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PubMed1982

Gene dependent differences in malignant osteopetrosis as evidenced by cellular induction of the disease.

Osteopetrosis was induced in lethally irradiated normal rats by cell infusion prepared from spleens of the osteopetrotic (op) mutant littermates. However, similar attempts to induce osteopetrosis in another strain of osteopetrotic rats, namely the "toothless" (tl) rats, were unsuccessful. This discrepancy between op and tl rats with regard to the transmission of the disease to normal littermates, parallels the response of the respective mutants to treatment by normal bone marrow cells: the op rat is cured, not the tl rat. The present findings confirm the cellular origin of osteopetrosis in the op rat, whereas the origin of the defect in the tl mutant remains obscure.

Animals↗

PubMed1977

Skeletal and reticuloendothelial imaging in osteopetrosis: case report.

Skeletal and reticuloendothelial images, using Tc-99m HEDP and Tc-99m sulfur colloid respectively, were obtained from two adult patients with osteopetrosis. Skeletal images demonstrated increased activity in multiple fracture sites, in mandibular osteomyelitis, in ends of splayed long bones adjacent to joints, and in the epiphyseal ends of short tubular bones. The remainder of the skeleton involved with osteopetrosis showed no generalized increased uptake of Tc-99m HEDP. These findings indicate that metabolic activity in this disease is abnormally increased in the usual areas of bone growth but appears normal elsewhere. Reticuloendothelial imaging showed an almost total lack of activity in the axial and peripheral skeletal marrow space. Anemia, however, was only moderate in these patients. Skeletal scintigraphy may be useful to evaluate the presence and extent of the frequent complications of osteopetrosis, namely fractures and osteomyelitis.

Adult↗

PubMed1997

[A case of osteopetrosis with an abnormal CK-MB/T-CK ratio].

Creatine kinase (CK)-MB subunit has been recognized as a useful marker for acute myocardial infarction (AMI). However, we recently experienced one case of osteopetrosis with moderately high CK-MB and an abnormal (more than 100%) CK-MB/total (T)-CK ratio without evidence of AMI in a medical examination. We have already experienced 17 cases with an abnormal CK-MB/T-CK ratios in addition to the present case. Those cases were patients with malignant tumor with metastasis (n = 13), leukemia (2), liver cirrhosis (1), and cerebral death (1), and thereby the band of macro-CK was found in the electrophoresis. However, we detected neither the band of macro-CK nor the abnormal levels of tumor markers such as CEA, alpha-fetoprotein, CA-19-9 in the present case. Instead of the macro CK, the high level of CK-BB was detected in electrophoresis. In the medical examination, especially in screening tests, the CK-MB was generally assayed with use of the immunoinhibition method in automated analyzers. The method principle was based on the absence of CK-BB in the patient serum. Since the patient had the past history of pathological fracture in his boyhood, this patient was diagnosed as osteopetrosis. These results suggest that we must consider the possibility of osteopetrosis when an abnormal CK-MB and CK-MB/T-CK ratio without evidence of serious diseases were found. This is simply because of the assay method of immunoinhibition for CK-MB activity.

Adult↗

PubMedDate not supplied

Osteopetrosis in children.

Over a 10-year period, 28 Arab children with autosomal recessive osteopetrosis were seen in two hospitals in Riyadh, Saudi Arabia. Eighteen (64%) had osteopetrosis associated with metabolic acidosis probably due to a renal tubular defect; nine (32%) had a malignant infantile form of osteopetrosis and one had a mild form with delayed onset. Parental consanguinity was 56% and 40% among patients with and without acidosis respectively. Somatic and psychomotor retardation and recurrent bone fractures were common in both groups. Dental caries, cerebral calcification and optic atrophy were more frequent in patients with acidosis, while anaemia, hepatosplenomegaly and deafness were more common in patients without acidosis. To guarantee optimal rehabilitation, children with this progressive disease require an early multiteam approach.

Acidosis, Renal Tubular↗

PubMed2006

Resolution of optic nerve edema and improved visual function after optic nerve sheath fenestration in a patient with osteopetrosis.

PURPOSE: To describe the outcome of a patient with visual loss and optic nerve edema that resulted from osteopetrosis who underwent an optic nerve sheath fenestration (ONSF). DESIGN: Interventional case report. METHODS: A 33-year-old man with osteopetrosis had bilateral visual field loss and optic nerve edema. Computed tomography and magnetic resonance imaging demonstrated open optic canals. Although a lumbar puncture showed a normal opening pressure, there were other findings that were suggestive of increased intracranial pressure. The patient elected to undergo a unilateral optic nerve sheath fenestration. RESULTS: After ONSF, the patient experienced markedly improved visual acuity, visual field, and optic nerve appearance. CONCLUSION: Individuals with visual loss and optic disk edema that is associated with osteopetrosis may benefit from ONSF if the optic canals appear to be open and the optic nerve edema is thought to be related to increased intracranial pressure.

Adult↗

PubMed1950

Hereditary osteopetrosis of the rabbit. III. Pathologic observations; skeletal abnormalities.

Gross and microscopic observations on the skeleton of rabbits with hereditary osteopetrosis have been described. All the bones were invariably and similarly affected. The outstanding abnormalities included the persistence of spongy bone and the presence of fibrous tissue together with the failure of development of a marrow cavity and medullary marrow. The amount of hemopoietic tissue, which was present only in comparatively small foci, was greatly reduced. The character of the lesions and their development as determined by examination of material at various stages of the disease suggested that the essential defect concerned the mesenchymal cell. The pathologic features observed generally resembled those of human osteopetrosis as did the manifestations of the disease during life (1, 2).

Animals↗

PubMed1981

Osteopetrosis of the temporal bone.

Osteopetrosis is a rare hereditary disorder of bone development. We examined the right temporal bone of a 17-year-old boy with recessive osteopetrosis and a conductive hearing loss and describe the histopathologic characteristics. The conductive deafness in this case was caused primarily by recurrent otitis media.

Adolescent↗

PubMed1982

Osteomyelitis of the mandible. An initial feature in late-onset osteopetrosis.

Osteopetrosis is a rare disease that may be seen with numerous disorders referable to the head and neck. It occurs in both a malignant and a benign form. The benign form is consistent with a long life span and, when clinically manifest, often does so as osteomyelitis of the mandible. An awareness of this association greatly simplifies diagnosis through standard osseous roentgenograms. The findings of osteopetrosis so characteristic on standard osseous roentgenograms may be inapparent if only mandibular roentgenograms are obtained.

Humans↗

PubMed1996

Cytophilic immunoglobulin G binding on neutrophils from a child with malignant osteopetrosis who developed fatal acute respiratory distress mimicking transfusion-related acute lung injury.

A 16-month-old boy, diagnosed at age 3 months with osteopetrosis, was treated since age 6 months with rhIFN-gamma in combination with rhM-CSF. The child developed acute respiratory distress within 1 hr of a paternal platelet transfusion. Both the child and the father were blood group type O, and platelets were collected the previous day from the father. Chest X-ray revealed right pulmonary consolidation and a complete "whiteout" on the left. By 24 hr, the lungs had the appearance of adult respiratory distress syndrome (ARDS). Over the course of the next 11 days, the child remained intubated and hypotensive, and died of respiratory insufficiency 11 days later. ARDS was confirmed at autopsy. Pre- and posttransfusion patient's sera, as well as paternal serum, were tested by granulocyte agglutination and flow cytometry against granulocytes (PMN) from the patient, father, mother, and routine cell-panel donors and lymphocytes for the presence of neutrophil-specific and lymphocyte (HLA) antibodies, to rule out classical transfusion-related acute lung injury (TRALI). Both the patient's and the paternal sera were devoid of antibodies, but the patient's neutrophils demonstrated strong binding of cytophilic IgG accompanied by extremely low serum IgG and IgG1 levels. Since rhIFN-gamma is known to upregulate Fc gamma receptor type I (Fc(gamma)RI) with high affinity for IgG1, the binding of cytophilic IgG suggests that the patient's neutrophils may have been activated in vivo. The case report of another child with osteopetrosis has also been described. Although the blood specimen was not available for serological studies, this 4 1/2-year-old child treated with rhIFN-gamma and rhM-CSF also died of adult respiratory distress syndrome, with similar clinical presentations.

Adult↗

PubMed2001

Spontaneous mutation in Mitf gene causes osteopetrosis in silver homozygote quail.

Silver homozygous quail was recently reported to have mutations in Mitf gene. Although numerous mutations in Mitf gene have been reported in mice, no mutations corresponding to the mutation in the homozygous silver (B/B) quail in Mitf gene have been reported to cause defects in pigmentation and bone. Therefore, we investigated the bones of the B/B homozygotes. Comparison of the bones of the B/B homozygotes with those of wild-type by X-ray examination revealed osteopetrosis in the long bones of B/B homozygotes. However, osteopetrosis in B/B homozygotes was less severe than that observed in mi/mi mice. Histological examination showed that there were less TRAP-positive multinucleated cells in the trabecular bones in B/B homozygote tibia than in the wild type. In vitro osteoclastogenesis study also suggested that formation of TRAP-positive multinucleated cell was suppressed in the marrow cells of the long bones of the B/B homozygotes. Furthermore, overexpression of chicken Mitf via retroviral transfection into B/B homozygote bone marrow cells in cultures increased the number of TRAP-positive cells 2-3 fold more than that in control. These results indicated that in addition to the previously reported defect in melanogenesis, osteoclastogenesis was inhibited in B/B homozygotes. These results indicate that the novel mutations in Mitf gene observed in the B/B homozygote quail impair osteoclastic bone resorption.

Aging↗

PubMed1976

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.

Animals↗

PubMed1978

Studies of the mechanism of spleen cell cure for osteopetrosis in ia rats: appearance of osteoclasts with ruffled borders.

After ia (osteopetrotic) rats receive whole body radiation and an injection of spleen cells from a normal littermate, the dense, sclerotic skeleton characteristic of osteopetrosis is rapidly remodeled and becomes normal in appearance radiographically and histologically within three weeks. The mechanism of this skeletal transformation has been explored in cured ia rats by light and electron microscopic examination of osteoclasts. In ia rats less than 25 days of age, osteoclasts viewed by electron microscopy lack a ruffled border - the extensive elaboration of plasma membrane next to the bone surface. Cured ia rats have osteoclasts with ruffled borders indistinguishable from those of normal littermates. In ia rats that receive only 600 rads whole body radiation, osteoclasts are still present three weeks later, but appear abnormal by light microscopy, with dense nuclei and lacking cytoplasmic vacuoles next to the bone surface. Cured ia rats have two types of osteoclasts, one type indistinguishable from osteoclasts of normal littermates by light microscopy, the other resembling osteoclasts of ia rats that received radiation only. These data indicate that the mechanism of the spleen cell cure for osteopetrosis in ia rats is rapid remodeling of the skeleton produced by osteoclasts with ruffled borders. Whether normal spleen cells produce these osteoclasts directly by cell division or indirectly by elaboration of some unknown local factor required for formations of ruffled borders by ia osteoclasts is not known.

Animals↗

PubMed1978

Studies of the cellular cure for osteopetrosis by transplanted cells: specificity of the cell type in ia rats.

Spleen cells from normal rats are known to cure osteopetrosis in ia littermates within 3 weeks. In this study cell suspensions from liver, thymus, bone marrow, salivary gland, skeletal muscle and brain from normal rats were tested for their ability to cure osteopetrosis in ia littermates whose ability to reject these cells had been suppressed by whole-body irradiation. Cells from liver, thymus and bone marrow cured the disease as effectively as spleen cells from normal littermates. Mutants that received cells from salivary gland, muscle and brain remained osteopetrotic. These data suggest that some cell found in spleen, liver, thymus and bone marrow of 10-day-old normal rats, such as a lymphoid cell or stem cell, can restore hemopoiesis and bone resorption in osteopetrotic (ia) rats.

Animals↗

PubMed2004

Carbonic anhydrase II deficiency syndrome (osteopetrosis with renal tubular acidosis and brain calcification): novel mutations in CA2 identified by direct sequencing expand the opportunity for genotype-phenotype correlation.

The carbonic anhydrase II (CA II) deficiency syndrome is an autosomal recessive disorder that produces osteopetrosis, renal tubular acidosis, and cerebral calcification. Other features include developmental delay, short stature, cognitive defects, and a history of multiple fractures by adolescence. With one exception, all patients with osteopetrosis and renal tubular acidosis examined have proven to have CA II deficiency. All CA II-deficient patients analyzed have been found to have mutations in the CA2 gene. Previously, we used single strand conformational (SSCP) analysis to identify exons to be sequenced from CA II-deficient patients. In this report, we amplified all seven exons by PCR from genomic DNA and directly sequenced the amplified products. Application of this method allowed identification of eleven new mutations in 21 patients referred for confirmation of the diagnosis of CA II deficiency. These mutations were scattered over the genome from exon 2 to 7. In two opportunities for prenatal diagnosis, one from cultured amniocytes and one from chorionic villus biopsy, we demonstrated the general utility of the direct sequencing method for prenatal DNA diagnosis. These studies expand our knowledge of the heterogeneity in mutations underlying the CA II deficiency syndrome.

Acidosis, Renal Tubular↗

PubMed1990

Retroviral expression in mononuclear blood cells isolated from a patient with osteopetrosis (Albers-Schönberg disease).

We report the presence of reverse transcriptase activity in the supernatant of long-term culture of mononuclear blood cells (monocytes and lymphocytes) isolated from a 27-year-old patient suffering from benign osteopetrosis. The enzyme was purified to homogeneity according to the technique of Chandra and Steel, by chromatography, first on DEAE-cellulose (DE 52) and then on phosphocellulose (P11). After purification, the enzyme was characterized biochemically for its template specificity and ionic requirements. The purified enzyme was able to transcribe poly(rA).(dT)12-18 and poly(rC).(dG)12-18 very efficiently and had a marked preference for Mg2+ ions over Mn2+ ions. The pattern of ionic dependency for this enzyme is similar to that of reverse transcriptases purified from human lymphotropic viruses. The patient was tested and found sero-negative for HIV-1, HIV-2, and HTLV-I and seropositive (immunoglobulin G) for cytomegalovirus. Epstein-Barr virus nuclear antigens (EBNA) were detected in the patient's B lymphocytes. Since reverse transcriptase is the hallmark of retroviruses, we suggest that a retrovirus may be involved in the etiology of osteopetrosis.

Adult↗

PubMed1995

Normalization of mineral homeostasis after reversal of osteopetrosis.

Whether a radiographic and histologic cure of osteopetrosis includes normalization of mineral homeostasis remains unknown. Thus, we explored the extent of defective mineral metabolism in the microphthalmic (mi/mi) mouse before and after cure. Under basal conditions mi mutants exhibit normocalcemia, hypophosphatemia, and elevated renal 25-hydroxyvitamin D-1-hydroxylase activity. However, administration of PTHrP (3 micrograms/h x 24 h) further stimulated enzyme activity in mi mutants with active disease, to a level no different than that in treated normals. Serum phosphorus levels also declined in mi/mi mice following PTHrP, suggesting a normal renal response to this hormone. In contrast, failure to suppress enzyme function in mi/mi mice following prolonged calcitriol infusion indicates that the observed enhancement of 1,25-dihydroxyvitamin D production occurred secondary to autonomous parathyroid function and/or nonparathyroid hormone-related stimuli. Although an increased fractional excretion and decreased tubular reabsorption of phosphate were demonstrated in mi/mi mice, serum PTH levels were no different in mi mutants compared with normal littermates. Following skeletal cure, the mi/mi mice surprisingly display normal serum phosphorus levels and renal enzyme activity. Moreover, treatment restored normal responsiveness to calcitriol suppression and maintained normal PTHrP responsiveness of enzyme activity. These data indicate that the cure of osteopetrosis in the mi mutant is universal and includes normalization of serum phosphorus and renal 25-hydroxyvitamin D-1-hydroxylase. Furthermore, these data suggest that phosphate depletion of unknown origin is the likely cause of elevated enzyme activity in this murine osteopetrotic mutant.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗

PubMed1994

Aberrant gene expression in cultured mammalian bone cells demonstrates an osteoblast defect in osteopetrosis.

Osteopetrosis is a skeletal condition in which a generalized radioopacity of bone is caused by reduced resorption of bone by osteoclasts. However, it has recently been shown that during skeletal development in several osteopetrotic rat mutations specific aberrations occur in gene expression reflecting the activity of the bone forming cells, osteoblasts, and the development of tissue organization. To evaluate their pathogenetic significance, progressive osteoblast differentiation was studied in vitro. Primary cultures of normal osteoblasts undergo a sequential expression of cell growth and tissue-related genes associated with development of skeletal tissue. We report that osteoblast cultures can be established from one of these mutants, toothless; that these cells in vitro exhibit similar aberrations in gene expression during cell proliferation and extracellular matrix formation and mineralization observed in vivo; and that an accelerated maturation sequence by mutant osteoblasts mimics the characteristic skeletal sclerosis of this disease. These data are the first direct evidence for an intrinsic osteoblast defect in osteopetrosis and establish an in vitro model for the study of heritable skeletal disorders.

Animals↗

PubMed1982

Transformations of osteoclast phenotype in ia rats cured of congenital osteopetrosis.

The reduced bone resorption characteristic of osteopetrosis is accompanied in the incisors-absent (ia) rat mutation by a significant increase in osteoclasts of inactive (mutant) phenotype. Restoration of bone resorption in ia rats by transfer of spleen cells from normal littermates is preceded by a transformation of osteoclasts from mutant to normal phenotype. In this investigation the proportions of osteoclasts of normal phenotype have been determined by light microscopy in untreated ia and normal rats and in ia rats treated with various cell populations from normal rats. Significant increases in numbers of osteoclasts of normal phenotype were seen in the mutant skeleton soon after cell treatments that eventually restored bone resorption and cured the disease. No changes in osteoclast phenotype were seen after cell transfers that did not cure the disease. These data establish transformation of osteoclast phenotype as an early event in the recovery from osteopetrosis and suggest that determination of osteoclast phenotype is a reliable predictor of the success of normal cell populations to restore bone resorption in this mutation.

Animals↗