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At least 703 records · Page 39Linked to original sources
PubMed2000

Mucopolysaccharidosis VII in a cat.

Mucopolysaccharidosis VII was diagnosed in a domestic shorthair cat from California. The cat was small and had multiple abnormalities, including a small body disproportionate to the size of the skull, angular deformities of the ribs, abnormally short forelimbs, luxating patellas, generalized epiphyseal dysplasia involving the vertebrae and long bones, cuboidal vertebrae, pectus excavatum, subluxation of both hips, osteosclerosis of the tentorium cerebelli and left petrous temporal bone, tracheal hypoplasia, and corneal clouding. Beta-glucuronidase activity was markedly decreased in peripheral blood leukocytes. The cat died at 21 months of age, and a complete necropsy was performed. Tissues were examined by light and transmission electron microscopy. Large clear, round vacuoles representing distended lysosomes were present in many epithelial and connective tissue cells, including fibrocytes, chondrocytes, smooth muscle cells, hepatocytes, astrocytes, and macrophages.

Abnormalities, Multiple↗
PubMedDate not supplied

The role of cathepsin K in normal bone resorption.

Cathepsin K is essential for normal bone resorption; humans lacking cathepsin K exhibit pycnodysostosis, which is characterized by short stature and osteosclerosis. Cathepsin K knockout mice develop osteopetrosis and display features characteristic of pycnodysostosis, and osteoclasts isolated from these mice exhibit impaired bone resorption in vitro. Bone resorption depends upon the synthesis of cathepsin K by osteoclasts and its secretion into the extracellular compartment at the attachment site between osteoclasts and the bone surface, wherein the organic matrix is subsequently degraded by cathepsin K. Factors that directly modulate osteoclastic bone resorption, including cytokines (RANK ligand, tumor necrosis factor-alpha and interferon gamma), hormones (retinoic acid and estrogen) and nuclear transcriptional factors (c-jun and Mitf) also regulate cathepsin K gene expression. Osteoporosis is one of the leading causes of morbidity in the elderly and is characterized by a persistent excess of osteoclastic bone resorption. Therefore, cathepsin K is an attractive target for therapeutic intervention to prevent and ameliorate the significant deleterious impact of osteoporosis.

Animals↗
PubMed2004

Characterization of common genetic variants in cathepsin K and testing for association with bone mineral density in a large cohort of perimenopausal women from Scotland.

UNLABELLED: BMD values in approximately 3000 perimenopausal Scottish women were adjusted by regression to identify and account for nongenetic factors. Adjusted BMD values were not associated with simple tandem repeat (STR) markers or single nucleotide polymorphisms (SNPs) at the Cathepsin K (CTSK) locus. We present a thorough analysis of common CTSK polymorphisms and genetic relatedness among CTSK haplotypes. INTRODUCTION: CTSK is a cysteine protease of the papain family and is thought to play a critical role in osteoclast-mediated bone degradation. Rare, inactivating mutations in CTSK cause pychodysostosis, an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature. However, there have been no studies of common genetic variants in CTSK and their possible association with bone density in the general population. MATERIALS AND METHODS: To identify common single nucleotide polymorphisms (SNPs) and simple tandem repeat (STR) polymorphisms in and around CTSK, we screened all CTSK exons, intron A, all intron-exon boundaries, and the putative CTSK promoter region in 130 random whites using both high-performance liquid chromatography (HPLC) and DNA sequencing. CTSK markers were genotyped in approximately 3000 perimenopausal Scottish women whose hip and spine bone mineral density (BMD) had been measured by DXA. We performed linear regression analysis to identify and adjust for nongenetic predictors of BMD, and adjusted BMD values (regression residuals) were tested for association with individual CTSK markers and haplotypes by ANOVA and the composite haplotype method of Zaykin et al. RESULTS AND CONCLUSIONS: We discovered two intronic SNPs (8% and 9% frequency), but no common exonic SNPs (> 1% frequency), and found that three STRs at the immediate 5' end of the CTSK locus are highly polymorphic. The population frequencies of haplotypes defined by these five polymorphisms were estimated, and a cladogram was derived showing proximity of relationship and likely descent of the 30 most common CTSK haplotypes. Regression analyses revealed that approximately 39% of spine and 19% of hip rate of change in BMD was accounted for by nongenetic factors. For baseline BMD values in premenopausal women, nongenetic predictors explained 11% of the variance at the spine and 13% at the hip. Adjusted BMD values showed no statistically significant association with any of the individual CTSK polymorphisms or CTSK haplotypes.

Analysis of Variance↗
PubMed2004

Severe malignant osteopetrosis caused by a GL gene mutation.

Infantile malignant autosomal recessive osteopetrosis is a genetically heterogeneous disease caused by the inability of OCLs to resorb and remodel bone, resulting in generalized osteosclerosis and obliteration of marrow spaces and cranial foramina. The classical clinical features are pathological fractures, visual impairment, and bone marrow failure. Two human genes have been described as the cause of this form of osteopetrosis: the T-cell immune-regulator-1 (TCIRG1) gene, which is mutated in >50% of the patients, and the chloride channel 7 (ClCN7) gene, which accounts for approximately 10% of cases. We report the clinical, radiographic, and histopathologic findings of the first human osteopetrosis case caused by a mutation in the grey-lethal (GL) gene. The patient, a 9-day-old male infant, presented with a very severe osteopetrotic phenotype including substantial hepatosplenomegaly since birth, cytopenia, and progressive major liver failure. Skeletal radiographs revealed a generalized increase in bone density with loss of corticomedullary differentiation. Histopathologic bone examination showed the typical osteopetrotic changes, with absence of resorptive activity, and osteoclasts, slightly decreased in number, with evident morphological alterations.

Bone and Bones↗
PubMed2002

Localization of the gene causing autosomal dominant osteopetrosis type I to chromosome 11q12-13.

The osteopetroses are a heterogeneous group of genetic conditions characterized by increased bone density due to impaired bone resorption by osteoclasts. Within the autosomal dominant form of osteopetrosis, the radiological type I (ADOI) is characterized by a generalized osteosclerosis, most pronounced at the cranial vault. The patients are often asymptomatic but some suffer from pain and hearing loss. ADOI is the only type of osteopetrosis not associated with an increased fracture rate. Linkage analysis in two families with ADOI from Danish origin enabled us to assign the disease-causing gene to chromosome 11q12-13. A summated maximum lod score of +6.54 was obtained with marker D11S1889 and key recombinants allowed delineation of a candidate region of 6.6 cM between markers D11S1765 and D11S4113. Previously, genes causing other conditions with abnormal bone density have been identified from this chromosomal region. The TCIRG1 gene was shown to underly autosomal recessive osteopetrosis (ARO), and, recently, mutations in the LRP5 gene were found both in the osteoporosis-pseudoglioma syndrome and the high bone mass trait. Because both genes map within the candidate region for ADOI, it can not be excluded that ADOI is caused by mutations in either the TCIRG1 or the LRP5 gene.

Adult↗
PubMed2003

Mechanisms of tumor metastasis to the bone: challenges and opportunities.

In human cancers, bone is a common site for metastasis. It is well known that metastasis is the cause of morbidity and mortality in patients with cancer. Both breast and prostate carcinomas have a propensity to metastasize to bone. In general, metastatic breast cancers result in osteolytic lesions. On the other hand, prostate cancer metastases are osteoblastic and result in osteosclerosis. Thus, bone formation and bone resorption are at the crux of the cancer metastasis problem. For example, in the prostate, there is a vicious cycle of metastasis to bone (Fig. 1). Metastases to bone causes excruciating bone pain, pathological fractures, and eventually death, and therefore is a serious challenge to both bone biologists and cancer cell biologists. The stromal-epithelial interactions in breast and prostate are critical in initiation of carcinogenesis and the progression of the metastatic cascade to bone (Fig. 2). Over a hundred years ago, Stephen Paget enunciated the seed and soil hypothesis in which seeds of metastatic cancer cells of breast preferentially settle in the soil of bone matrix. Thus, the prostate/breast cancer bone interface and continuum has continuously presented challenges and opportunities and were discussed at a recent workshop.

Animals↗
PubMed2005

Dynamics of bone marrow changes in patients with chronic idiopathic myelofibrosis following allogeneic stem cell transplantation.

Scant knowledge exists about the dynamics of fibro-osteosclerotic bone marrow (BM) lesions and regeneration of hematopoiesis following allogeneic peripheral stem cell transplantation (SCT) in chronic idiopathic myelofibrosis. Therefore, an immunohistochemical and morphometric study was performed on BM biopsies in 20 patients before and at standardized intervals (days 30 through 384) following SCT. In responding patients, a total regression of the pretransplant increased fibrosis was completed in the posttransplant period after about six months, while the extent of osteosclerosis did not change significantly during observation time. The quantity of CD61+ megakaryocytes including precursors was strikingly variable after SCT and, by using planimetric methods, atypical microforms exhibiting a dysplastic aspect could be demonstrated. These anomalies may be responsible for posttransplant thrombocytopenia. CD34+ progenitor cells were increased before transplantation, however, their number declined rapidly to normal values in responding patients. Nucleated erythroid precursors revealed a decreased amount before and after SCT accounting for anemia. Large clusters of this cell lineage indicated an initial hematopoietic reconstitution comparable with the expansion of the neutrophil granulopoiesis. Proliferative activity and apoptosis showed an increase until one year after SCT that implied a still regenerating hematopoiesis in keeping with an enhanced cell turnover.

Adolescent↗
PubMed1994

Cortical bone osteocalcin content and matrix composition in autosomal dominant osteopetrosis type I.

Several bone matrix protein constituents, including the major component collagen type I and the hydroxyapatite binding protein, osteocalcin, have been implicated in the regulation of bone turnover. Cortical bone osteocalcin, collagen and mineral content were studied in autosomal dominant osteopetrosis type I (ADO), a disorder characterized by diffuse symmetrical osteosclerosis. Iliac crest bone biopsies were obtained from eight patients (mean age 43.0 years, range 17-63 years) and compared with 16 age- and sex-matched normal controls (mean age 44.1 years, range 20-61 years). The osteocalcin level in cortical bone was increased (p < 0.03) in ADO (51.4 +/- 3.9 mg/kg bone) compared with controls (38.0 +/- 3.6 mg/kg bone). Total collagen, protein and calcium expressed per kilogram bone dry weight were without significant difference between patients and controls. The pathogenesis of ADO is most likely not related to cortical bone osteocalcin content, a protein implicated in osteoclast ontogeny and activation. These observations are in contrast to recent observations of reduced bone osteocalcin levels in osteopetrotic mutations in the rat and underscore the interspecies heterogeneity of this disorder.

Adolescent↗
PubMed1997

Restoration of disturbed tooth eruption in osteopetrotic (op/op) mice by injection of macrophage colony-stimulating factor.

Osteopetrotic (op/op) mice show severe osteosclerosis caused by an inherited deficiency of osteoclast and resultant failure of tooth eruption, which can be cured by the injection of macrophage colony-stimulating factor (M-CSF). The present study revealed that consecutive injections of M-CSF in these mutant mice brought about a recovery of bone resorption resulting in the resumption of growth of tooth root and periodontal ligament. Bone resorption at the inner surface of bony crypts was noted on the 5th day after the start of M-CSF injections. This activity was reduced with the progress of root and periodontal ligament formation, being confined to the basal and crestal portion of bony crypts by the 15th day of the experiment. Second molars emerged into the oral cavity on the 15th day, but no eruption of first molars was observed until the 20th day. Throughout the experiment, first molars exhibited appreciable root deformity, which was less severe in second molars. Delayed eruption of first molars was thought to be related to the severity of the disturbance of root formation.

Age Factors↗
PubMed2002

Hyperostotic bone disease in red pandas (Ailurus fulgens).

Three adult red pandas (Ailurus fulgens) developed multiple periarticular exostoses in their elbow joints. Two of these animals also had extensive periosteal new bone formation and osteosclerosis of the ulnae and radii and mild periosteal new bone deposition on the femurs. One animal also showed extensive hyperostosis of the cranium and mandibles. Dietary concentrations of calcium and phosphorus were estimated to be adequate, but dietary vitamin A and D appeared excessive when compared with recommended levels for this species. Serum vitamin A concentrations were not elevated in the two most severely affected animals, but their liver vitamin A content was higher than what is considered normal for most domestic animal species. Serum 25-hydroxy vitamin D concentrations were within normal ranges for domestic species. A definitive diagnosis for the cause of the lesions was not established, but hypervitaminosis A was suspected.

Animals↗
PubMed1991

Breast carcinomas synthesize factors which influence osteoblast-like cells independently of osteoclasts in vitro.

Bone metastases in breast cancer may be osteolytic, osteosclerotic, or a mixture of the two. Although stimulation of bone resorption by breast cancer cells has attracted some interest, the formation of osteosclerotic secondary tumours and the influence of human mammary carcinoma cells on osteoblasts (bone forming cells), both important in understanding breast cancer--bone interactions, have been largely neglected. We therefore examined the effects of conditioned medium (CM) from two cultured human breast cancer cell lines (MCF7 and ZR-75) and from primary cultures of breast carcinomas from two patients, on osteoblasts and recruitment of bone-resorbing cells (osteoclasts) in vitro. Osteoblast-like cells (BDC) were cultured from human trabecular bone explants. Osteoclast maturation was studied in fetal rat calvaria cultured on collagen gels. CM from the MCF-7 line and cells derived from one patient each inhibited BDC DNA synthesis, but stimulated osteoclast recruitment. In contrast, CM from the second patient's cells or ZR-75 enhanced DNA synthesis in BDC, but blocked osteoclast maturation. This suggests that human breast carcinomas secrete soluble factors which influence both osteoclasts and osteoblasts. A further unexpected implication is that mammary carcinoma cells may cause local osteosclerosis by directly stimulating osteoblasts, rather than through raised bone turnover in metastases.

Animals↗
PubMed2002

Bone defects in latent TGF-beta binding protein (Ltbp)-3 null mice; a role for Ltbp in TGF-beta presentation.

The latent transforming growth factor (TGF)-beta binding proteins (LTBP)-1, -3 and -4 bind the latent form of the multipotent cytokine TGF-beta. To examine the function of the LTBPs, we made a null mutation of Ltbp-3 by gene targeting. The homozygous mutant animals developed cranio-facial malformations by 12 days. By three months, there was a pronounced rounding of the cranial vault, extension of the mandible beyond the maxilla, and kyphosis. The mutant animals developed osteosclerosis of the long bones and vertebrae as well as osteoarthritis between 6 and 9 months of age. These latter phenotypic changes were similar to those described for mice that have impaired TGF-beta signaling. Thus, we suggest that Ltbp-3 plays an important role in regulating TGF-beta bioavailability as the phenotype of the Ltbp-3 null mouse appears to result from decreased TGF-beta signaling. Histological examination of the skulls from null animals revealed no effects on calvarial suture closure. However, the synchondroses in the skull base were obliterated within 2 weeks of birth. This is in contrast to the wild-type synchondroses, which remain unossified throughout the life of the animal and enable growth of the skull base through endochondral ossification. Histological changes in mutant basooccipital-basosphenoid synchondrosis were observed 1.5 days after birth. Compared with wild-type or heterozygous littermates, the basooccipital-basosphenoid synchondrosis of Ltbp-3 null mice contained increased numbers of hypertrophic chondrocytes. The expression of bone sialoprotein-1 (a marker for osteoblasts) was observed in cells surrounding the synchondrosis at postnatal day 1.5 indicating ectopic ossification. The expression of Indian hedgehog (Ihh) (a marker for chondrocytes committed to hypertrophic differentiation) was found through the basooccipital-basosphenoid synchondrosis, whereas the expression of parathyroid hormone related protein (PTHrP), which inhibits chondrocyte differentiation, appeared to be diminished in Ltbp-3 null mice. This suggests that Ltbp-3 may control chondrocyte differentiation by regulating TGF-beta availability. TGF-beta may regulate PTHrP expression either downstream of Ihh or independently of Ihh signaling.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Arthroscopic drilling for the treatment of osteochondral lesions of the talus.

BACKGROUND: An osteochondral lesion of the talus is a relatively rare disorder of the ankle. While a number of treatment options have been reported, it appears to be difficult to manage all lesions with a single approach. We evaluated the indications for and the results of arthroscopic drilling for the treatment of an osteochondral lesion of the talus. METHODS: Eighteen ankles (seventeen patients) with a symptomatic osteochondral lesion of the talus were examined. The ages of the patients ranged from ten to seventy-eight years (mean, 28.0 years) at the time of the operation, and the patients were followed postoperatively for two to 9.5 years (mean, 4.6 years). After the continuity of the cartilage overlying the lesion and the stability of the lesion had been confirmed, arthroscopic drilling was performed with use of a Kirschner wire that was 1.0 to 1.2 millimeters in diameter. A cast was not applied postoperatively, and full weight-bearing was allowed six weeks after the procedure. RESULTS: The clinical result was good for thirteen ankles and fair for five; all ankles had improvement. Twelve of the thirteen ankles that were in patients who were less than thirty years old had a good result. In contrast, only one of the five ankles in patients who were fifty years old or more had a good result. Thus, the clinical results tended to be better for younger patients. Improvement was seen radiographically in fifteen ankles. However, the three ankles in patients who were more than sixty years old were found to have no improvement on radiographic examination. Analysis of the group of patients who had a history of trauma revealed that the mean interval between the injury and the operation was 6.3 months for the three ankles that had a good radiographic result and 11.3 months for the six that had a fair result. Thus, the radiographic results tended to be better when the interval between the injury and the operation was shorter. CONCLUSIONS: Arthroscopic drilling for the treatment of medial osteochondral lesions of the talus does not require osteotomy of the medial malleolus or postoperative immobilization; thus, the procedure is less invasive than other types of operative treatment for the condition and it allows early resumption of daily activities and sports. On the basis of the results in this study, we believe that the procedure is effective and useful in young patients, especially those who have not yet had closure of the epiphyseal plate. A specific indication for the procedure is an early lesion with only mild osteosclerosis of the surrounding talar bone, continuity of the cartilaginous surface, and stability of the osteochondral fragment.

Adolescent↗
PubMed1996

[A 26-week repeated percutaneous dose toxicity study of calcipotriol (MC903) in rats].

A 26-week repeated percutaneous dose toxicity of calcipotriol (MC903), an anti-psoriasic agent, was studied in Slc:SD rats at doses of 0.8, 4 and 20 micrograms/kg/day as low, mid and high dose levels. 1. No mortality were observed in both sexes of all groups including control. An increased water consumption was observed in females at mid dose and in both sexes at high dose. 2. An increased incidence of the corneal opacity in males at mid dose and in both sexes at high dose was noted significantly as compared with that observed in control. Urinalysis revealed a slight increased urinary volume, increased excretions of Ca and IP, and lower pH in both sexes at more than mid dose. Levels of the serum IP in females and Ca in both sexes were elevated at high dose. 3. The increased weights of the kidney in males and adrenal gland in females were observed at high dose. The kidney in females at mid dose and in both sexes at high dose showed a higher incidence of mineralization than in control. Furthermore, osteosclerosis of the sternum and femur in both sexes, and hyperkeratosis of the skin at application site in females at high dose were observed. Electron microscopic examination revealed no abnormality in the liver and kidney. 4. On the basis of results obtained in the present study, it is considered that 0.8 microgram/kg/day is the no-toxic dose of MC903 applied percutaneously in both sexes of rats.

Administration, Cutaneous↗
PubMed2003

Chinese herbs and bone disease.

We treated a patient with an unusual bone disease at least partly associated with Chinese herbs. Seven years after 65-year-old man had begun to consume Chinese herbs, multifocal osteoarthralgias were noted, and the patient was hospitalized for renal dysfunction (serum creatinine, 2.8 mg/dl; urea nitrogen, 19 mg/dl). Fanconi syndrome also was apparent. A renal biopsy specimen showed tubulo-interstitial fibrosis. Chinese herbs were discontinued and prednisolone was started, but bone and joint pain as well as renal function gradually worsened. Four years later, creatinine was 9.0 mg/dl and alkaline phosphatase was 571 IU/l. As bone scintigraphy revealed localized asymmetric lesions, Paget's disease of bone was suspected at first. However, neither osteosclerosis nor hypertrophy was seen in radiographs. Based on a bone specimen histology we diagnosed as mixed-type renal osteodystrophy including osteomalacia and osteitis fibrosa. Mosaic pattern of cement lines was not present. This case was not compatible with either Paget's disease or typical renal osteodystrophy as seen in dialysis patients. Etidronate disodium was effective in alleviating bone symptoms. The patient's bone disorder may be a new disease at least partly related to Chinese herbs independently of nephropathy.

Aged↗
PubMed2004

Myelofibrosis with myeloid metaplasia: new developments in pathogenesis and treatment.

Myeloid metaplasia with myelofibrosis (MMM) is a chronic myeloproliferative disorder (CMPD) characterized by progressive anemia, massive splenomegaly, both hepatosplenic and non-hepatosplenic extramedullary hematopoiesis (EMH), a leukoerythroblastic blood smear, circulating progenitor cells, and marked bone marrow stromal reaction including collagen fibrosis, osteosclerosis and angiogenesis. The overall median survival is 5 years although it might range from 2 to 15 years depending on the presence or absence of clinically defined prognostic factors. Death is often due to leukemic transformation, portal hypertension or infection. In addition to shortened survival, quality of life is often affected by frequent red blood cell transfusions, profound constitutional symptoms, and cachexia. Drug therapy and autologous hematopoietic stem cell transplantation (HSCT) are of only palliative value and have not been shown to improve survival. The role of allogeneic HSCT, both myeloablative and non-myeloablative, is actively being investigated. Both splenectomy and radiation therapy have defined therapeutic roles to control EMH-associated symptoms. Analysis of the molecular biology of the disease is underway with the aid of animal models leading to the identification of novel therapeutic targets. Among the novel agents tested, thalidomide seems the most promising although newer agents are on the horizon.

Aged↗
PubMed1976

Chordoma: radiologic evaluation of 20 cases.

Experience with 20 cases of chordoma is summarized. Three of four intracranial tumors presented as sellar tumors. The clivus remained intact for 2, 3 1/2, and 4 years, respectively, in three patients despite extensive destructive lesions of the sellar region. Our data and those of others indicate that approximately half the patients with chordomas have erosion of the clivus at the time of initial medical evaluation. The other half mainly have sellar destructive lesions with or without associated clival erosion. Calcification occurs in 50%-70% of intracranial chordomas. A nasopharyngeal mass is present in one-third. Vertebral chordomas often involve two or more vertebrae, producing destructive lesions which often have a sclerotic rim. The intervertebral discs are commonly affected. A paraspinal soft tissue mass, half the time containing calcification, is often present. Sacral lesions are characterized by a midline destructive lesion, occasionally associated with expansion, with or without osteosclerosis. A firm, fixed, extrarectal, presacral mass which may contain calcification or fragments of bone is almost always present.

Adult↗
PubMed1981

Skeletal metastases of melanoma: radiographic, scintigraphic, and clinical review.

The radiographic manifestations of 127 skeletal metastases in 50 patients with melanoma were reviewed and correlated with the scintigraphic findings. Although the features of most of the metastases were nonspecific and appeared similar to those of other osteolytic metastases, several of them had unusual features, including expansion, subarticular location, osteosclerosis, and a thin, sclerotic rim. These features could result in some of the metastases being mistaken for other lesions. The radionuclide bone scans were more sensitive in that they detected the lesions earlier and in greater numbers than the radiographs. Prognosis was poor once skeletal metastasis was diagnosed, the mean survival time being 4.7 months.

Adolescent↗