Tissue repopulation during cure of osteopetrotic (mi/mi) mice using normal and defective (We/Wv) bone marrow.

Resorption of petrotic bone in osteopetrotic (mi/mi) mice was brought about by transplantation of bone marrow to X-irradiated recipients. In an attempt to learn more about the donor cell line involved in this process, both normal and defective marrow were used. The consequent repopulation of the lympho-myeloid complex was monitored by isoenzymes of glucose phosphate isomerase. The progress of normal marrow grafts was contrasted with that of a defective marrow (We/Wv). Despite the observation with We/Wv marrow showed reduced ability to form colonies in the spleen of an irradiated recipient, this marrow was as effective as normal marrow in inducing resorption of petrotic bone. The primordial stem cell for the osteoclast (haematopoietic stem cell?) is thus not a CFUS. Chimaeras with resolution of osteopetrosis by We/Wv bone marrow may exhibit erythropoiesis from residual stem cells of the host but leucocytes and platelets from the donor.

Longevity of osteoclasts in radiation chimaeras of osteopetrotic beige and normal mice.

Beige mice, osteopetrotic from incorporated mi/mi genes, and their skeletally normal siblings were X-irradiated and converted to radiation chimaeras by rescue with normal CBA bone marrow. The procedure produced rapid cure of the osteopetrosis. Electron micrographic measurement of the decline in giant lysosomes of the host mice indicated that the longevity of the host's osteoclasts was up to 30 days in the osteopetrotic and 40 days in the skeletally normal mice. In each case the decline was roughly exponential with half-times of about 6 and 8 days respectively. Monogenetic and perhaps polygenetic and teleological factors are invoked. Absence of a latent period before decline in the score seen in the companion paper is attributed to the presence of partially mature osteoclast precursors in bone marrow, not present in spleen.

Osteopetrosis in the IA rat cured by spleen cells from a normal littermate.

Osteopetrosis in ia rats has been cured by combining whole-body irradiation with infusion of spleen cells from a normal littermate. The cure, first seen radiographically and histologically as areas of resorption below the epiphyseal plates of long bones, progressed to produce marrow cavities of normal proportions. Treatment of ia rats with either radiation or normal spleen cells alone was not successful. Furthermore, osteopetrosis was induced in normal littermates when radiation was combined with infusion of mutant (ia) spleen cells. These results show that spleen cells contribute to the resorbing capacity of the skeleton and suggest that osteoclasts might have a hematogenous origin.

Osteoclast kinetics in osteopetrotic (ia) rats cured by spleen cell transfers from normal littermates.

Excessive skeletal mass and reduced bone resorption characteristic of osteopetrosis in young ia rats can be corrected by irradiation and transfer of spleen cells from normal littermates. Cell population analyses and 3H-thymidine (3H-TdR) autoradiographic methods were used to determine osteoclast population dynamics and kinetics of incorporation of nuclei following whole-body irradiation and spleen cell transfer in ia/ia rats and in untreated ia rats and their (ia/+) normal littermates. The numbers of osteoclasts per metaphyseal area were greater in ia rats than in (ia/+) normal littermates. Untreated ia rats had greater rates of incorporation of 3H-TdR-labeled nuclei into osteoclasts but were reduced to near normal values following irradiation and spleen cell transfer. Labeled osteoclast nuclei were first seen in the primary spongiosa of the femoral metaphysis and with increasing time appeared at greater distances from the epiphyseal growth plate as the bones grew In length. These sites of osteoclast neogenesis correspond to sites where restoration of bone resorption is initially seen following bone marrow and splenic transplants in the treatment of osteopetrosis.

Tooth eruption depends on bone resorption: experimental evidence from osteopetrotic (ia) rats.

Resorption of alveolar bone around erupting teeth is known to be independent of tooth eruption. However, the failure of tooth eruption and reduction in bone resorption in the osteopetrotic rat mutation, incisors absent (ia), suggest that tooth eruption depends upon bone resorption. This hypothesis was tested by determining the effects of neonatal restoration of bone resorption in ia rats on eruption of first molars. Newborn ia rats were treated with irradiation and spleen cells and tooth eruption and bone resorption were examined 30 days later. In 24 treated ia rats at least two molars erupted in every rat and all four molars erupted in 14. In 24 untreated ia littermates, no molars erupted in 21, one molar erupted in two and two molars erupted in one rat. All molars erupted in 38 untreated normal littermates. Alveolar bone overlying unerupted first molars in untreated ia rats was not present in treated mutant littermates. Neonatally treated ia rats had osteoclasts with ruffled borders and no skeletal sclerosis by 30 days. Within 48 hours after treatment two types of osteoclasts could be found in treated rats. One type resembled those found in untreated ia littermates and the other those found in normal rats. These data suggest that failure of tooth eruption in ia rats is directly related to the reduction in bone resorption and that alveolar bone resorption is required for tooth eruption.