The intervertebral disc is a cartilaginous structure that resembles articular cartilage in its biochemistry, but morphologically it is clearly different. It shows degenerative and ageing changes earlier than does any other connective tissue in the body. It is believed to be important clinically because there is an association of disc degeneration with back pain. Current treatments are predominantly conservative or, less commonly, surgical; in many cases there is no clear diagnosis and therapy is considered inadequate. New developments, such as genetic and biological approaches, may allow better diagnosis and treatments in the future.

/pdf/degeneration-of-the-intervertebral-disc-297lygwdik.pdf

Degeneration of the intervertebral disc

http://www.gs.washington.edu/academics/courses/pbyers/53105/myllyharju.pdf

Collagens, modifying enzymes and their mutations in humans, flies and worms

Study design A cross-sectional population study of magnetic resonance imaging (MRI) changes. OBJECTIVE.: To examine the pattern and prevalence of lumbar spine MRI changes within a southern Chinese population and their relationship with back pain. Summary of background data Previous studies on MRI changes and back pain have used populations of asymptomatic individuals or patients presenting with back pain and sciatica. Thus, the prevalence and pattern of intervertebral disc degeneration within the population is not known. Methods Lumbar spine MRIs were obtained in 1043 volunteers between 18 to 55 years of age. MRI changes including disc degeneration, herniation, anular tears (HIZ), and Schmorl's nodes were noted by 2 independent observers. Differences were settled by consensus. Disc degeneration was graded using Schneiderman's classification, and a total score (DDD score) was calculated by the summation of the Schneiderman's score for each lumbar level. A K-mean clustering program was used to group individuals into different patterns of degeneration. Results Forty percent of individuals under 30 years of age had lumbar intervertebral disc degeneration (LDD), the prevalence of LDD increasing progressively to over 90% by 50 to 55 years of age. There was a positive correlation between the DDD score and low back pain. L5-S1 and L4-L5 were the most commonly affected levels. Apart from the usual patterns of degeneration, some uncommon patterns of degeneration were identified, comprising of subjects with skip level lesions (intervening normal levels) and isolated upper or mid lumbar degeneration. Conclusion LDD is common, and its incidence increases with age. In a population setting, there is a significant association of LDD on MRI with back pain.

Prevalence and pattern of lumbar magnetic resonance imaging changes in a population study of one thousand forty-three individuals.

Study design A review of current knowledge and opinions concerning the biologic changes that take place during development, maturation and degeneration of the intervertebral disc. Objective To provide an overview of the changes that occur in structure and composition of the extracellular matrix of the intervertebral disc and to explain the origin of such changes and their functional consequences. Summary of background data The structure of the intervertebral disc, and, in particular, the composition of its extracellular matrix, changes throughout life, ultimately resulting in tissue degeneration in the adult. Methods A review of the published scientific literature. Results In the young disc, the outer anulus fibrosus and inner nucleus pulposus have clear physical and molecular properties, although these differences become less distinct in the adult. The age changes are due to variations in both the abundance and structure of the macromolecules, particularly aggrecan, and the structural variations may be due to changes in both synthesis and degradation. It is not clear how many of the changes are by design to adapt to the altered environment of the growing spine. However, it is commonly thought that the degradative changes are detrimental to disc function, a property that is exacerbated by the inability of the mature avascular disc to remove and replace accumulated degradation products. The rate at which these detrimental changes occur may vary between individuals because of genetic, biomechanical, and nutritional differences. Such changes are thought to form the basis of tissue loss associated with disc degeneration. Conclusion Changes in intervertebral disc structure throughout life ultimately result in tissue degeneration and the need for medical intervention. Current research is aimed at trying to restore the integrity of the degenerate disc matrix by biologic means, although at present it is not clear what the structure of the most appropriate repair tissue should be or how it can be achieved.

Biology of intervertebral disc aging and degeneration: involvement of the extracellular matrix.

The collagen superfamily of proteins plays a dominant role in maintaining the integrity of various tissues and also has a number of other important functions. The superfamily now includes more than 20 collagen types with altogether at least 38 distinct polypeptide chains, and more than 15 additional proteins that have collagen-like domains. Most collagens form polymeric assemblies, such as fibrils, networks and filaments, and the superfamily can be divided into several families based on these assemblies and other features. All collagens also contain noncollagenous domains, and many of these have important functions that are distinct from those of the collagen domains. Major interest has been focused on endostatin, a fragment released from type XVIII collagen, which potently inhibits angiogenesis and tumour growth. Collagen synthesis requires eight specific post-translational enzymes, some of which are attractive targets for the development of drugs to inhibit collagen accumulation in fibrotic diseases. The critical roles of collagens have been clearly illustrated by the wide spectrum of diseases caused by the more than 1,000 mutations that have thus far been identified in 22 genes for 12 out of the more than 20 collagen types. These diseases include osteogenesis imperfecta, many chondrodysplasias, several subtypes of the Ehlers-Danlos syndrome, Alport syndrome, Bethlem myopathy, certain subtypes of epidermolysis bullosa, Knobloch syndrome and also some cases of osteoporosis, arterial aneurysms, osteoarthrosis, and intervertebral disc disease. The characterization of mutations in additional collagen genes will probably add further diseases to this list. Mice with genetically engineered collagen mutations have proved valuable for defining the functions of various collagens and for studying many aspects of the related diseases.

https://www.tandfonline.com/doi/pdf/10.3109/07853890109002055

Collagens and collagen-related diseases

Intervertebral disc disease is one of the most common musculoskeletal disorders. A number of environmental and anthropometric risk factors may contribute to it, and recent reports have suggested the importance of genetic factors as well. The COL9A2 gene, which codes for one of the polypeptide chains of collagen IX that is expressed in the intervertebral disc, was screened for sequence variations in individuals with intervertebral disc disease. The analysis identified a putative disease-causing sequence variation that converted a codon for glutamine to one for tryptophan in six out of the 157 individuals but in none of 174 controls. The tryptophan allele cosegregated with the disease phenotype in the four families studied, giving a lod score (logarithm of odds ratio) for linkage of 4.5, and subsequent linkage disequilibrium analysis conditional on linkage gave an additional lod score of 7.1.

http://science.sciencemag.org/content/sci/285/5426/409.full.pdf

An Allele of COL9A2 Associated with Intervertebral Disc Disease

Previously, an assay called conformation sensitive gel electrophoresis (CSGE) was developed for scanning PCR products for the presence of single-base and larger base mismatches in DNA. The assay was based on the assumption that mildly denaturing solvents in an appropriate buffer can accentuate the conformational changes produced by single-base mismatches in double-stranded DNA and thereby increase the differential migration in electrophoretic gels of heteroduplexes and homoduplexes. Here the sensitivity of assays by CSGE was improved by limiting the maximal size of the PCR products to 450 bp and making several changes in the conditions for PAGE. With the improved conditions, CSGE detected all 76 previously identified single-base changes in a large series of PCR products from collagen genes that contain multiple exons with highly repetitive and GC-rich sequences. In a survey of 736 alleles of collagen genes, CSGE detected 223 unique single-base mismatches that were confirmed by nucleotide sequencing. CSGE has the advantage over other methods for scanning PCR products in that it is simple, requires no special preparation of PCR products, has a large capacity, and does not use radioactivity.

https://www.pnas.org/content/pnas/95/4/1681.full.pdf

Conformation sensitive gel electrophoresis for simple and accurate detection of mutations: Comparison with denaturing gradient gel electrophoresis and nucleotide sequencing

The human COL11A2 gene structure indicates that the gene has not evolved with the genes for the major fibrillar collagens

Complete structure of the human COL11A2 gene: the exon sizes and other features indicate the gene has not evolved with genes for other fibriller collagens.

Tero Pihlajamaa

Papers

An Allele of COL9A2 Associated with Intervertebral Disc Disease

Conformation sensitive gel electrophoresis for simple and accurate detection of mutations: Comparison with denaturing gradient gel electrophoresis and nucleotide sequencing

The human COL11A2 gene structure indicates that the gene has not evolved with the genes for the major fibrillar collagens

Complete structure of the human COL11A2 gene: the exon sizes and other features indicate the gene has not evolved with genes for other fibriller collagens.