Talk:Paper - On the mechanism controlling the growth in length of the long bones (1934)

ON THE MECHANISM CONTROLLING THE GROWTH IN LENGTH OF THE LONG BONES

By HANS SELYE, M.D. Department of Biochemistry, McGill University, Montreal, Canada

Ir has been well known, since the classical experiments of John Hunter(1) in 1794, that the growth in length of the long bones occurs only at the junction cartilages. These structures are especially adapted for the process of endochondral ossification leading to the apposition of new bone in a certain direction. It seems also that the normal function of these growth cartilages is dependent upon the pituitary growth hormone. The latter, however, is a_ general growth stimulus and as such dependent again on the junction cartilage for the determination of the direction of the growth.

The generally accepted conception is that the junction cartilages are highly specialized structures, formed during foetal life, and that therefore the growth of the long bones in length is only possible as long as derivatives of the original junction cartilage anlage are present. This conception has been substantiated by the observations in human subjects and in animals that experimental or pathological destruction of the epiphyseal cartilages stops the growth in length of the injured bone for ever.

The high degree of specialization of these structures as compared with other types of cartilage is not only suggested by their singular histological appearance, and by the observation mentioned above, but also by transplantation experiments, which show that their structure and appearance is not changed if their relation to the shaft of the bone is altered. Thus Helferich @) and later Rehn and Wakabayashi (3) showed that autoplastic transplants of the epiphyseal cartilage continue to form new bone if the graft takes. Still more interesting in this respect are the experiments of Briicke(4) who reimplanted the junction cartilage of the ulna and radius in rabbits after rotating them through 180 degrees. He found that after this operation bone apposition took place only on the side originally facing the diaphysis, so that the epiphyses became greatly elongated. Thus the orientation of the cartilage columns was not changed.

Experiments performed in this laboratory lead us to believe that during the first weeks of life the autonomy of the bone, in so far as the determination of its growth in length is concerned, is much greater than has been suspected. It seems to us that the growth of very young bones is largely independent both of the pituitary growth hormone and of the derivates of the epiphyseal cartilage anlage. We have already published our experiments on the first point, showing that rats hypophysectomized at the age of 21-24 days may continue to grow

Anatomy LXV 19 290 Hans Selye

for several weeks (5). In the present paper we intend to report our observation that even removal of the original anlage of the epiphyseal cartilage does not necessarily stop the growth in length of immature bones.

Twenty-five rats, 12-15 days of age, were used. In fifteen of them the right leg was amputated, with transverse section, above the junction cartilage of the femur, so that the entire growth-zone was removed. The animals were killed at intervals and the amputation stumps examined histologically. A few days after operation the end of the stump was closed by proliferating spindle cells showing all the morphological characteristics of osteoblasts. Somewhat later, after 8-11 days, these osteoblasts begin to transform into chondroblasts and

Fig. 1. Amputation stump 8 days after operation; in the lower part of the field is the marrow cavity; above this a layer of irregular trabeculae can be seen, while the top part of the field shows numerous osteoblasts and chondroblasts, with a small cartilage islet in the centre.

more or less irregularly arranged islets of cartilage appear around the bone strings (see fig. 1). Still later, after 19-25 days, the end of the bone is closed by a regular layer of cartilage, the proximal part of which shows the typical structure of the growth-zone (see fig. 2). Measurements of the length of the femur stump at operation and at autopsy show that this cartilage leads to very active growth in length.

In a second series, 10 rats 14 days of age were used. The experiment was performed under the same conditions as the previous one, but the femur was amputated with an oblique section. The result was that numerous osteoclasts formed on the pointed end of the stump and led to its rapid resorption. The bone did not grow in length until the processes of transformation on the stump made the end of the bone exactly perpendicular to the length axis of the shaft. Growth in Length of Long Bones 291

Then a growth cartilage formed—in very much the same way as in the previous series—and the growth in length was resumed (see fig. 3): Similar experiments on rats more than 5 months of age have never been successful. These results may be compared with Child’s demonstration that diagonal slices from Planarian worms retain their original axis in regeneration.

Fig. 2. Amputation stump 19 days after operation, showing newly formed typical growth cartilage line.

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Fig. 3. Diagram showing formation of new junction cartilage line on an obliquely cut amputation stump.

A. Normal bone; broken line indicates plane of amputation. B. Stump immediately after amputation. C. Beginning reconstruction of the stump.

D. The amputation stump with newly formed, regular growth-zone, developed in the same plane as the epiphyseal cartilage which has been removed from the original bone.

These experiments show that in early post-foetal life the long bones are to a great extent autonomic in their growth and probably much more under the controlling influence of formative centres situated within themselves than in later stages of development. The young animal’s independence of endocrine control may perhaps be regarded as an instance of phylogenetic recapitula- tion (6).

19—2 292 Hans Selye

SUMMARY

If the distal end of the femur is removed in rats during the first few weeks of life a new growth cartilage is formed and the growth in length is resumed.

This new growth cartilage forms always in a plane at right angles to the long axis of the shaft, quite irrespective of the plane of amputation.

REFERENCES

(1) Hunter, J. (1837). The Works of John Hunter, ed. by J. F. Palmer. London: Longmans. (2) HetrericH. Quoted by Briicke (4).

(3) Rean and WaxkaBayasHI (1912). Arch. f. klin. Chirurg. xcvm.

(4) Bricks (1931). Virchows Arch. f. path. Anat. CCLXxIx, 641.

(5) Cotiir, SELYE and THomson (1933). Nature, cxxx1, 56.

(6) THomson (1932). Nature, cxxx, 543.