Investigations on Congenital and Induced Osteopetrosis

Investigations on Congenital and Induced Osteopetrosis DONALD G. WALKER Department of Anatomy, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 Osteopetrosis, or marble bone roid body and bone obtained from thermore, the fact that bone ero disease, is a disturbance of skeletal a normal littermate, little or no evi sion failed to occur, even when the development in which the rate of dence of bone erosion was demon parathyroid body was in direct con bone resorption fails to keep pace strable at the end of the culture tact with the calvarial bone, rules with the rate of bone formation. period. out the possibility that a parathor Bone matrix accumulates exces In another experiment (Barnicot, mone-destroying tissue intervenes sively throughout the skeletal sys 1941) , ribs from a grey-lethal between the gland and its target. tem, causing damage to neighbor mouse were transplanted into a In seeking additional information ing tissues-particularly the dental, normal littermate. When exam as a basis for an alternative to hematopoietic and nervous tissues. ined histologically two weeks later, Barnicot's explanation, I first de The line of investigation on the rib grafts appeared normal. voted my efforts to measuring the osteopetrosis which has led to the In the reciprocal transplantation, plasma calcium concentration in current point of view that the thy in which a rib from a normal untreated animals of both sexes at roid gland represents the primary mouse was cultured subcutaneously various ages. All of the grey-lethals site of the disturbance was initiated in a grey-lethal littermate, the graft examined, including the younger soon after an experimental animal underwent osteopetrotic changes. well-nourished group, were found became available. In 1935 Hans From these results it was evident to be hypocalcemic, with a total Grlineberg described a mutant of that the failure of bone remodelling plasma calcium averaging 20% be the house mouse, named the grey in the osteopetrotic mouse was not low the mean value of plasma cal lethal, whose skeletal system explicable on the basis of incompe cium obtained from the normal showed manifestations of osteope tence on the part of either osteo littermates. In response to a single trosis which closely resembled clasts or the chief cells of the para injection of PTE at a dosage of those in man originally described thyroid gland. In an effort to 5 units/ gm of body weight, the by Albers-Schonberg in 1904. promote the resorption of the ex plasma calcium level of normal Barnicot (1948), working at Uni cess bone, Barnicot ( 1945) dis mice one to four weeks of age versity College, was the first to covered that the grey-lethal mouse increased by 100% in 18 hours show that osteopetrosis is an endo suffered no ill effects from repeated and 200% in 36 hours. Grey-lethal crine disorder. His most interesting injections of parathyroid extract mice given the same dosage of work involved the reciprocal trans (PTE) at a dose level that was PTE showed a maximum elevation plantation of parathyroid tissue and toxic enough to kill the normal of plasma calcium concentration of bone. In one experiment he took siblings after only one exposure. only 25 % , reached within 18 from a grey-lethal mouse a piece of Thus, Barnicot terminated his study hours. By 36 hours the plasma cal calvarial bone and a parathyroid of the grey-lethal mouse by sug cium fell to a tetanic threshold body, attached the gland to the gesting that osteopetrosis is a form level. In response to injections of surface of the bone, and implanted of hypoparathyroidism which can PTE administered at intervals of the graft intracerebrally in a normal not be cured by parathormone 12 hours for as long as eight days, sibling. A few days later, when the therapy alone. the grey-lethal mouse never be graft was removed for examination, There are two reasons why the came hypercalcemic, whereas the the calvarial bone was found to "hypoparathyroid hypothesis" is normal littermates invariably died have been perforated in the region not tenable. It has long been known by the second or third day with underlying the parathyroid gland. that normal mice which have been extreme hypercalcemia and nephro When the grey-lethal mouse was thyroparathyroidectomized at birth calcinosis. used as host for grafting a parathy- do not develop osteopetrosis. Fur- In an effort to locate the basis MCV QUARTERLY 5(1): 17-19, 1969 17 OSTEOPETROSIS for the great resistance to parathy activity than to decreased osteo three other mutants with osteope roid hormone observed in the grey clastic activity. In attempting to trosis have recently been studied. lethal, a thorough cytological and locate an abnormally enlarged The implication of the findings ob histochemical assessment of osteo source of an osteoblastic-stimulat tained in microphthalmic and os clasts was conducted. Bone samples ing factor, the pituitary and thyroid teosclerotic mice is essentially the obtained from grey-lethals between glands were surveyed thoroughly same as the implication of the find 12 and 24 hours after the admin by means of light and electron mi ings obtained from the grey-lethal istration of parathormone showed croscopy. No evidence of increased (S. C. Marks and D. G. Walker, widespread or intense signs of os somatotroph or follicle cell activi unpublished data) . teoclastic activity, including an ex ties was disclosed; however, a Rabbits with hereditary osteope ceptionally high level of collagen parafollicular cell hyperplasia was trosis as well as the mice with con ase (Walker, l 966a). However, in discovered in the parathormone genital osteopetrosis are hypocal the untreated mice and at all time treated grey-lethals. In electron mi cemic throughout life. They fail points later than 24 hours in the crographs the parafollicular cell to develop hypercalcemia even parathormone-treated animals, os differs from the follicle cell in when placed on an intensive para teolytic activity was subnormal, several respects. It is of a larger thormone regimen. However, the whereas the signs of increased os size, has a shape that is oval instead abnormal tolerance · to parathor teoblastic activity were most im of polygonal, and occupies a more mone in the rabbit does not seem pressive. The endosteum was hyper peripheral (parafollicular) posi to be related to parafollicular cell plastic, containing several layers tion, resting against the basement · activity, as it was in osteopetrotic of osteoprogenitor cells as well as membrane of the follicle but never mice. The parafollicular cell popu a prominent layer of large osteo bordering directly on the colloid. lation is not elevated in the rabbits, blasts; adjacent to the endosteum Unlike all other epithelial cells, the and, even after thyroidectomy or was a thick seam of osteoid. The parafollicular cells are devoid of thyroparathyroidectomy, the osteo hyperplastic endosteum was dis intercellular attachment devices, petrotic rabbits are refractory to tributed over most of the trabecular such as desmosomes, light junc the influence of parathormone. Fur surface in the grey-lethal bones. In tions, and interlocking processes. thermore, the rabbit mutants never order to place the osteogenic eval The most distinctive feature of the show increased osteogenic activity; uation on a quantitative basis, I parafollicular cells is the abundance in fact, according to tritiated pro employed tritiated proline incor of cytoplasmic secretory vesicles. line incorporating studies carried poration studies. Tritiated proline These vesicles are about 0.2µ, in out at various ages from birth to was administered intraperitoneally diameter and appear to be empty one month of age, their capacity to at a dosage of 4µ,c to 8µ,c per but may contain thyrocalcitonin, make bone matrix is only about gm of body weight, and the animal a substance of homogeneous ap half that of the normal littermates. was sacrificed six hours later. pearance and low electron opacity. Osteopetrotic rabbit bones show re Samples of calvarial and tibial bone Since the parafollicular cell has duced numbers of osteoblasts, os were pulverized, extracted in ether, been shown to be the source of teoclasts of abnormal appearance suspended in scintillation fluid and thyrocalcitonin, the presence of a and an abundance of mesenchyme counted by means of a well-type parafollicular cell hyperplasia may throughout the intertrabecular automated scintillation counter. The represent an excessive capacity to spaces (D. G. Walker and R. R. counts obtained from the untreated produce thyrocalcitonin. Chronic Fox, unpublished data) . animals indicated that the grey hypercalcitoninemia would be as On the basis of the fragmentary lethal incorporated 50% more of sociated with sustained hypocal data available at present, the pri the 3H-proline into bone matrix cemia, hypophosphatemia, and a mary defect in hereditary osteo than the normal control. Parathy retardation of bone resorption. All petrosis of the rabbit appears to be roid hormone was found to depress of these signs are characteristic of located in osseous tissue rather incorporation in the normal by osteopetrosis as manifested in the than in the endocrine system. about 50% but in the grey-lethal grey-lethal mouse. The increased Recently, osteopetrosis has been by only about 15% (Walker, rate of bone formation observed in induced in normal mice (S. C. 1966b). the grey-lethal might indicate that Marks, unpublished data), rabbits According to our interpretation thyrocalcitonin has a dual action on and rats (D. G . Walker and M.A. of the results of the evaluation of bone-inhibiting osteolytic activity, Shepp, unpublished data) by means osteolytic and osteogenic activities yet stimulating osteogenic activity of daily injections of PTE at the in the osteopetrotic mouse, the im -a combination of effects di moderately low dose level of 0.5 balance leading to the excessive ac ametrically opposed to the effects of units/ gm of l:\ody weight.

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