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PubMed1998

Androgen-dependent gene expression of bone morphogenetic protein 7 in mouse prostate.

BACKGROUND: What is the molecular basis of the osteotrophic action of prostatic metastases? Demineralized bone matrix has the potential to induce new bone formation. The identification of bone morphogenetic proteins (BMPs) as the primary inducers of new bone formation in demineralized bone matrix has set the stage for studying prostate cancer-bone interrelationships. We have hypothesized that BMPs may be expressed in prostate and may be involved in the osteotrophic actions of metastatic prostate cancer cells. METHODS: Using polymerase chain reaction (PCR)-based quantitation, this study examined the presence of BMPs in mouse prostate and their potential regulation by orchidectomy and androgen replacement. RESULTS: BMP-7 and BMP-4 genes were expressed in mouse prostate. Quantitative PCR analysis showed that the BMP-7 mRNA level was significantly decreased following orchidectomy and increased by testosterone and dihydrotestosterone. Therefore, the BMP-7 mRNA level is androgen-dependent. On the other hand, BMP-4 was expressed constitutively in the prostate. CONCLUSIONS: The regulated expression of BMP-7 mRNA in the prostate suggests that BMP-7 may explain in part the stimulation of bone formation and osteosclerosis by metastatic prostate adenocarcinoma.

Animals↗
PubMed1997

Bone turnover and biochemical markers in malignancy.

There are three principal disturbances in bone remodelling that occur in neoplasia affecting the skeleton. The first is an increase in bone turnover that in solid tumors may be confined to sites of metastases or be a generalized phenomenon, most likely related to the secretion of parathyroid hormone-related protein. In the bone remodelling sequence, bone resorption precedes formation, so that increases in turnover result in substantial skeletal deficits more marked at cancellous than cortical bone sites. The second abnormality in bone remodelling is an imbalance between the amount resorbed and that formed at each remodelling site. This is a conspicuous feature of myelomatosis with moderate grades of plasma cell infiltration. The third phenomenon is the process of uncoupling. In osteolytic disease this is associated with the creation of erosion cavities that are never subsequently repaired. Progressive waves of bone resorption result in the destruction of skeletal elements and focal osteolysis. Osteosclerotic metastases formed by uncoupled bone formation represent the deposition of new bone either on quiescent bone surfaces or arising from stromal condensations within the marrow cavity. In solid tumors biopsy evidence suggests that uncoupled bone resorption and formation occur within the same metastases and that the radiographic expression (osteosclerosis, osteolysis) depends on the predominant component. The understanding that abnormalities of skeletal metabolism are mediated by authentic bone cells raises the possibility that skeletal specific markers of bone turnover might be utilized for the diagnosis of metastases, to assess the skeletal prognosis, or to monitor treatment. A variety of skeletal markers have been assessed. The pyridinium crosslinks currently provide the markers of greatest predictive value. Although they have high specificity, their sensitivity is low (< 30%). This indicates that many individuals with skeletal metastases would be missed. In contrast, skeletal markers have proven invaluable in the assessment of the natural history of the disease and response to intervention. They have been particularly useful in assessing the pharmacodynamics of bisphosphonate treatment. However, their day-to-day precision is sufficiently low that they are of limited value in the monitoring of individuals.

Biomarkers, Tumor↗
PubMed2001

Incontinentia pigmenti in a surviving male is accompanied by hypohidrotic ectodermal dysplasia and recurrent infection.

Familial Incontinentia pigmenti (IP) is a rare X-linked dominant condition. The affected cases have characteristic skin lesions, hair, eye, teeth and nail abnormalities and may also have neurological problems. The diagnosis has traditionally been made on clinical grounds. Segregation analysis has suggested that it is lethal in males. Only one liveborn male has been reported who died at one day of age. Female cases of IP survive because of the moderating effects of Lyonization. This child was the affected son of a female with IP. He had a novel phenotype consistent with hypohidrotic ectodermal dysplasia with immune deficiency (HED-ID) but with additional features: he had major problems with hematological disturbances, failure to thrive due to malabsorption, recurrent infections, generalized osteosclerosis and lymphedema of his lower limbs. He also demonstrated some typical features of IP with a generalized reticular skin hyperpigmentation, sparse hair and delayed eruption of teeth. The gene for NEMO (NF-kappa B Essential Modulator) has recently been shown to be mutated in cases of IP. Furthermore, most (80%) of patients possess a recurrent genomic rearrangement that deletes part of the gene resulting in an inactive NEMO protein. In the male case described here, a NEMO stop codon mutation has been identified that has arisen de novo in his affected mother. This mutation is likely to have a less severe effect on NEMO activity and may explain why this child survived for two years and 7 months.

Codon, Terminator↗
PubMed1980

Effect of sodium fluoride, calcium carbonate, and vitamin D on the skeleton in multiple myeloma.

Fifteen patients with multiple myeloma were treated with sodium fluoride (50 mg twice daily) plus calcium carbonate (1 g four times daily) or with the same fluoride-calcium dosage plus vitamin D (50,000 U twice weekly). All patients had increased bone formation, as shown by microradiography and videodensitometry. Ten patients had osteosclerosis demonstrated by roentgenograms. Compressive strength of the vertebral bodies was greater among those who received fluoride-calcium than among controls. Densitometry studies were not helpful. Side-effects were minimal and consisted of nausea and fibrositic symptoms. Hypocalcemia occurred less frequently in patients who received vitamin D along with fluoride-calcium. Administration of sodium fluoride and calcium carbonate produces an increase in bone mass and is a useful adjunct treatment for patients with multiple myeloma.

Bone Diseases↗
PubMed1980

Diffuse purely osteolytic lesions in myelofibrosis.

In myelofibrosis, the skeletal bones present radiologically as normal or with osteosclerotic or osteoporotic changes. Lytic lesions are very rare and when present are usually associated with osteosclerosis. We report on a case of a patient with myelofibrosis exhibiting diffuse purely osteolytic lesions.

Bone Neoplasms↗
PubMed1987

The osteopetrotic rabbit: skeletal cytology and ultrastructure.

The lethal, autosomal recessive osteopetrotic mutation in the rabbit, osteosclerosis (os/os), has recently been made available for experimental investigation. We have examined the cytology and ultrastructure of skeletal cells in mutants and report abnormalities in osteoblasts, osteocytes, and osteoclasts. Mutant osteoclasts lack a well-defined ruffled border and show few morphological signs of bone resorption. Osteoblasts in mutants form bone in neonatal life but show signs of degeneration by 2 weeks after birth. Mutant osteoblasts and osteocytes contain large, electron-dense cytoplasmic inclusions. External surfaces of mutant long bones show no evidence of bone resorption by scanning electron microscopy, and fibrosis of intertrabecular spaces is a prominent feature in mutants. These data, considered with recent evidence that the functions of osteoblasts and osteoclasts are interrelated, suggest that reduced bone resorption, a characteristic feature of osteopetrosis, may be related to osteoblast incompetence in this mutation.

Animals↗
PubMed2002

Follow-up examinations including sequential bone marrow biopsies in essential thrombocythemia (ET): a retrospective clinicopathological study of 120 patients.

Diagnosis of essential thrombocythemia (ET) has been usually established by regarding the criteria of the Polycythemia Vera Study Group. Accordingly, a retrospective clinicopathological study was performed on 120 patients with a follow-up ranging between 5 and 13 years and repeated bone marrow trephine examinations. Following the new WHO classification, at presentation patients revealed three distinctive patterns of bone marrow (BM) features: (true) ET in 43 patients, prefibrotic idiopathic myelofibrosis (IMF) in 50 patients, and early IMF in 27 patients. Heterogeneity of morphological features was associated with correspondingly expressed laboratory data. Contrasting initial and early IMF, patients with true ET displayed an about 80% probability to lack splenomegaly, anemia, and increase in the LDH and LAP values and also failed to show any myeloblasts or erythroblasts on the peripheral blood films. Follow-up examinations including sequential BM biopsies (mean interval 39 +/- 31 months) disclosed that of the 43 patients with true ET only one developed an increase in reticulin. On the other hand, 65 of 77 patients with prefibrotic and early IMF evolved into overt myelofibrosis-osteosclerosis. Moreover, survival analysis demonstrated significant differences in our patients. A neglectable proportion of life loss according to a sex- and age-matched general population was found in true ET (less than 11%) opposed to IMF without or mild fibrosis (range 21% to 32%).

Adult↗
PubMed1982

Occupational fluorosis through 50 years: clinical and epidemiological experiences.

Fifty years ago, in 1932, skeletal fluorosis was discovered as an occupational disease in cryolite workers in Copenhagen, Denmark. Following the initial reports, new cases were identified in other industries, such as the production of aluminum and superphosphate fertilizer. In light cases of fluorosis, the bone changes are often associated with nonspecific joint and muscle pains, but the disease may be entirely asymptomatic. The fluoride-induced osteosclerosis seems to be reversible, but the long-term significance of fluoride accumulation in the body is not known. Family cases of dental fluorosis have been occurred in long-term residents near fluoride-emitting industries, and in hot areas with high, natural fluoride levels in the drinking water. Skeletal fluorosis has only played a minor role in the discussion concerning fluoridation of drinking water, however. Changing and increasing uses of fluorides have led to a renewed interest in this occupational disease.

Bone Diseases↗
PubMed1982

Spondylometepiphyseal dysplasia, Strudwick type.

The clinical and radiographic observations in eight patients, radiographs on an additional six patients, and morphologic observations on chondro-osseous tissue from two of these 14 patients form the basis for delineating an entity distinct from the heterogeneous group of skeletal dysplasia involving spine and tubular bones, the spondyloepiphyseal, and spondylometaphyseal dysplasias. Disproportionately short limbs and delayed epiphyseal maturation are present at birth, and the entity is radiographically indistinguishable from spondyloepiphyseal dysplasia (SED) congenita during infancy. The metaphyseal change that allows identification of the entity described here develops during early childhood, and radiographically is seen as "dappling," ie, the mottled appearance of alternating zones of osteosclerosis and osteopenia. Severe scoliosis and cord compression may be important clinical problems related to the spine changes in adulthood. We have identified one family with two affected sibs and normal parents, suggesting autosomal recessive inheritance and distinguishing the entity from SED congenita that has autosomal dominant inheritance.

Adult↗
PubMed2006

Metaphyseal dysplasia of Braun-Tinschert type: report of a Japanese girl.

We report on a 7-year-old Japanese girl with metaphyseal dysplasia (MD) of Braun-Tinschert type, a recently recognized, autosomal dominant sclerosing bone dysplasia. All individuals with the disorder from four families in the literature originated from a small town in Bohemia or its vicinity. The occurrence of the disorder in a Japanese girl indicates that it is not restricted to Germans. The radiographic hallmarks of the disorder include metaphyseal undermodeling (Erlenmeyer-flask deformity); osteosclerosis of the chondroosseous junctions, metaphyseal cortices, and epiphyseal margins; and exostosis-like bone excrescences at the metaphyseal-diaphyseal junctions. In the girl we described, the latter two findings were conspicuous at age 4 years, but became less prominent with increasing age. The metaphyseal trabeculae were somewhat coarse. The humeri exhibited varus deformity, and the ulnae and fibulae mild bowing. The mean bone mineral density of the lumbar spine was lower than that of age-matched controls. The patient exhibited premature loss of primary teeth, likely to be a sign of increased periodontal bone resorption. Markers of bone formation and resorption were both increased, an indication of a high rate of bone turnover.

Abnormalities, Multiple↗
PubMed1986

Strategies of hemopoietic stress adaptation within the medullary cavity.

Gravimetric determination of total bone water space was used as an index of available bone marrow space in mice following various specific stressors, i.e., splenectomy, hypoxia, bone fracture, and estrone-induced osteosclerosis. Data was corrected for bone weight and was reported as specific bone marrow volume (total bone water space/mg dry bone X 100). A direct relationship was observed between specific bone marrow volume and medullary hemopoietic activity induced by stress. Absolute and/or relative marrow space increased following splenectomy, hypoxia, and fracture. Osteosclerotic animals shift most hemopoietic activity from marrow to spleen, and splenectomized osteosclerotic animals become anemic. Both intact and splenectomized hypoxic animals develop increased specific bone marrow volume and successfully compensate for hypoxia with enhanced erythropoiesis. Animals sustaining a fracture callus increase both specific bone marrow volume and hemopoietic activity at the callus without an increase in hemopoietic demand. Increased specific bone marrow volume extends the marrow bone interface, where primitive stem cells accumulate, while expanding marrow stromal space, where stem cells lodge, proliferate and differentiate. Therefore, it would appear that availability of competent marrow space may play an integral part in passively permitting hematopoiesis and in determining hemopoietic reserve capacity. Stem cell migration increases during intensified hemopoietic demand, which also may be related to available marrow space. Mice have a low medullary hemopoietic reserve capacity; subsequently, when available medullary hematopoietic stroma becomes occupied, stem cells are more likely to migrate from the marrow to extra-medullary sites where they mature before entering the circulating pool.

Adaptation, Physiological↗
PubMed1980

Bone histomorphometry in Paget's disease. Quantitative and dynamic analysis of pagetic and nonpagetic bone tissue.

Transiliac bone biopsies from 136 untreated pagetic patients, taken from both pagetic (72 cases) and nonpagetic bone (64 cases), were quantitatively analyzed. Tetracycline double labeling analysis demonstrated that osteosclerosis of pagetic bone results from an overproduction of woven bone by the osteoblasts. Increased bone cell populations appeared as the consequence of an increased birthrate of the basic multicellular units. In 45% of patients biopsied in nonpagetic bone, there were prints of an increased bone remodeling attributed to a hyperparathyroidism secondary to the high calcium demand of pagetic bones.

Bone and Bones↗
PubMed2006

Immunohistochemical evidence of a cytokine and chemokine network in three patients with Erdheim-Chester disease: implications for pathogenesis.

OBJECTIVE: Erdheim-Chester disease (ECD) is a rare form of non-Langerhans' cell histiocytosis (LCH) of unknown etiology, characterized by diffuse histiocyte infiltration of bones and soft tissue. The purpose of this study was to assess cell proliferation and expression of cytokines, chemokines, and chemokine receptors that may potentially be important in histiocyte accumulation in ECD lesions. METHODS: Biopsies were performed on 3 patients with ECD. The diagnosis of the disease was based on clinical signs including typical radiologic osteosclerosis, and on the detection of foamy CD68+,CD1a- non-Langerhans' cell histiocytes on histologic examination. The expression of the proliferation marker Ki-67 as well as of selected chemokine/chemokine receptor pairs and cytokines was analyzed by immunohistochemistry. RESULTS: In all samples, Ki-67 was undetectable in CD68+ histiocytes. Conversely, these cells expressed the chemokines CCL2 (monocyte chemotactic protein 1), CCL4/macrophage inflammatory protein 1beta (MIP-1beta), CCL5/RANTES, CCL20/MIP-3alpha, and CCL19/MIP-3beta, and their counter-receptors CCR1, CCR2, CCR3, CCR5, CCR6, and CCR7. Moreover, ECD histiocytes expressed interferon-gamma-inducible 10-kd protein (CXCL10), which is specifically induced by interferon-gamma, and interleukin-6 and RANKL, which are both implicated in bone remodeling. Finally, all cases showed a Th1-type lymphocyte infiltrate. CONCLUSION: Our data indicate that, similar to LCH, ECD lesions are characterized by a complex cytokine and chemokine network, which may orchestrate histiocyte activation and accumulation through an autocrine loop and contribute to the pathogenesis of the disease.

Alendronate↗
PubMed2004

Identification of a novel mutation in the coding region of the grey-lethal gene OSTM1 in human malignant infantile osteopetrosis.

Autosomal recessive malignant infantile osteopetrosis (ARO) is characterized by severe osteosclerosis, pathologic fractures, hepatosplenomegaly, and pancytopenia. The pathophysiological basis is inadequate bone resorption due to osteoclast dysfunction. In the majority of cases, mutations in either of two human genes cause this fatal disorder: TCIRG1, encoding a subunit of the osteoclast H(+)-ATPase, and the voltage-gated chloride channel gene CLCN7. We excluded both genes in a small inbred family with malignant infantile osteopetrosis and undertook linkage analysis of several candidate loci that are involved in murine osteopetrosis. A region spanning more than 20 cM between the markers D6S1717 and D6S1608 on chromosome 6q21 was found to be homozygous in the affected child. This locus is syntenic to the genomic region harboring the gene for the osteopetrotic mutant mouse grey-lethal (gl). Recently, mutations in a novel gene of unknown function were described in the grey-lethal mouse and in one human patient. Mutation screening of the grey-lethal gene (OSTM1), revealed a homozygous 2-bp deletion in exon 2 (c.415_416delAG) in the affected child. No mutations could be found in six independent ARO patients who had tested negative for mutations in TCIRG1 and CLCN7. In summary, we describe the identification of a novel mutation in the coding sequence of the human grey-lethal gene, which is the second OSTM1 mutation found in human ARO, confirming the involvement of this gene in the pathogenesis of this severe bone disease.

Amino Acid Sequence↗
PubMed2006

Werner syndrome and mutations of the WRN and LMNA genes in France.

Werner syndrome (WS) is a pleiotropic disease of premature aging involving short stature, tight, atrophied, and/or ulcerated skin; a characteristic 'birdlike' facies and high, squeaky or hoarse voice; premature greying and thinning of the hair; and early onset cataracts. Additional common symptoms include diabetes mellitus, hypogonadism, osteoporosis, osteosclerosis of the digits, soft tissue calcification, premature atherosclerosis, rare or multiple neoplasms, malformed teeth, and flat feet. Diagnosis can be difficult due to the variable presentation and rarity of the disorder. Transmission is usually autosomal recessive. The WS gene, WRN, is member of the RecQ DNA helicase family. Biallelic mutations of WRN are responsible for most patients. Although heterozygous missense mutations in the LMNA gene have been observed in severely affected WS patients, this only accounts for a small fraction of non-WRN patients. Eighteen WS cases were referred to us for molecular analysis. Eleven had definite and three had probable WS according to the University of Washington Registry clinical criteria. All exons of the WRN gene and their splice junctions were sequenced. Of the fourteen definite or probable cases, 11 had one or more WRN mutation. Thirteen different mutations were found, and ten of these were previously undescribed. There were few phenotypic differences between patients with WRN mutation(s) and those who met clinical criteria though lacking WRN mutations. However, patients with mutations tended to have more symptoms overall, and mutations were not observed in the two cases with cardiomyopathy.

Adult↗
PubMed1991

Results and conclusions of the National Toxicology Program's rodent carcinogenicity studies with sodium fluoride.

The US National Toxicology Program (NTP) has conducted toxicity and carcinogenicity studies with sodium fluoride administered in the drinking water to F344/N rats and B6C3F1 mice. The drinking water concentrations used in the 2-year studies were 0, 25, 100, or 175 ppm sodium fluoride (equivalent to 0, 11, 45 or 79 ppm fluoride). Survival and weight gains of rats and mice were not affected by fluoride treatment. Animals receiving sodium fluoride developed effects typical of dental fluorosis, and female rats given 175 ppm had increased osteosclerosis. There were no increases in neoplasms in female rats or in male or female mice that were attributed to sodium fluoride administration. There was equivocal evidence of carcinogenic activity of sodium fluoride in male rats based on the occurrence of a small number of osteosarcomas in treated animals.

Animals↗
PubMed1987

Procollagen type I carboxy-terminal extension peptide in serum as a marker of collagen biosynthesis in bone. Correlation with Iliac bone formation rates and comparison with total alkaline phosphatase.

We measured iliac bone formation rates on all surfaces after double tetracycline labeling, serum levels of type 1 procollagen carboxy-terminal extension peptide (pColl-I-C), and serum levels of total alkaline phosphatase activity (TAP) in four normal subjects and in 44 patients with various forms of metabolic bone disease. In three patients with enzymatic evidence of liver disease both biochemical serum markers were disproportionately raised. In a patient with idiopathic axial osteosclerosis serum pColl-I-C was selectively increased by more than ten-fold. In the remaining 44 subjects pColl-I-C and TAP levels correlated significantly with each other (r = 0.70) and both showed the same directional changes and broadly similar correlations with iliac bone formation rate expressed in different ways. In general, pColl-I-C levels correlated better with cancellous bone formation rates and TAP levels cortical bone formation rates. There was a modest improvement in prediction of bone formation rate with multiple regression using both markers. In 15 patients with typical uncomplicated postmenopausal osteoporosis, neither biochemical marker, singly or jointly, correlated significantly with any expression of bone formation rate. Disadvantages to the use of pColl-I-C as a marker include a significant contribution to the serum level from type 1 collagen biosynthesis in tissues other than bone, and (probably) variable metabolic clearance. For both biochemical markers the most consistently high correlations (r = 0.77-0.79) were found with total bone formation rate for the entire biopsy core volume, which is the best estimate available from a biopsy of formation rate at the bone organ level of organization in vivo. The core volume as a referent also allows the amount of bone formed on cortical, endocortical, and cancellous surfaces to be compared. Measurement of serum pColl-I-C levels merits further study as a noninvasive index of bone metabolism. Differences between normal and abnormal subjects in the relationships between a variety of biochemical markers and a variety of histologic indices have the potential for providing insight into the pathogenesis of osteoporosis.

Adolescent↗
PubMed1987

Effects of 1 alpha,25- and 24R,25-dihydroxyvitamin D3 on aluminum-induced rickets in growing uremic rats.

Rats were subjected to a two-stage subtotal nephrectomy or sham operation, and treated with aluminum (Al) or both aluminum and vitamin D3 metabolites for 5 weeks with a cumulative dose of 13.6 mg aluminum. Animals were injected with 3H-thymidine and 3H-proline. The following analyses were performed: quantitative histology of tibial metaphyses and cytomorphometric electron microscopy of osteoclasts, quantitative (ICP-spectroscopy) and qualitative determination (histochemical staining) of aluminum within organs, and serum biochemistry (Ca, P, Mg, vitamin D3 metabolites, alkaline phosphatase, urea). The following new facts of the aluminum-related bone disease became evident: (a) Application of aluminum to growing uremic rats induced rickets, whose major epiphyseal growth plate changes were 1 alpha,25(OH)2D3-dependent. Addition of 1 alpha,25(OH)2D3 prevented the formation of rachitic metaphysis, but failed to prevent osteoid accumulation on epiphyseal and metaphyseal trabecular surfaces. Moreover, calcitriol produced hyperosteoidosis and osteosclerosis in the same rats. Aluminum did not alter the function of osteoblasts, while osteoclasts seemed inactivated. (b) The development of rickets was associated with suppressed serum levels of 1,25(OH)2D3, reduced phosphorus level and the high content of aluminum in the bone, kidney, and liver. The addition of 24R,25(OH)2D3 markedly exaggerated the reduction of serum levels of calcitriol. We suggested that aluminum induces rickets in growing uremic rats, which consists of two components: vitamin D refractory osteomalacia and 1 alpha,25(OH)2D3-dependent epiphyseal growth plate changes.

24,25-Dihydroxyvitamin D 3↗