Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The main "shock absorbing" molecule in cartilage is the proteoglycan, aggrecan, which is trapped within a meshwork of collagen fibrils. Articular cartilage damage in osteoarthritis is associated with damage to the aggrecan protein moiety. This results in abnormal loss of aggrecan which in turn increases the propensity of the joint surface to be damaged. Presently, the treatment for arthritis, pain-relieving drugs, affects the symptoms. End-stage osteoarthritis requires joint replacement surgery. To a certain extent, both the degradation and the repair of cartilage can be understood at the level of the biochemistry of cartilage matrix and the biology of the chondrocyte.
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PMID:Cartilage aggrecan. Biosynthesis, degradation and osteoarthritis. 819 77

Hyaline articular cartilage is a specialised connective tissue with weight bearing and adsorbing functions. Injury or loss of which often leads to impaired joint function and severe pain. Since the self-renewing abilities of hyaline articular cartilage are limited, there is major interest in the development of bioengineered cartilaginous implants. A cell-matrix-biocomposite composed of a collagen I/III scaffold seeded with autologous chondrocytes is currently being used in clinical trials; however, in order to optimise culture conditions, we cultured human condrocytes and seeded them on type I/III collagen membranes and on Thermanox plastic coverslips with media containing 0 to 500 microg/ml Hyaluronic Acid. After 4 days, the cells were either fixed or BrdU incorporation procedures begun. HE staining clearly demonstrated that cells grown in HA form three dimensional clusters and produce secretory vesicles as opposed to the monolayer control cells with noticeably fewer secretory vesicles. BrdU incorporation revealed a noticeable increase in cell proliferation in cells grown in 100 microg/ml; however, no comparable increase in 500 micorg/ml but rather a slight depression in proliferation. Immunohistochemistry for collagen II and aggrecan revealed an obvious increase in deposition of these two substances with increased HA administration as compared to the control; however, again, the higher concentration of HA, 500 microg/ml, did not result in a further increase in production. These results suggest that HA at 100 microg/ml not only influences chondrocytes to differentiate and produce more Collagen II and aggrecan, but also increases proliferation. We, therefore, propose that the addition of HA at low to middle dosages in condrocyte culturing might help improve condrocyte redifferentation and thus, the bioengineered cartilage.
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PMID:Effects of hyaluronic acid on the morphology and proliferation of human chondrocytes in primary cell culture. 1120 79

Lumbar disc disease (LDD) is a common musculoskeletal disease affecting about 5% of all individuals. It is characterized by lumbar disc herniation, which causes nerve root irritation, either mechanically or via inflammatory mediators, and results in radiating pain, known as sciatica. Numerous studies have been conducted to identify the causes and risk factors for LDD. Lifting heavy loads, torsional stress and motor vehicle driving are among the best-identified environmental risk factors. However, it has become evident recently from family and twin studies that genetic factors may also be important in LDD. This hypothesis was strengthened by the identification of two collagen IX alleles associated with sciatica and lumbar disc herniation. In addition, disc degeneration has been shown to be related to an aggrecan gene polymorphism, a vitamin D receptor and matrix metalloproteinase-3 gene alleles.
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PMID:Genetic risk factors for lumbar disc disease. 1201 33

Intervertebral disk disease has multiple radiological expressions and is probably multifactorial, although being generally considered univocal. Mechanical factors have been the best studied etiological factors and appear to be capable of starting and aggravating the different components of disk degeneration. This process also depends on genetic influences such as a collagen type IX mutation, a polymorphism in the aggrecan gene and a polymorphism in the vitamin D receptor gene. Intervertebral disk cells produce numerous cytokines with catabolic and anabolic activity. One of the elements of disk degeneration could be the unbalance between catabolic/inflammatory cytokines (IL1, TNF alpha...) and anabolical/antiinflamatory cytokines (IL 10, IL1 Ra, growth factors...). The main driver force of disk matrix destruction is the unbalance between metaloproteases (collagenases, stromelysines and gelatinases) and its natural inhibitors. It is this process that characterizes the active disk disease. It implies a reduction in the radiological intervertebral space in a few months and a vertebral plate oedema sign in MRI, around degenerated disks. This is clinically manifested as pseudo-inflammatory pain, with increased severity during the morning. These periods of active disk disease respond to non steroidal anti-inflammatory drugs and to steroids, particularly when locally administered. The evidence of the existence of an active disk disease has not only clinical and management pertinence but also scientific, as it allows to better understand the process of disk destruction.
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PMID:[The concept of discolysis in intervertebral disk disease]. 1705 59

This review article describes anatomy, physiology, pathophysiology and treatment of intervertebral disc. The intervertebral discs lie between the vertebral bodies, linking them together. The components of the disc are nucleus pulposus, annulus fibrosus and cartilagenous end-plates. The blood supply to the disc is only to the cartilagenous end-plates. The nerve supply is basically through the sinovertebral nerve. Biochemically, the important constituents of the disc are collagen fibers, elastin fibers and aggrecan. As the disc ages, degeneration occurs, osmotic pressure is lost in the nucleus, dehydration occurs, and the disc loses its height. During these changes, nociceptive nuclear material tracks and leaks through the outer rim of the annulus. This is the main source of discogenic pain. While this is occurring, the degenerative disc, having lost its height, effects the structures close by, such as ligamentum flavum, facet joints, and the shape of the neural foramina. This is the main cause of spinal stenosis and radicular pain due to the disc degeneration in the aged populations. Diagnosis is done by a strict protocol and treatment options are described in this review. The rationale for new therapies are to substitute the biochemical constituents, or augment nucleus pulposus or regenerate cartilaginous end-plate or finally artificial disc implantation..
Pain Pract
PMID:Intervertebral disc: anatomy-physiology-pathophysiology-treatment. 1821 91

Analysis of disc gene expression implicated IL-1 in the development of intervertebral disc degeneration (IDD) in a rabbit stab model. The purpose of these studies is to determine the role of p38 Mitogen Activated Protein Kinase (p38 MAPK) signaling in nucleus pulposus cell response to IL-1, and to compare rabbit nucleus pulposus (rNP) cell responses to IL-1 activation with those in a stab model of disc degeneration. NP cells maintained in alginate bead culture were exposed to IL-1, with or without p38 MAPK inhibition. RNA was isolated for reverse transcription polymerase chain reaction (RT-PCR) analysis of gene expression, conditioned media analyzed for accumulation of nitric oxide (NO) and prostaglandin E-2 (PGE-2), and proteoglycan synthesis measured after 10 days. IL-1 upregulation of mRNA for cycloxygenase-2 (COX-2), matrix metalloproteinase-3 (MMP-3), IL-1, and IL-6, was blunted by p38 inhibition while downregulation of matrix proteins (collagen I, collagen II, aggrecan) and insulin-like-growth-factor I (IFG-1) was also reversed. mRNA for tissue inhibitor of matrixmetalloproteinase-1 (TIMP-1) was modestly increased by IL-1, while those for Transforming Growth Factor-beta (TGF-beta) SOX-9, and versican remained unchanged. Blocking p38 MAPK reduced IL-1 induced NO and PGE-2 accumulation and partially restored proteoglycan synthesis. p38 MAPK inhibition in control cells increased mRNA for matrix proteins (aggrecan, collagen II, versican, collagen I) and anabolic factors (IGF-1, TGF, and SOX-9) from 50% to 120%, decreased basal PGE-2 accumulation, but had no effect on message for TIMP-1, MMP-3, or COX-2. Inhibition of p38 MAPK in cytokine-activated disc cells blunts gene expression and production of factors associated with inflammation, pain, and disc matrix catabolism while reversing IL-1 downregulation of matrix protein gene expression and proteoglycan synthesis. The results support the hypothesis that IL-1 could be responsible for many of the mRNA changes seen in rabbit NP in the stab model of disc degeneration, and uphold the concept that development of molecular techniques to block p38 MAPK could provide a therapeutic approach to slow the course of intervertebral disc degeneration.
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PMID:p38 MAPK inhibition modulates rabbit nucleus pulposus cell response to IL-1. 1830 37

Painful degenerative disc disease is a major health problem and for successful tissue regeneration, MSCs must endure and thrive in a harsh disc microenvironment that includes matrix acidity as a critical factor. MSCs were isolated from bone marrow of Sprague-Dawley rats from two different age groups (<1 month, n=6 and 4-5 months, n=6) and cultured under four different pH conditions representative of the healthy, mildly or severely degenerated intervertebral disc (pH 7.4, 7.1, 6.8, and 6.5) for 5 days. Acidity caused an inhibition of aggrecan, collagen-1, and TIMP-3 expression, as well as a decrease in proliferation and viability and was associated with a change in cell morphology. Ageing had generally minor effects but young MSCs maintained greater mRNA expression levels. As acidic pH levels are typical of increasingly degenerated discs, our findings demonstrate the importance of early interventions and predifferentiation when planning to use MSCs for reparative treatments.
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PMID:MSC response to pH levels found in degenerating intervertebral discs. 1913 33

The manifestation of chronic back pain depends on structural, psychosocial, occupational and genetic influences. Heritability estimates for back pain range from 30% to 45%. Genetic influences are caused by genes affecting intervertebral disc degeneration or the immune response and genes involved in pain perception, signalling and psychological processing. This inter-individual variability which is partly due to genetic differences would require an individualized pain management to prevent the transition from acute to chronic back pain or improve the outcome. The genetic profile may help to define patients at high risk for chronic pain. We summarize genetic factors that (i) impact on intervertebral disc stability, namely Collagen IX, COL9A3, COL11A1, COL11A2, COL1A1, aggrecan (AGAN), cartilage intermediate layer protein, vitamin D receptor, metalloproteinsase-3 (MMP3), MMP9, and thrombospondin-2, (ii) modify inflammation, namely interleukin-1 (IL-1) locus genes and IL-6 and (iii) and pain signalling namely guanine triphosphate (GTP) cyclohydrolase 1, catechol-O-methyltransferase, mu opioid receptor (OPMR1), melanocortin 1 receptor (MC1R), transient receptor potential channel A1 and fatty acid amide hydrolase and analgesic drug metabolism (cytochrome P450 [CYP]2D6, CYP2C9).
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PMID:Current evidence for a modulation of low back pain by human genetic variants. 1922 64

Tendons are dense, fibrous connective tissues that are responsible for transmitting mechanical forces from skeletal muscle to bone. From a clinical perspective, tendinopathy (defined as a syndrome of tendon pain, tenderness and swelling that affects function) is very common, both within the sporting arena and in the workplace. Importantly, proteoglycans are essential components of the tendon extracellular matrix (ECM) and changes in their expression and metabolism/turnover have been associated with tendinopathy. Within tendons, the small leucine-rich proteoglycans (SLPRs), decorin, fibromodulin, lumican and keratocan predominate within tensional regions, while in tendon fibrocartilage, increased concentrations of proteoglycans common to the articular cartilage phenotype are present, including aggrecan, biglycan and proteoglycan 4. However, the rate of proteoglycan turnover within tendon is markedly higher than that of cartilage, mediated via the "aggrecanases," which are constitutively active in the tendon matrix. Data suggest that this increased proteoglycan turnover is likely to be required to maintain normal tendon homeostasis, with perturbations in proteoglycan metabolism contributing to tissue dysfunction. Thus, future studies aimed at furthering our fundamental knowledge of tendon proteoglycan metabolism in health and disease are important in the development of improved treatments for tendon disorders.
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PMID:Metabolism of proteoglycans in tendon. 1942 35

Degenerative diseases are still a challenging issue in clinical therapy; even though in several cases it is possible to treat symptoms, drugs able to block disease progression are lacking at present. Osteoarthritis (OA) and Rheumatoid Arthritis (RA) are degenerative diseases leading to serious cartilage destruction, affecting joint functions and giving rise to restricted movement, pain and chronic disability. Current clinical treatment for arthritis is confined to Non Steroidal Anti-Inflammatory Drugs (NSAIDs), which are effective in treating symptoms but fail to block the progression of the disease. Matrix Metalloproteases (MMPs) inhibitors have been clinically studied as possible drugs for cartilage degradation prevention. However, their clinical use has been limited by severe side-effects. Aggrecan, which plays a fundamental role in maintaining the structural and mechanical properties of cartilage, has recently been found to be specifically cleaved by "aggrecanases". Aggrecanases are multidomain zinc metalloproteases, different from MMPs, which cleave the aggrecan within the interglobular domain (IGD). Aggrecan breakdown at this site has been found to be crucial for cartilage degradation. These new findings re-addressed the interest of the research for new arthritis therapeutic agents focusing on aggrecanases rather than on MMPs. This review is meant to provide a critical appraisal of the ongoing developments of Zn-chelating and non chelating aggrecanase inhibitors, with a particular emphasis on the related structure-activity relationships (SARs), in the light of the protein structural information recently made available.
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PMID:Progress towards the identification of new aggrecanase inhibitors. 1960 88


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