Relaxin's induction of metalloproteinases is associated with the loss of collagen and glycosaminoglycans in synovial joint fibrocartilaginous explants.
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Diseases of specific fibrocartilaginous joints are especially common in women of reproductive age, suggesting that female hormones contribute to their etiopathogenesis. Previously, we showed that relaxin dose-dependently induces matrix metalloproteinase (MMP) expression in isolated joint fibrocartilaginous cells. Here we determined the effects of relaxin with or without beta-estradiol on the modulation of MMPs in joint fibrocartilaginous explants, and assessed the contribution of these proteinases to the loss of collagen and glycosaminoglycan (GAG) in this tissue. Fibrocartilaginous discs from temporomandibular joints of female rabbits were cultured in medium alone or in medium containing relaxin (0.1 ng/ml) or beta-estradiol (20 ng/ml) or relaxin plus beta-estradiol. Additional experiments were done in the presence of the MMP inhibitor GM6001 or its control analog. After 48 hours of culture, the medium was assayed for MMPs and the discs were analyzed for collagen and GAG concentrations. Relaxin and beta-estradiol plus relaxin induced the MMPs collagenase-1 and stromelysin-1 in fibrocartilaginous explants--a finding similar to that which we observed in pubic symphysis fibrocartilage, but not in articular cartilage explants. The induction of these proteinases by relaxin or beta-estradiol plus relaxin was accompanied by a loss of GAGs and collagen in joint fibrocartilage. None of the hormone treatments altered the synthesis of GAGs, suggesting that the loss of this matrix molecule probably resulted from increased matrix degradation. Indeed, fibrocartilaginous explants cultured in the presence of GM6001 showed an inhibition of relaxin-induced and beta-estradiol plus relaxin-induced collagenase and stromelysin activities to control baseline levels that were accompanied by the maintenance of collagen or GAG content at control levels. These findings show for the first time that relaxin has degradative effects on non-reproductive synovial joint fibrocartilaginous tissue and provide evidence for a link between relaxin, MMPs, and matrix degradation. (+info)
Jacob's disease associated with temporomandibular joint dysfunction: a case report.
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Jacob's disease is regarded a rare condition in which a joint formation is established between an enlarged mandibular coronoid process and the inner aspect of the zygomatic body. Chronic temporomandibular joint (TMJ) disk displacement has been proposed as etiological factor of coronoid process enlargement. We present a 23-year-old woman with long-standing TMJ dysfunction and restricted interincisal opening, who developed a progressive zygomatic asymmetry. The patient underwent treatment by intraoral coronoidectomy and homolateral TMJ arthroscopy in the same surgery. The histopathological diagnosis of the coronoid sample was cartilage-capped exostoses with presence of articular fibrous cartilage. Although the low prevalence of this entity, it should be considered as a possible diagnosis in patients with progressive limitation of mouth opening, although a TMJ syndrome may be present as a cause of this entity. (+info)
Growth factor expression in degenerated intervertebral disc tissue. An immunohistochemical analysis of transforming growth factor beta, fibroblast growth factor and platelet-derived growth factor.
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Degenerated intervertebral disc has lost its normal architecture, and there are changes both in the nuclear and annular parts of the disc. Changes in cell shape, especially in the annulus fibrosus, have been reported. During degeneration the cells become more rounded, chondrocyte-like, whereas in the normal condition annular cells are more spindle shaped. These chondrocyte-like cells, often forming clusters, affect extracellular matrix turnover. In previous studies transforming growth factor beta (TGFbeta) -1 and -2, basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) have been highlighted in herniated intervertebral disc tissue. In the present study the same growth factors are analysed immunohistochemically in degenerated intervertebral disc tissue. Disc material was obtained from 16 discs operated for painful degenerative disc disease. Discs were classified according to the Dallas Discogram Description. Different disc regions were analysed in parallel. As normal control disc tissue material from eight organ donors was used. Polyclonal antibodies against different growth factors and TGFbeta receptor type II were used, and the immunoreaction was detected by the avidin biotin complex method. All studied degenerated discs showed immunoreactivity for TGFbeta receptor type II and bFGF. Fifteen of 16 discs were immunopositive for TGFbeta-1 and -2, respectively, and none showed immunoreaction for PDGF. Immunopositivity was located in blood vessels and in disc cells. In the nucleus pulposus the immunoreaction was located almost exclusively in chondrocyte-like disc cells, whereas in the annular region this reaction was either in chondrocyte-like disc cells, often forming clusters, or in fibroblast-like disc cells. Chondrocyte-like disc cells were especially prevalent in the posterior disrupted area. In the anterior area of the annulus fibrosus the distribution was more even between these two cell types. bFGF was expressed in the anterior annulus fibrosus more often in chondrocyte-like disc cells than in fibroblast-like disc cells. Control discs showed cellular immunopositivity for only TGFbeta-1 and -2 and TGFbeta receptor type II . We suggest that growth factors create a cascade in intervertebral disc tissue, where they act and participate in cellular remodelling from the normal resting stage via disc degeneration to disc herniation. (+info)
The potential value of blood biomarkers of intervertebral disk metabolism in the follow-up of patients with sciatica.
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STUDY DESIGN: This is a prospective study with a follow-up period of 4 years. OBJECTIVES: The study aimed to evaluate the possible clinical utility of three biomarkers [i.e., keratan sulfate (KS), hyaluronan, and cartilage oligomeric matrix protein] measured in peripheral blood in severe acute sciatica at intake and follow-up. SUMMARY OF BACKGROUND: Our previous study and others have pointed out the interest of different laboratory tests in the acute phase of sciatica. Several blood biomarkers have been reported useful in the long-term follow-up of patients with osteoarthritis. We have found no information about the potential interest of these tests in spinal disorders. METHODS: Patients were admitted to the hospital for intensive conservative management of acute sciatica (n=82). A subgroup of patients (n=33) was selected based on the duration of symptoms at visit 1, and included those with the shortest (n=24) as well as those with the longest (n=9) duration of sciatica. Blood samples were drawn, centrifuged, and the plasma frozen. Antigenic KS, hyaluronan, and cartilage oligomeric matrix protein were measured by ELISA. Patients were re-evaluated at an average of 4.3 years (range: 2.1-6.8 years). RESULTS: Thirty-three subjects with an average age of 49.2+/-10.2 years participated. At intake, levels of the three biomarkers evaluated were within the range of normal values. No significant differences were found between the results of patients with a short history of sciatica (< or =3 weeks) and those with a long duration of symptoms (>20 weeks). At follow-up, a significant increase (P<0.05) in all three biomarkers was found. CONCLUSIONS: A single measurement of these three biomarker molecules does not seem to have any diagnostic or therapeutic relevance in patients with acute radicular compression. The significance of the increase in all three biomarkers after a mean follow-up of 4.3 years is unclear; it might reflect metabolic processes involved in degenerative spinal disorders. Even though we found no correlation with clinical outcome, we believe that more research is needed. (+info)
The pathogenesis and clinical significance of a high-intensity zone (HIZ) of lumbar intervertebral disc on MR imaging in the patient with discogenic low back pain.
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Recently, the presence of a high-intensity zone (HIZ) within the posterior annulus seen on T2-weighted MRI has aroused great interest and even controversy among many investigators, particularly on whether the HIZ was closely associated with a concordant pain response on awake discography. The study attempted to interpret the correlation between the presence of the HIZ on MRI and awake discography, as well as its characteristic pathology. Fifty two patients with low back pain without disc herniation underwent MRI and discography successively. Each disc with HIZ was correlated for an association between the presence of a HIZ and the grading of annular disruption and a concordant pain response. Eleven specimens of lumbar intervertebral discs which contain HIZ in the posterior annulus from 11 patients with discogenic low back pain were harvested for histologic examination to interpret the histologic basis of a nociceptive response during posterior lumbar interbody fusion (PLIF). The study found that in all of 142 discograms in 52 patients, 17 presented HIZ. All 17 discs with HIZ showed painful reproduction and abnormal morphology with annular tears extending either well into or through the outer third of the annulus fibrosus. The consecutive sagittal slices through the HIZ lesion showed that a notable histologic feature of the formation of vascularized granulation tissue in the outer region of the annulus fibrosus. The current study suggests that the HIZ of the lumbar disc on MRI in the patient with low back pain could be considered as a reliable marker of painful outer anular disruption. (+info)
Intervertebral disc degeneration in relation to the COL9A3 and the IL-1ss gene polymorphisms.
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Disc degeneration is a complex condition in which environmental factors and multiple genes are expected to act together to determine the degenerative phenotype. Recently associations of COL9A2 (Trp2 allele) and COL9A3 (Trp3 allele) polymorphisms with lumbar disc disease characterized by sciatica have been reported. However, it is not known whether the Trp2 or Trp3 alleles contribute to disc degeneration (DD). In this study, the association between the collagen genes polymorphisms and lumbar DD was investigated. Furthermore, the influence of the IL-1beta(C(3954)-T) polymorphism on the association of collagen genes polymorphisms with DD was examined. Lumbar intervertebral discs of 135 middle-aged occupationally active men were evaluated with magnetic resonance imaging, using decreased signal intensity of the nucleus pulposus, disc bulges, and decreased disc height as signs of degeneration. Blood samples were analysed for the presence of COL9A3 and COL9A2 tryptophan alleles (Trp3 and Trp2 alleles). The COL11A2, COL2A1 and IL-1beta(C(3954)-T) polymorphisms were also analysed. Multivariate logistic regression analysis allowing for occupation and body mass index showed that the carriage of the Trp3 allele in the absence of the IL-1betaT(3954) allele increased the risk of dark nucleus pulposus (OR 7.0, 95% CI 1.3-38.8) and joint occurrence of degenerative changes (OR 8.0, 95% CI 1.4-44.7). There was no effect of the Trp3 allele on DD in the presence of the IL-1betaT(3954) allele. The carriers of the COL11A2 minor allele had an increased risk of disc bulges (OR 2.1, 95% CI 1.0-4.2) as compared with non-carriers. The results suggest that the effect of the COL9A3 gene polymorphism on DD might be modified by the IL-1beta gene polymorphism. (+info)
Intradiscal pressure measurements in normal discs, compressed discs and compressed discs treated with axial posterior disc distraction: an experimental study on the rabbit lumbar spine model.
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Intervertebral disc (IVD) pressure measurement is an appropriate method for characterizing spinal loading conditions. However, there is no human or animal model that provides sufficient IVD pressure data. The aim of our study was to establish physiological pressure values in the rabbit lumbar spine and to determine whether temporary external disc compression and distraction were associated with pressure changes. Measurements were done using a microstructure-based fibreoptic sensor. Data were collected in five control rabbits (N, measurement lying prone at segment L3/4 at day 28), five rabbits with 28 days of axial compression (C, measurement at day 28) and three rabbits with 28 days of axial compression and following 28 days of axial distraction (D, measurement at day 56). Disc compression and distraction was verified by disc height in lateral radiographs. The controls (N) showed a level-related range between 0.25 MPa-0.45 MPa. The IVD pressure was highest at level L3/4 (0.42 MPa; range 0.38-0.45) with a decrease in both cranial and caudal adjacent segments. The result for C was a significant decrease in IVD pressure (0.31 MPa) when compared with controls (P=0.009). D showed slightly higher median IVD pressure (0.32 MPa) compared to C, but significantly lower levels when compared with N (P=0.037). Our results indicate a high range of physiological IVD pressure at different levels of the lumbar rabbit spine. Temporary disc compression reduces pressure when compared with controls. These data support the hypothesis that temporary external compression leads to moderate disc degeneration as a result of degradation of water-binding disc matrix or affected active pumping mechanisms of nutrients into the disc. A stabilization of IVD pressure in discs treated with temporary distraction was observed. (+info)
Regulation of matrix metalloproteinase expression by dynamic tensile strain in rat fibrochondrocytes.
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OBJECTIVE: We sought to determine the molecular basis for the anticatabolic effects of mechanical signals on fibrocartilage cells by studying the expression of a variety of matrix metalloproteinases (MMPs). Furthermore, we examined whether the effects of biomechanical strain on MMP gene expression are sustained. METHODS: Fibrochondrocytes from temporomandibular joint (TMJ) discs were exposed to dynamic tensile strain for various time intervals in the presence of interleukin (IL)-1beta. The regulation of the messenger RNA (mRNA) expression and synthesis of MMPs and tissue inhibitors of MMPs (TIMPs) were examined by end-point and real-time reverse transcriptase-polymerase chain reaction (RT-PCR) as well as Western blot analysis. RESULTS: Fibrochondrocytes expressed mRNA for MMP-2, -3, -7, -8, -9, -11, -13, -14, -16, -17, and -19 as well as TIMP-1, -2, and -3, IL-1beta induced a significant (P<0.05) upregulation of mRNA for MMP-3, -7, -8, -9, -13, -16, -17, and -19. The IL-1beta-stimulated upregulation of these MMPs was significantly (P<0.05) abrogated by dynamic tensile strain. However, MMP-2, -11, -14, and TIMPs were not affected by either IL-1beta or tensile strain. Biomechanical strain also inhibited the IL-1beta-stimulated protein synthesis of MMP-3, -7, -8, -9, -13, -16, and -17. Application of mechanical strain for various time intervals during a 24-h incubation with IL-1beta showed that the suppressive effects of mechanical signals are sustained. CONCLUSIONS: The data provide evidence that biomechanical signals can downregulate the catabolic activity of fibrocartilage cells in an inflammatory environment by inhibiting the expression of a variety of MMPs. Furthermore, the matrix-protective effects of biomechanical signals are sustained even in an inflammatory environment. (+info)