochordal cells (7.5-14 weeks post-conception) and separate them from sclerotomal cells. Methodologies were developed to allow extraction of RNA of sufficient quality for microarray analysis from fixed, permeabilised (in the case of KRT18) and/or, labelled and sorted cells (CD24). Microarray analysis identified and real-time qPCR and, for some markers, immunohistochemistry, validated GRB14, SLC19A1, FGF10, ADORA3, TBXA2R, CDH6, ANPEP, CD69, CD24, RTN1, PRPH, MAP1B, ISL1 and CLDN1 as human notochordal cell markers. Ingenuity pathway analysis was performed to investigate the pathways/networks and upstream regulators and downstream effectors of notochordal cells. Inhibition of inflammation and angiogenesis were identified as relevant to notochordal cell biology, function and, possibly, to the known protective and anabolic role notochordal cells display in the IVD. Notochordal marker gene expression was identified in adult NP tissue, and negatively correlated with degeneration. Proteins encoded by ADORA3 and MAP1B were expressed by a proportion of adult NP cells, suggesting the presence of notochord-derived cells in the adult NP.Importantly, this is the first study to detail a methodology and successfully isolate human notochordal cells. Such methodology has the potential to be used to culture and investigate the biology of viable human notochordal cells (CD24+ve). Future studies aimed at developing cell-based therapies for IVD degeneration could also use these identified markers to assess appropriate stem cell differentiation to notochordal cells.

No description available.

Introdução: A degeneração do disco intervertebral tem alta prevalência e é sabidamente associada à dor lombar. O objetivo deste trabalho foi correlacionar os valores de relaxometria T2 dos discos intervertebrais lombares com os parâmetros espinopélvicos em pacientes com dor lombar crônica. Materiais e métodos: Entre março a setembro de 2015, 91 pacientes consecutivos (56 mulheres, média de idade 53,5 anos, DP 11,6 anos, 23-76 anos e 35 homens, média de idade 53,6 anos, DP 11,9 anos, 19-73 anos) com dor lombar crônica foram incluidos neste estudo prospectivo. O Comitê de Ética Local aprovou o estudo e o consentimento foi obtido de cada paciente. Todos os indivíduos foram avaliados pelo índice de incapacidade Oswestry e escala visual analógica e não possuiam outras doenças da coluna vertebral, exceto degeneração discal. Os parâmetros espinopélvicos incidência pélvica (IP) versão pélvica (VP), inclinação sacral (IS), eixo vertical sagital (EVS), versão global (VG), ângulo espinopélvico (ASP), ângulo espinossacral (ASS), ângulo T1 pélvico (ATP), lordose lombar (LL), cifose torácica (CT), diferença entre a incidência pélvica e a lordose lombar (IP-LL) e a falta de lordose lombar (FLL) foram mensurados a partir de radiografias panorâmicas da coluna e pelve com o paciente na posição supina utilizando o software Surgimap®. O grupo de estudo foi categorizado de acordo com a classificação de Roussouly. Os mapas de relaxometria T2 foram adquiridos em aparelho de ressonância magnética de 1.5 Tesla para extrair os tempos de relaxação T2 e a segmentação manual completa dos discos lombares intervertebrais de cada paciente foi realizada no software Display®. Para verificar a reprodutibilidade desta avaliação, a concordância inter-observador para a segmentação manual dos discos intervertebrais lombares e mensuração dos parâmetros espinopélvicos foi avaliada. A significância estatística foi aceita quando p <0,05. Resultados: Os valores de relaxação T2 se correlacionaram significativamente com os parâmetros VP, VG, ASP, ATP, IP-LL e FLL em pacientes com dor lombarcrônica. Não encontramos correlação significativa entre os valores de relaxação T2 e os parâmetros IS, IP, ASS, EVS, LL, CT e questionários clínicos. A divisão por subtipos de Roussouly não se correlacionou com a degeneração discal avaliado pelo tempo de relaxação T2. A mensuração dos parâmetros espinopélvicos e a segmentação manual dos discos intervertebrais lombares mostraram uma alta reprodutibilidade interobservador. Conclusões: Indivíduos com maiores VP, VG, ATP, IP-LL e FLL apresentaram valores mais baixos de relaxação T2 nos discos intervertebrais. Para o nosso conhecimento, esse é o primeiro estudo a correlacionar os parâmetros espinopélvicos com a degeneração discal avaliada por meio da relaxometria T2. / Purpose: Intervertebral disc degeneration has a high prevalence and is known to be associated with low back pain.The purpose of this study was to correlate quantitative T2 relaxation measurements of lumbar intervertebral discs (IVD) with spinopelvic parameters and clinical symptoms in patients with chronic low back pain. Methods: From March to September 2015, 455 intervertebral discs from 91 consecutive patients (56 women, mean age 53.5 years, SD 11,7 years, 23-76 years and 35 men, mean age 53,6 years, SD 11.9 years, 19-73 years) with chronic low back pain were included in this prospective study. The study was approved by the local ethics committee, and written consent was obtained from all patients. All subjects were assessed by Oswestry Disability Index and Visual Analog Score questionnaires and were confirmed to have no other spine diseases except disc degeneration. Spinopelvic parameters including pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), sagittal vertical axis (SVA), global tilt (GT), spinopelvic angle (SPA), spinosacral angle (SSA), T1-pelvic angle (TPA), lumbar lordosis (LL), thoracic kyphosis (TK), PI-LL (pelvic incidence minus lumbar lordosis) and lack of lumbar lordosis (LLL) were measured from standing spine and pelvis lateral radiographs using the software Surgimap®. The study group was categorized according to the Roussouly classification. Saggital T2 maps were acquired in a 1.5T MRI scanner to extract the IVD relaxation times and the complete manual segmentation of the IVD of each patient in all levels was performed using the software Display®. To assess the reproducibility of this evaluation, the interobserver agreement fot the manual segmentation of the lumbar intervertebral discs and measurement of the spinopelvic parameters was performed. Statistical significance was accepted when p <0.05. Results: Lumbar intervertebral discs T2 relaxation times correlated significantly with PT, GT, SPA, TPA, PI-LL and LLL in patients with chronic low back pain. We found no significant correlation between T2 values and SS, PI, ASS, SVA, LL, TK andclinical questionnaires. Roussouly subtypes and clinical questionnaires did not correlate with T2 relaxation times. Conclusions: Individuals with higher PT, GT, TPA, PI-LL and LLL showed decreased intervertebral disc T2 relaxation values. To our knowledge, this is the first study to correlate spinopelvic parameters with disc degeneration evaluated by T2 relaxometry.

Abstract Low back pain (LBP) is the leading cause of years lived with disabilities worldwide. Intervertebral disc (IVD) degeneration is a strong contributing factor to LBP. Recent studies have shown that genetic determinants contribute markedly to IVD degeneration but knowledge about the actual genes involved as well as their roles is still limited. The aim of this thesis work was to study genetic factors that may predispose to IVD degeneration. Using both family and case-control association study designs, variants in five genes showed association with IVD degeneration on magnetic resonance imaging (MRI) in a population-based sample and among patients with sciatica due to lumbar disc herniation (LDH). We performed a candidate gene association study of the known variants implicated in IVD degeneration in a Finnish cohort of 538 young individuals with a moderate degree of lumbar IVD degeneration on MRI. We were able to confirm the associations of variants in the IL6, SKT, and CILP genes, which provides further evidence for true associations. Based on our earlier linkage study in Finnish sciatica families, we performed a candidate gene analysis and identified IL17F as a potential candidate gene. To the best of our knowledge this is the first study to observe an association between this gene and discogenic sciatica. Both IL-6 and IL-17 are pro-inflammatory cytokines with elevated expression levels in herniated tissues, which suggest a role in IVD degeneration. Study of the role of genes coding for inflammatory mediators is of interest as it may contribute to the understanding of the overall inflammatory response of the disc. In addition, we reported on the involvement of SKT in the etiology of lumbar disc herniation (LDH) both in Japanese and Finnish case-control samples. Experimental studies in mice have shown that Skt homozygous mutants exhibit disc abnormalities resulting in a kinky tale phenotype. We hypothesized that the human homolog SKT could have long-term importance in the onset of IVD degeneration by making the discs more vulnerable. Finally, through linkage studies and in the subsequent association analyses, the role of CHST3 as a novel risk factor for IVD degeneration was identified. CHST3 encodes an enzyme that catalyzes the sulfation of chondroitin, and mutations in this gene are associated with spondylepiphyseal dysplasia and humerospinal dysostosis. In our study, we identified this gene using genome –wide linkage based on data from a Southern Chinese family and speculated that mild CHST3 reduction caused by the reported susceptibility SNP could result in disc degeneration in adults in conjunction with other risk factors. This thesis provides new information about the genetic background of IVD degeneration and new insights into the etiology of the disease. The specific roles of these genes in the IVD function and pathogenesis of sciatica are not clear however, and need to be elucidated. / Tiivistelmä Alaselkäkipu on yksi yleisimmistä sairauksista ja johtava syy työkyvyttömyyteen. Välilevyrappeuma myötävaikuttaa merkittävästi alaselän kipuun. Vaikka aiemmat tutkimukset ovat osoittaneet, että perintötekijöillä on vahva osuus välilevyrappeumaan, altistavat geenit ja niiden rooli tunnetaan huonosti. Tämän tutkimuksen tavoitteena oli arvioida tiettyjen perintötekijöiden osuutta välilevyrappeumassa ja tunnistaa taudille altistava geeni perheaineistossa aiemmin havaitulta kromosomialueelta. Aineistoina tutkimuksessa olivat perheaineistot sekä laajat potilas-kontrolliaineistot suomalaisesta ja aasialaisista väestöistä. Tutkimuksessa osoitimme, että perimän vaihtelut viidessä tutkitussa geenissä altistivat erilaisille välilevyrappeuman taudin muodoille. Tutkimus, jossa analysoimme aiemmin tunnistettuja alttiusgeenejä, vahvisti IL6, SKT ja CILP geenien vaihteluiden osuuden taudin alttiustekijöinä. Tutkimusaineistona oli pohjoissuomalainen syntymäkohortti, jossa välilevyrappeuma oli määritetty magneettikuvauksella (MRI). Suomalaisessa perheaineistossa tehdyn kokogenomin laajuisen kartoituksen pohjalta analysoimme IL17F geenin mahdollisena uutena alttiusgeeninä oireiselle välilevytaudille. Kahdesta geenin variantista koostuva haplotyyppi assosioitui tautiin merkitsevästi. Lisäksi osoitimme, että SKT-geenin tietty muutos altistaa välilevyn pullistumille sekä japanilaisessa että suomalaisessa potilasaineistossa. Hiirikokeissa on havainnoitu, että SKT-geenin homotsygootti mutaatio johtaa välilevy-poikkeamaan, joka edelleen aiheuttaa hiiren poikkeavan häntäilmiasun-. Hypoteesimme oli, että ihmisen SKT -geeni voi myötävaikuttaa välilevypullistuman kehittymiseen altistamalla välilevyt rappeumalle. Edelleen, laajassa usean populaation aineiston käsittävässä tutkimuksessa osoitimme CHST3-geenin muutoksen altistavan välilevyrappeumalle. Peittyvästi periytyvät muutokset tässä geenissä aiheuttavat perinnöllisiä harvinaisia luusairauksia. Tämä väitöstutkimus tarjoaa uutta tietoa välilevyrappeuman geneettisestä taustasta ja auttaa taudin syiden tutkintaa. Geenien rooli välilevyn toiminnassa ja muutosten vaikutus taudin kulkuun vaativat kuitenkin vielä lisätutkimuksia.

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INTRODUÇÃO: A degeneração do disco intervertebral (DIV) é um processo crônico e apontado como o maior causador de cervicalgia e lombalgia. Esse processo geralmente conta com a degradação da matriz extracelular, expressão de citocinas inflamatórias e fatores angiogênicos e axonogênicos. Entretanto, muito pouco se sabe sobre esse processo em DIVs assintomáticos durante o envelhecimento, principalmente no segmento cervical. O objetivo desse estudo foi de delinear o perfil de moléculas relacionadas à degeneração discal em DIVs cervicais e lombares. MÉTODOS: Discos intervertebrais humanos cervicais e lombares (C4-C6 e L4-S1) foram coletados em autópsia de 30 indivíduos presumivelmente assintomáticos e divididos em grupos jovem (GJ < 35 anos, n=60) e idoso (GI > 65 anos, n=60). O nível de degeneração foi constatado pela escala de Thompson, e foi correlacionado com a detecção imuno-histoquímica das moléculas de MMP-1, -2, -3, TIMP-1, IL-1beta, TNF-alfa, VEGF, NGF-beta e BDNF. RESULTADOS: Todos os DIVs mostraram algum grau de degeneração, embora mais acentuadas no GI. As moléculas empenhadas no estudo foram identificadas em ambos grupos. A detecção imuno-histoquímica foi prevalente no citoplasma das células nativas do DIV e na região de interseção entre a placa vertebral e o arranjo fibro-colágeno. O envelhecimento propiciou, no disco cervical, maior expressão de MMP-2, -3, VEGF, NGF-beta e BDNF, enquanto que no disco lombar, a maior expressão foi de MMP-1, -2 -3, TIMP-1, TNF-alfa, VEGF e NGF-beta. DISCUSSÃO: O envelhecimento de DIVs cervicais e lombares caracterizou-se por exibir um processo catabólico e extensivo remodelamento da matriz extracelular, os quais podem ser interpretados como eventos que antecipam a doença degenerativa discal. Esse processo é capaz de levar a angiogênese e axonogênese de modo a ampliar o metabolismo aeróbio do DIV e captar informação nociceptiva como forma de defesa, uma vez que até nos discos lombares de indivíduos jovens essa última característica pôde ser observada. Discos assintomáticos também exibem moléculas relacionadas à doença degenerativa discal e talvez a inibição de parte dessas possa resultar em terapia preventiva / INTRODUCTION: Degeneration of the intervertebral disc (DIV) is a chronic process that pointed as a major cause of neck and low back pain. This process generally includes an extracellular matrix degradation, expression of inflammatory cytokines, angiogenesis and axonogenesis factors. However, there is a little known about this process in asymptomatic DIVs during aging, especially in the cervical region. The aim of this study was to delineate the profile of molecules related to disc degeneration in the cervical and lumbar discs. METHODS: Human cervical and lumbar intervertebral discs (C4-C6 e L4-S1) were harvested at autopsy from 30 asymptomatic individuals, and divided according to age with young (GJ < 35 years old, n=60) and elderly (GI > 65 years old, n=60) groups. Gross degeneration was graded according to the Thompson scale and this was correlated to the immunohistochemical detection of molecules of MMP-1, -2, -3, TIMP-1, IL-1beta, TNF-alfa, VEGF, NGF-beta e BDNF. RESULTS: Discs from GJ were significantly less degenerated than those of GI. The molecules involved in the study were identified in both groups. The immunohistochemical detection was prevalent in the cytoplasm of native disc cells and the region between the vertebral plate and fibrous collagen arrangement (intersection). Aging provided in cervical disc, increased expression of MMP-2, -3, VEGF, NGF and BDNF-beta, whereas in the lumbar disc the highest expression of MMP-1, -2, -3, TIMP-1, TNF-alfa, VEGF and NGF-beta was seen. DISCUSSION: The aging of cervical and lumbar DIV was marked by catabolic process and a extensive remodeling on extracellular matrix which can be interpreted as a predict event of the degenerative disc disease. This process can lead to angiogenesis and axonogenesis in order to expand the aerobic metabolism of the DIV and get nociceptive information as a defense, since even in the lumbar discs of young individuals this last feature can be observed. Asymptomatic discs also exhibit molecules related to degenerative disc disease and perhaps the inhibition some of these can result in preventive therapy

INTRODUÇÃO: A degeneração do disco intervertebral (DIV) é um processo crônico e apontado como o maior causador de cervicalgia e lombalgia. Esse processo geralmente conta com a degradação da matriz extracelular, expressão de citocinas inflamatórias e fatores angiogênicos e axonogênicos. Entretanto, muito pouco se sabe sobre esse processo em DIVs assintomáticos durante o envelhecimento, principalmente no segmento cervical. O objetivo desse estudo foi de delinear o perfil de moléculas relacionadas à degeneração discal em DIVs cervicais e lombares. MÉTODOS: Discos intervertebrais humanos cervicais e lombares (C4-C6 e L4-S1) foram coletados em autópsia de 30 indivíduos presumivelmente assintomáticos e divididos em grupos jovem (GJ < 35 anos, n=60) e idoso (GI > 65 anos, n=60). O nível de degeneração foi constatado pela escala de Thompson, e foi correlacionado com a detecção imuno-histoquímica das moléculas de MMP-1, -2, -3, TIMP-1, IL-1beta, TNF-alfa, VEGF, NGF-beta e BDNF. RESULTADOS: Todos os DIVs mostraram algum grau de degeneração, embora mais acentuadas no GI. As moléculas empenhadas no estudo foram identificadas em ambos grupos. A detecção imuno-histoquímica foi prevalente no citoplasma das células nativas do DIV e na região de interseção entre a placa vertebral e o arranjo fibro-colágeno. O envelhecimento propiciou, no disco cervical, maior expressão de MMP-2, -3, VEGF, NGF-beta e BDNF, enquanto que no disco lombar, a maior expressão foi de MMP-1, -2 -3, TIMP-1, TNF-alfa, VEGF e NGF-beta. DISCUSSÃO: O envelhecimento de DIVs cervicais e lombares caracterizou-se por exibir um processo catabólico e extensivo remodelamento da matriz extracelular, os quais podem ser interpretados como eventos que antecipam a doença degenerativa discal. Esse processo é capaz de levar a angiogênese e axonogênese de modo a ampliar o metabolismo aeróbio do DIV e captar informação nociceptiva como forma de defesa, uma vez que até nos discos lombares de indivíduos jovens essa última característica pôde ser observada. Discos assintomáticos também exibem moléculas relacionadas à doença degenerativa discal e talvez a inibição de parte dessas possa resultar em terapia preventiva / INTRODUCTION: Degeneration of the intervertebral disc (DIV) is a chronic process that pointed as a major cause of neck and low back pain. This process generally includes an extracellular matrix degradation, expression of inflammatory cytokines, angiogenesis and axonogenesis factors. However, there is a little known about this process in asymptomatic DIVs during aging, especially in the cervical region. The aim of this study was to delineate the profile of molecules related to disc degeneration in the cervical and lumbar discs. METHODS: Human cervical and lumbar intervertebral discs (C4-C6 e L4-S1) were harvested at autopsy from 30 asymptomatic individuals, and divided according to age with young (GJ < 35 years old, n=60) and elderly (GI > 65 years old, n=60) groups. Gross degeneration was graded according to the Thompson scale and this was correlated to the immunohistochemical detection of molecules of MMP-1, -2, -3, TIMP-1, IL-1beta, TNF-alfa, VEGF, NGF-beta e BDNF. RESULTS: Discs from GJ were significantly less degenerated than those of GI. The molecules involved in the study were identified in both groups. The immunohistochemical detection was prevalent in the cytoplasm of native disc cells and the region between the vertebral plate and fibrous collagen arrangement (intersection). Aging provided in cervical disc, increased expression of MMP-2, -3, VEGF, NGF and BDNF-beta, whereas in the lumbar disc the highest expression of MMP-1, -2, -3, TIMP-1, TNF-alfa, VEGF and NGF-beta was seen. DISCUSSION: The aging of cervical and lumbar DIV was marked by catabolic process and a extensive remodeling on extracellular matrix which can be interpreted as a predict event of the degenerative disc disease. This process can lead to angiogenesis and axonogenesis in order to expand the aerobic metabolism of the DIV and get nociceptive information as a defense, since even in the lumbar discs of young individuals this last feature can be observed. Asymptomatic discs also exhibit molecules related to degenerative disc disease and perhaps the inhibition some of these can result in preventive therapy