2.6. Utilización de concentrado
2.6.8. Métodos de formulación de dietas (Ensminger, 1983)
It is apparent from the previous 80 years of reported research, that despite superficial similarities in the biochemistry, histology, histochemistry and ultrastn^ural morphology, each patient has their own unique set of features. This may simply reflect the unique phenotype resulting from individual management and environmental influences (i.e. diet, exercise, degree of mobility) or may represent the more subtle influence of changes at the genetic level that is individual to the patient or family affected with OI. It is well known that the gene mutation in the a 1(1) or a2(I) chain may occur at different places between the C- and N -t^iinal propeptides and that the position of the mutation affects the severity of the phenotype.
This short review demonstrates how confused the literature concerning the morphology and biochemistry of 01 has become, each publication naturally reporting on the most obvious gross pathological features without performing any in-depth histomorphometric analysis to quantitate aspects such as osteoclast and osteoblast number. Only one report has addressed this problem and found that osteoblast and osteoclast number were not significantly raised above the normal (Riley and Brown, 1971).
These morphological studies do, however, still have an important role in understanding the pathogenesis of OI. Discrete ultrastructural changes in cell and extracellular matrix morphology will help understand the effects subsequent to the mutation of the collagen gene. Gene therapy will ultimately be the treatment of choice, but this is many years of research into the future. Drug therapies that influence the secondary changes at the cellular level will only be possible when there is a better understanding of the metabolic changes as visualised by correlative biochemical and ultrastructural studies.
The technology has now sufficiently advanced for quantitative changes in the cells, collagen and bone mineral to be made with some degree of accuracy and precision. The advances in fixation and processing technology for the ultrastructural preservation of cellular morphology are now at their peak and researchers can be confident that artefactual changes are at a minimum. This is important since previous ultrastructural reports could only be accepted to a degree because of the unknown artefactual influences.
The analytical equipment is of a ’new generation’ and only now can bone mineral structure and composition be analysed with confidence. A number of questions relating to various aspects of possible collagen and mineral changes can be asked:
1. What cellular and matrix changes are found in 01? A reappraisal has been made of the ultrastructural changes observed in a number of bone specimens from a spectrum of OI patients with differing clinical types and of different ages. This is more valid than the ’one-off case report that seems to make up the main body of literature on OI. Many correlative observations have been made to confirm previous reports and many new observations have also been made.
2. Can the alteration in type I collagen genes be visualised indirectly by ultrastructural changes in the collagen fibrils? The large body of molecular biological and biochemical data on type I collagen has not been matched by any in-depth correlative ultrastructural data. Image analysis allows a quantitative study of ultrastructural features converting ’pictures to numbers’. Reported here is such a study which reviews previous reports and their conclusions and puts forward new theories in the light of new and conflicting data on the quaternary structure of type I collagen in OI.
3. Would an alteration in bone type I collagen affect the mineral formed in bone? The association between the ultrastructural alteration in type I collagen and the formation of bone mineral has been considered. There has been no in-depth analytical data concerning the structure of calcium-phosphates formed in the presence of abnormal type I collagen in OI. Reported here are a number of analytical techniques looking at different aspects of the mineral composition and crystal structure.
4. Can experimentally induced mutations of type I collagen genes in animal models give rise to a phenotype resembling the human diseae? The revolution in molecular biology has allowed the breeding of mice with abnormalities in their type I collagen genes very similar to those found in many 01 patients. An in-depth histological, ultrastructural and analytical study has been performed on transgenic mice and compared with the data from OI patients. If gene therapy is ever to be a realistic treatment, then a valid experimental model is necessary. Once gene therapy has been ’perfected’ in the mouse, work can begin on erradicating human 01 by such therapy.
The fundamental question of what causes 01 still has not yet been properly addressed. The thesis presented here attempts to put the past work and the present data into context to direct a new assault on the panoramic conundrum of OI.
Figure 1.1: Patient suffering from type III osteogenesis imperfecta. Note the severe deformity of the right arm (arrow) and the sabre-like bowing of the legs.
Figure 1.2: Radiograph of the right arm of the patient in Figure 1.1. Note the deformity of the radius and ulna (arrow).
Figure 1.3: The left arm of the patient in Figure 1.1 showing the characteristic bowing of the bones.
Figure 1.4: Patient suffering from type III or type V OI. Clinical diagnosis can often be a problem in determining the exact type of OI.
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Figure 1.5: "Wavy ribs", characteristic of frequent fracture and repair in type II OI.
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Figure 1.6; The characteristic blue sclera of types IA and IB OI. The blueness is due to the colour of the choroid showing through.
Figure 1.7: Brittle and discoloured teeth are characteristic of types I, III and IVB 01.
Figure 1.8: The management of 01 involves cutting the deformed bones into segments and placing rods through them to straighten and support them. This radiograph shows the radius and ulna from the patient in Figure 1.1, with rods in them.