The Effect Of Starvation, Infection, Or Septicaemia Inflammation On Growth Cartilage Plates

From the department of National Institute of Health website PDF HERE

This study I found I felt was important in showing how different types of maladies, whether external in source or internal will affect the growth plates.

Analysis & Interpretation:

The results are obvious but the mechanics are not well known. The researchers found that from stuff like a traumatic episode, or an illness, or from starvation the growth of the skeleton in adolescent lab rats slowed down, but the effect was not so damaging in the long term if the external malady is removed. The researchers conclude with “withdrawal of the somatotrophic hormone of the anterior pituitary gland may initiate the changes in starvation, and possibly also during septicaemia and other illness.” All the signs from studying the metaphysis of the rats showed that chondroplasia was reduced. There was more vascularization of the cartilage and reduced ossification later in the process.

From the discussion, the researchers speculated that “The thinning of the cartilage plate suggests that the normal balance between rates of cartilage growth and bone formation is disturbed, and that osteogenesis is, for a time at any rate, outstripping the provision of the cartilaginous scaffolding upon which the new bone is laid down…For whereas in health the distension and vacuolation of the cartilage cells causes the intercellular matrix to be pressed thin before calcification occurs, in the experimental animals extensive calcification precedes these changes and indeed seems to prevent them from occurring at all”

From careful reading of the study, here is what I have figured out on the detail on how normal cartilage cell go through their life cycle. The cell comes from the reserve zone and eventually reaches the point where both its nucleus and itself increases in size. This seems to come about from these air pockets that develop in the cytoplasm of the cell. The fact that the nucleus grows in size is a bit strange. The nucleus will go through the process of enlarging in size, and then disintegrate and then die completely. The whole structure itself will also increase in size, which we have been calling hypertrophy before. In normal healthy people, I would guese either during or after the nucleus disappears completely, the other sutff inside the cell membrane also disintegrate. The expanding of the cell means that the cell out edges push the extracellular matrix of the cartilage to be thinner. The cell eventually goes away leaving hollow cavities in the cartilage. The stuff like osteoblasts that come from the other side of the bone, from the metaphysis will rise up and fill in the empty cavities building the bone cells which will go in the place of where the cartilage cells used to be at.

From the testing, it seems that chronic starvation has similar effects on the growth plate cartilage as septicaemia. The researchers noted that the growth plate width was smaller, being much thinner. This seems to be from smaller chondrocyte columns. Before in healthy cartilage, the process of calcification would not occur in the cartilage until after the chondrocytes have hypertrophied and then degenerated and died out leaving empty cavities ready for calcification, the growth plate here had calcification going on already in the cartilage that still had the cells who hadn’t even gotten a chance to expand/hypertrophy yet. This means that the amount of longitudinal growth possible from hypertrophied has been stunted. The chondrocytes will have to push against the hardened extracellular matrix which now have calcium in them. In the case of the septicaemia, it seems that the effects are seen after just 24 hours. With healthy cartilage, there is a gradual easily seen change from the first bone formation and where the metaphysis elements first first get into the empty cavities. With starvation and septicaemia, it seems that the line that divides when new bone is formed and the cartilage is far more sharply defined and abrupt with little space in between. The results from chronic illness showed “The growth cartilage plate was very narrow and inactive”. The researchers would conclude that unlike chronic starvation, with acute starvation, from testing the trabecular bone in the metaphysis of growing children, you can detect when the child suffered either starvation, illness, septicaemia, etc. because in that band of region the bone density will be much higher than in the other areas. The child will still be able to get longitudinal growth after say starvation or illness pass but in that area of the bone the signs of something happening is from bone density increases which means that calcification was more serious and that the normal cartilage cell to bone material was disrupted or stunted in some way.



Moyne Institute of Preventive Medicine, Trinity College, Dublin

The effects of a short-lasting period of total starvation, and of pneumococcal septicaemia treated with penicillin, upon the skeletal development of the 25-day-old albino rat have been the subject of a recent experiment (Acheson & Macintyre, 1958; Macintyre, Acheson & Oldham, 1958). Daily records were taken of weight and length of the experimental animals and of their litter-mate controls, and assessments were made of skeletal maturity by radiographing the rats once a week. It was found that the traumatic episode, whether illness or starvation, caused an abrupt slowing of skeletal growth, but that the effect upon skeletal maturation was not so marked. The present paper describes the histological appearances of the tissues in the region of the growth cartilage plate of some of the animals which succumbed during the traumatic episode and of others from a similar experiment carried out more recently.


The normal growth cartilage plate and metaphysis

The growth cartilage plate is a unipolar structure, that is to say, it grows in one direction only. The site of growth is in the reserve layer, where mitosis
occurs, and this is situated in immediate relation to the bony epiphysis. As each new cell forms it pushes away its predecessor, thus forming columns of cartilage cells, first of increasing maturity and later of advancing degeneracy. The cells passing through this cycle make up the serial and columnar layers of the growth cartilage plate. The process of degeneration of the cartilage cells has two distinct characteristics: first the nucleus enlarges, disintegrates, and finally disappears, and secondly, the cell itself becomes vacuolated and greatly enlarged. As a consequence the vessels and osteoblasts of the metaphysis are invading a hollow scaffolding. The uprights of this scaffolding are pressed thin by the vacuolation of the cells between them, but maintain their pliability until their contact with the bone-forming tissue is imminent, when they become calcified lamellae. The dominant cells at the metaphyseal margin are osteoblasts, which are marshalled in their thousands against the calcified lamellae, where they form bone. During rapid growth, which is characteristic of the healthy young animal, calcification does not penetrate far, and much of the cartilaginous matrix between the metaphysis and the reserve layer of the growth cartilage plate is uncalcified. There is, however, an appreciable distance between the earliest new bone and the osteogenic elements which are most advanced into the cartilage. Capillaries can be traced between the delicate newly calcified lamellae, reaching up as far as the degenerate vacuolated cartilage cells. Nowhere does this process of invasion appear to be held back or restricted; in fact the osteogenic tissues give the appearance of growing freely into empty spaces created by the degeneration of the cartilage.

The growth cartilage plate and metaphysis in septicaemia and acute starvation

The changes in the normal pattern which occur in response to septicaemia and to starvation are similar, and will be described together. There is a pronounced decrease in the depth of the growth cartilage plate, which is mostly due to a reduction in the size of the columnar layer. Distended and degenerate cells are no longer to be seen at the metaphyseal margin, nor is the delicate intercellular matrix which characterizes normal growth any longer evident. As a consequence, the calcified cartilage, which penetrates as far as the serial layer of the plate, has lost its filigree appearance, and has become stout and thick; calcification is also visible in many of the septae between the cells of the columnar layer. The effect of this increased penetration of calcification is that whereas in health only degenerate or empty cells are being surrounded by calcification, with slowed growth due to septicaemia or starvation, calcium salts are being laid down in a matrix which has not yet been pressed thin by vacuolation, and cartilage cells which only show the earliest evidence of degeneracy become enmeshed in a calcified network. In septicaemia these appearances manifest themselves within 24 hr. of the animal showing obvious signs of illness. Changes at the chondro-metaphyseal boundary, and in the metaphysis itself, are less dramatic and slower to develop. The line of demarcation between cartilage and newly forming bone is sharper than in health; and the new bone gradually comes nearer to the cartilage, and as this happens the number of osteoblasts becomes reduced. In contrast the number of osteoclasts and chondroclasts increase, and many of these are to be seen at calcified intercellular septa which seem to act as barriers to free capillary and osteoblastic penetration of the cartilage. The newly formed bony trabeculae are much thicker than in healthy animals of the same age, and frequently the transverse as well as the longitudinal septae become ossified.

The growth cartilage plate and metaphysis in chronic illness

One male rat recovered from its initial septicaemia, but a few days later developed an otitis media from which it died aged 36 days, when its litter-mate control, also a male, was sacrificed. Throughout its illness the sick rat was fed on a full laboratory diet which was supplemented with milk given by hand from a dropper. Thus, the considerable interference which took place with its developmental processes cannot be ascribed to starvation in this case. The growth cartilage plate was very narrow and inactive and a deep blue coloration with haematoxylin suggested extensive calcification (P1. 4, figs. 12, 13), a suggestion which was supported by the radiographic appearances (P1. 4, figs. 14, 15). The animal was dead for about 8 hr. before the bones were fixed, so that the changes in cell structure may, in part, be the result of post-mortem degeneration: nevertheless the general acellularity of the metaphysis is unlikely to be entirely due to this cause.


Measurements of the animals subjected to starvation or septicaemia had previously shown that growth stopped almost immediately after exposure to these adverse circumstances (Acheson & Macintyre, 1958). Histological studies now indicate that narrowing and increased calcification of the growth cartilage plate accompany the slowing of growth, and that later there is a decrease in the rate of osteogenesis in the metaphysis. The thinning of the cartilage plate suggests that the normal balance between rates of cartilage growth and bone formation is disturbed, and that osteogenesis is, for a time at any rate, outstripping the provision of the cartilaginous scaffolding upon which the new bone is laid down. The altered pattern of calcification whereby calcium salts are deposited deeper and deeper along the interstitial matrix and through the septa of the growth cartilage plate is likewise explicable in terms of slowed cartilage growth and maturation. For whereas in health the distension and vacuolation of the cartilage cells causes the intercellular matrix to be pressed thin before calcification occurs, in the experimental animals extensive calcification precedes these changes and indeed seems to prevent them from occurring at all.

Osteogenesis continues fairly normally for a while and, as a result, new bone is brought up to the very margin of the cartilage, but then osteoblasts become fewer,
and further osteogenesis only proceeds with the help of numerous chondroclasts, which permit capillary penetration by eroding the hardened cartilage. Finally, however, if the general systemic disturbance continues, the osteoblasts vanish, and the whole process of skeletal development is brought almost to a halt. These histological appearances in experimental animals are consistent with findings in the living child. Increase in stature is a measure of the chondroplasia
in the tibiae, femora and the vertebrae; osteogenesis in the epiphyses can be studied in radiograms where it shows up as a series of shape changes in the shadow of the bony epiphysis (in this context it is usually called ‘skeletal maturation’) (Acheson, 1954, 1957). Study of these two processes has shown that when a child is sick, or when it lives in a poor home, increase in stature suffers a more serious setback than does skeletal maturation (Acheson & Hewitt, 1954; Hewitt, Westropp & Acheson, 1955; Falkner, 1958). Using similar radiographic methods it has been found that in the rat also longitudinal growth seems much more susceptible to interference than skeletal maturation (Acheson & Macintyre, 1958). Thus, the clinical and histological evidence go to support the suggestion already made by Park and his collaborator Follis (Follis & Park, 1952; Park, 1954) that chondroplasia and osteogenesis are dissociable. The nature and degree of dissociation would seem to depend upon the duration and severity of the adverse experience.

Pathogenesis of lines of increased density in radiographs of growing bones

Although Stettner (1920, 1921) and Harris (1926, 1981) both realized that a line of increased density in the radiogram of the metaphysis indicated that a child had
suffered a period of arrested or slowed growth, Follis & Park (1952) were the first to suggest that a dissociation between chondroplasia and osteogenesis was the immediate cause of such lines. They differentiate between a ‘transverse stratum’ of thickened bone, and a ‘growth retardation lattice’ of calcified cartilage, both of which are radio-opaque. The first, they believe, is due to continued osteoblastic activity when cartilage growth has slowed, the second to ‘the continued growth of the cartilage’ with ‘osteoblastic and vascular failure’ (Follis & Park, 1952). They state (loc. cit.) that ‘transverse strata in bones may be the result of illnesses of a most temporary and relatively mild nature’, whereas ‘lattice formation is the result of a growth disturbance of a number of days or weeks’ such as ‘the severe pneumonias following whooping cough’. This hard and fast differentiation between the two is almost certainly artificial. The formation of a calcified lattice (the penetration of calcium salts deep into the cartilage) followed immediately upon systemic disturbance in the rats discussed in this paper; Harris (1933) commented upon similar changes in puppies which were starved for 72 hr. It is a little more than an exaggeration of the physiological calcification of cartilage which is an essential step in normal bone formation; and the thickened trabeculae illustrated in PI. 2, fig. 6, and P1. 3, fig. 11, are evidently the result of ossification occurring on the bulky cartilaginous matrix of the growth retardation lattice. These thickened trabeculae show up very clearly in the radiogram of the metaphysis as a dense shadow and, in animals which survived the systemic disturbance, radiographs taken after recovery revealed a classical ‘line or arrested growth’ in the diaphysis. In cases where the systemic disturbance is protracted and osteoblastic activity diminishes, the retardation lattice will have less and less bone formed on it, and eventually will itself become the principal reason for a dense shadow in an X-ray of the metaphysis. It seems, however, that even in the most unfavourable conditions cartilage growth does not come to a complete halt. Study of serial radiograms of children in prolonged coma due to tuberculous meningitis show that a certain amount of new bone is still being formed at the metaphysis (Acheson, 1958, and unpublished data). In the experimental animal, Winters, Smith & Mendel (1927) and Quimby (1951) found that immature rats, whose weight was held constant for several weeks, continued to enlarge their skeletons a little, and Follis & Park (1952) observed some growth occurring in the ribs of chronically ill children, which post-mortem were found to have a pronounced ‘growth retardation lattice’.

There is a considerable amount of evidence to suggest that the pars anterior of the pituitary gland undergoes atrophic structural changes during starvation which involve, in particular, the acidophil cells (Jackson, 1917; Meyer, 1917; Sedlezky, 1924; Stefko, 1927; Kylin, 1987) and that in such circumstances, there is some withdrawal of the somatotrophic and other hormones (Kylin, 1987; Werner, 1939; Mulinos & Pomerantz, 1940; Stephens, 1941; Vollmer, 1948). Furthermore, it has been shown that anterior pituitary extract, given as a supplement to normal feeding, after the starvation of young rats, improves the quality of recovery (Quimby, 1951; Fabry & Hruza, 1956).

It is well known that normal cartilage growth cannot take place without adequate secretion of somatotrophic hormone (Asling, Simpson, Li & Evans, 1950, 1954; Ray, Simpson, Li, Asling & Evans, 1950; Ray, Asling, Walker, Simpson, Li & Evans, 1954; Simpson, Asling & Evans, 1950), so it may be postulated that the slowing of chondroplasia in the starved rat is due to the withdrawal of the somatotrophic hormone, and that a similar mechanism is brought into action during septicaemia and other illness. The phenomenon may, in fact, be looked upon as an example of what Hubble (1957) has called endocrine homeostasis.


The changes evoked by acute starvation, pneumococcal septicaemia or chronic otitis media, in the growth cartilage plates and metaphyses of immature rats are described. There appears to be immediate slowing of chondroplasia, with more extensive calcification of the cartilage than is normal, followed later by a reduction of osteoblastic activity. The pathogenesis of lines of arrested growth, often visible in the radiogram of the metaphysis of the growing child, is discussed in the light of these findings. It is suggested that withdrawal of the somatotrophic hormone of the anterior pituitary gland may initiate the changes in starvation, and possibly also during septicaemia and other illness.

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