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PubMed1997

Quality of life measurement in bone marrow transplantation: development of the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) scale.

We developed a 12-item bone marrow transplant subscale (BMTS) for the general Functional Assessment of Cancer Therapy (FACT) measure. The subscale combined with the FACT, (FACT-BMT) is a 47-item, valid and reliable measure of five dimensions of quality of life in bone marrow transplant patients. The three-step validation process involved the generation and selection of BMT-specific items and the testing of the overall measure. Items were selected from a list produced by seven oncology experts and 15 patients and were designed to assess content not represented in the general FACT items. A total of 182 patients completed the FACT-BMT at baseline, prior to BMT. An analysis measuring sensitivity to change was performed with 74 patients after transplantation and 60 patients over the three time-points of baseline, hospital discharge and 100 days. The FACT-BMT and all subscales were correlated, sensitivity to change was measured, and the internal consistency for each scale was calculated. Coefficients of reliability and validity ranged from 0.86 to 0.89 for the entire FACT-BMT and 0.54 to 0.63 for the BMTS. The BMTS was able to discriminate patients on the basis of performance status rating and also demonstrated sensitivity to change over time. The FACT-BMT has good psychometric properties for use in assessing quality of life in bone marrow transplant patients. The addition of the bone marrow transplant subscale to the general FACT measure makes it an excellent choice for use in BMT clinical trials.

Adolescent↗

PubMed1986

Heterotopically induced bone does not develop functional periosteal membrane.

Heterotopic bone induced in mice by implantation of demineralized rat bone matrix does not respond to Moloney sarcoma. The biochemical and morphological parameters of osteogenesis (alkaline and acid phosphatase activity, 45Ca-uptake and total calcium content) are similar in the sites of Moloney sarcoma as in the contralateral, unexposed to the sarcoma, side. In contrast, periosteum of implants of syngeneic costal bone in response to Moloney sarcoma proliferates and produces new bone in the same manner, as orthotopic bones at the sites of Moloney sarcoma do. It is concluded that ectopically induced bones do not develop a true periosteum.

Animals↗

PubMed1998

Transcriptional coactivators potentiating AP-1 function in bone.

The AP-1 proteins are formed by the heterodimerization of Fos family members and Jun family members through a structural motif called the leucine zipper. The heterodimer can then bind DNA at a consensus site termed the AP-1 site and act as a transcription factor to modulate the expression of AP-1-responsive genes. All the Jun family members can also homodimerize to exert the same function. Genetic studies including gain-of-function and loss-of-function mutations have shown that AP-1 components, particularly the c-Fos protein, are essential for proper bone development. Both Fos and Jun family members interact with coactivator molecules to activate transcription. To date, the coactivator proteins CBP (CREB-binding protein), JAB1 (Jun-activation domain-binding protein 1), and alpha-NAC (Nascent polypeptide associated complex And Coactivator alpha) have been shown to potentiate the AP-1 transcriptional activating function. We have shown that all three proteins are expressed in bone during mouse development. These findings raise the intriguing possibility that multiple coactivators may be involved in mediating AP-1-dependent transcription and increase the specificity of target gene activation by AP-1 proteins in differentiating bone cells.

Animals↗

PubMed2004

Longitudinal monitoring of bone accretion measured by quantitative multi-site ultrasound (QUS) of bones in patients with delayed puberty (a pilot study).

OBJECTIVE: to compare the effect of anabolic agents on bone accretion in boys with constitutional delay of puberty (CGDP). RATIONALE: it has been suggested that an appropriate timing of puberty is necessary for normal bone mineral density (BMD) acquisition. Proper bone development during childhood is the key factor in achieving higher peak bone mass during middle age, which may not be achievable in CGDP children, and thereby osteoporosis may appear at an earlier age then expected. PATIENTS AND METHODS: 45 boys with CGDP aged 14-16 years were monitored longitudinally, every 3 months over 12 months with Sunlight Omnisense, a quantitative ultrasound device (Tel Aviv, Israel). The apparatus is a multi-site bone sonometer that obtains axial Speed of Sound (SOS). Based on a reference database obtained on n=1,085 (490 boys) 0-18 years, a normative curve was determined. Fifteen (14-16 years old) of the CGDP patients were treated with I.M. testovirone depot 100 mg monthly for 6 months, 15 (14-16 years old) were treated with oxandrolone 5 mg/m(2) daily for 6 months, and 15 (14-16 years old) were in an observation group. RESULTS: whereas the quantitative ultrasound (QUS) Z-score had shown some increase over time in CGDP-treated patients, an increase was found in tibia Z-score from -0.5(-0.64, -0.36) to -0.4(-0.54, -0.26) and from -0.52(-0.67, -0.38) to -0.31(-0.44, -0.11) in the testosterone and oxandrolone-treated groups, respectively, [median (25%, 75%)]. An increase in radius Z-score from -0.52(-0.65, -0.25) to -0.4(-0.54, -0.15) and from -0.51(-0.61, -0.21) to -0.37(-0.47, -0.07) in the testosterone- and oxandrolone-treated groups respectively [median (25%,75%)]. Z-score SOS decreased in the observation group -0.5(-0.66, -0.3) to -0.69(-0.85, -0.54) and -0.5(-0.59, -0.41) to -0.81(-0.95, -0.55) in tibia (P = 0.032) and radius (P = 0.029), respectively. Despite the fact that QUS remained in the normative range in all patients, a clear deterioration was demonstrated in untreated CGDP patients. CONCLUSION: longitudinal follow-up of patients with CGDP may detect an early pattern of deterioration of bone mass.

Adolescent↗

PubMed1998

FGF signaling in skeletal development.

The fibroblast growth factor receptor family consists of four receptor tyrosine kinases which bind with varying affinity and specificity to a family of at least fifteen polypeptide ligands. The receptors and ligands perform many essential functions during growth, development and repair. Recent discoveries show that a growing number of skeletal abnormalities result from mutations in the fibroblast growth factor receptors. These findings have led to a greater understanding of the role of fibroblast growth factor signaling during skeletogenesis and have focused research interests on the effects of fibroblast growth factors on endochondral and intramembranous bone development.

Alternative Splicing↗

PubMed2006

Marginal zinc deficiency exacerbates bone lead accumulation and high dietary zinc attenuates lead accumulation at the expense of bone density in growing rats.

Environmental lead exposure is associated with reduced bone growth and quality, which may predispose to osteoporosis. Zinc supplementation may reduce lead accumulation; however, effects on bone development have not been addressed. Our objective was to investigate the effects of marginal zinc (MZ) and supplemental zinc (SZ) intakes on bone lead deposition and skeletal development in lead-exposed rats. In a factorial design, weanling Sprague-Dawley rats were assigned to MZ (8 mg/kg diet); zinc-adequate control (CT; 30 mg/kg); zinc-adequate, diet-restricted (DR; 30 mg/kg); or SZ (300 mg/kg) groups, with and without lead acetate-containing drinking water (200 mg Pb/l) for 3 weeks. Excised femurs were analyzed for bone mineral density (BMD) by dual-energy x-ray absorptiometry, morphometry, and mineral content. MZ had higher femur lead and lower femur zinc concentrations and impaired skeletal growth and mineralization than CT. DR inhibited growth but did not result in higher femur lead concentrations than CT. SZ had higher femur zinc and lower femur lead concentrations than the other treatments. DR and SZ had impaired BMD versus CT and MZ. Lead also retarded skeletal growth and impaired BMD, but an interaction between lead and MZ was only found for femoral knee width, which was lower in MZ exposed to lead. In summary, while MZ deficiency exacerbated bone lead concentration, it generally did not intensify lead toxicity. SZ was protective against bone lead but was detrimental to BMD, suggesting that the optimal level of SZ to reduce lead absorption, while supporting growth and bone development, requires further investigation.

Animals↗

PubMed2006

Effect of ethnicity and sex on the growth of the axial and appendicular skeleton of children living in a developing country.

Bones in the axial and appendicular skeletons exhibit heterogeneous growth patterns between different ethnic and sex groups. However, the influence of this differential growth on the expression of bone mineral content is not yet established. The aims of the present study were to investigate: 1) whether there are ethnic and sex differences in axial and appendicular dimensions of South African children; and 2) whether regional segment length is a better predictor of bone mass than stature. Anthropometric measurements of stature, weight, sitting height, and limb lengths were taken on 368 black and white, male and female 9-year-old children. DXA (dual-energy x-ray absorptiometry) scans of the distal ulna, distal radius, and hip and lumbar spine were also obtained. Analyses of covariance were performed to assess differences in limb lengths, adjusted for differences in stature. Multiple regression analyses were used to assess significant predictors of site-specific bone mass. Stature-adjusted means of limb lengths show that black boys have longer legs and humeri but shorter trunks than white boys. In addition, black children have longer forearms than white children, and girls have longer thighs than boys. The regression analysis demonstrated that site-specific bone mass was more strongly associated with regional segment length than stature, but this had little effect on the overall pattern of ethnic and sex differences. In conclusion, there is a differential effect of ethnicity and sex on the growth of the axial and appendicular skeletons, and regional segment length is a better predictor of site-specific bone mass than stature.

Anthropometry↗

PubMed2003

Detection of bone sialoprotein in human (pre)neoplastic lesions of the uterine cervix.

Bone sialoprotein (BSP) is a secreted glycoprotein primarily found in the mineral compartment of developing bones. BSP is detected in a variety of human cancers, particularly those that metastasize to the skeleton. High expression of BSP in breast and prostate primary carcinomas is associated with progression and bone metastases development. Since squamous cell carcinoma (SCCs) of the uterine cervix also frequently metastasizes to bone, we investigated whether BSP is expressed in human cervical cancer. We examined BSP expression in cervical tissue samples from 47 patients, including 19 normal tissues, 20 squamous intraepithelial lesions (SILs) (9 low and 11 high grade) and 8 invasive SCCs. BSP protein expression was evaluated by the immunophosphatase technique using a BSP polyclonal antibody in paraffin-embedded cervical biopsies. The abundance of BSP protein was significantly higher in invasive SCCs and high grade SILs than in normal cervix tissue samples and low grade SILs, which showed no or a low level of anti-BSP immunoreactivity. In situ hybridization experiments performed on representative cervix invasive SCCs frozen sections revealed that BSP transcripts were detectable in these lesions. Our study demonstrates that BSP expression is a common feature in high grade SILs and invasive SCCs of the uterine cervix. The prognostic value of BSP detection in these lesions and the potential role of BSP as an angiogenic factor in this type of cancer are currently under investigation.

Biomarkers, Tumor↗

PubMed2001

Neuropilin-1 expression in osteogenic cells: down-regulation during differentiation of osteoblasts into osteocytes.

The expression of neuropilin-1 (NRP1), a recently described VEGF and semaphorin receptor expressed by endothelial cells (EC) but some non-EC types as well, was analyzed in osteoblasts in vitro and in vivo. Cultured MC3T3-E1 osteoblasts expressed NRP1 mRNA and bound VEGF(165) but not VEGF(121), characteristic of the VEGF isoform-specific binding of NRP1. These cells did not express VEGFR-1 or VEGFR-2 so that VEGF binding to osteoblasts was strictly NRP1-dependent. In a chick osteocyte differentiation system, NRP1 was expressed by osteoblasts but its expression was absent as the cells matured into osteocytes. Immunohistochemical localization of NRP1 within the developing bones of 36-day-old mice and embryonic Day 17 chicks demonstrated that NRP1 was expressed by osteoblasts migrating alongside invading blood vessels within the metaphysis of the growth plate, as well as by osteoblasts at the developing edge of trabeculae within the marrow cavity. On the other hand, NRP1 was not expressed by osteocytes in either species, consistent with the in vitro results. In addition to osteogenic cells, NRP1 expression by EC was observed throughout the bone. Together these results suggest that NRP1 might have a dual function in bone by mediating osteoblast function directly as well as angiogenesis.

3T3 Cells↗

PubMed1986

Aluminum and renal osteodystrophy.

Bone disease is recognized as a major problem in dialysis patients. initially, hyperparathyroidism was thought to be the major cause of bone disease in these patients. However, an aluminum-related bone disease has been identified in dialysis patients receiving exogenous aluminum. Patients with hyperparathyroidism and aluminum toxicity present with similar clinical and laboratory features; therefore, diagnosis of these two bone abnormalities is often difficult. Understanding normal bone development helps to elucidate the distinctions between aluminum and renal osteodystrophy. Patients with either bone syndrome may present with hypercalcemia, elevations in parathyroid hormone levels, bone pain, fractures, and radiographic evidence of subperiosteal resorption. The subtleties of these syndromes must be understood to avoid misdiagnosis. A diagnosis of hyperparathyroidism may lead to a parathyroidectomy, exacerbating the development of aluminum toxicity. Hyperparathyroidism is associated with increased surface osteoid, a high bone formation rate, increased numbers of bone cells, abnormal "twoven" osteoid, and low serum aluminum levels. Aluminum toxicity is associated with a low rate of bone turnover, paucity of bone cells, maintenance of a "laminar" osteoid, and significant aluminum bone deposition. Serum aluminum level measurements are key to the diagnosis of aluminum toxicity. For patients displaying intermediate aluminum values, the deferoxamine (DFO) challenge test is necessary for diagnosis. If noninvasive methods fail to determine a definitive diagnosis, a bone biopsy is required.

Aluminum↗

PubMed1993

1,25-Dihydroxy vitamin D3 stimulation of TGF-beta expression in chick embryonic calvarial bone.

Bone is a highly active producer of the cytokine, transforming growth factor-beta (TGF-beta), which is likely to be functionally involved in the regulation and maintenance of bone development and growth. In addition, bone functions are also regulated by the major calciotropic hormone, 1,25-dihydroxy vitamin D3 (1,25(OH)2D3). This investigation aims to examine the possible relationship between TGF-beta and 1,25(OH)2D3 using an unique calcium-deficient chick embryonic model. By means of long-term culture without the eggshell (shell-less or SL culture), chick embryos may be rendered severely calcium-deficient with gross undermineralization of the skeleton. We have previously observed that the calvaria of these SL embryos develop abnormal chondrogenic phenotype, with production of collagen type II, and elevated TGF-beta expression. Administration of 1,25(OH)2D3 to the SL embryos in vivo on incubation days 10 and 12 (SL + D embryos) resulted in near-normal serum calcium on day 14 and improved calvarial calcification. However, TGF-beta expression in the SL + D calvaria was further increased compared to untreated SL calvaria, when analyzed at both the mRNA and protein levels. Histolocalization of gene expression by immunohistochemistry and in situ hybridization revealed that cells in the less mineralized orbital and temporal zones of the calvarium are particularly affected by the 1,25(OH)2D3 treatment. Interestingly, the increased TGF-beta expression resulting from 1,25(OH)2D3 treatment did not correct the aberrant collagen phenotype in the SL calvaria. These observations suggest that TGF-beta expression by bone cells in situ is stimulated by 1,25(OH)2D3, and that normal cellular differentiation and morphogenesis of the embryonic calvaria are dependent on proper and balanced TGF-beta expression as well as the state of tissue mineralization.

Animals↗

PubMed2006

The role of bone markers in metastatic bone disease.

Patients with advanced cancer often develop bone metastases that lead to significant skeletal morbidity and substantially reduced functionality and autonomy [Coleman RE, Rubens RD. Bone metastases. In: Clinical Oncology, 2nd edn. New York: Churchill Livingstone. 2004, p. 1091-128]. As current methods of diagnosing bone metastases are cumbersome and not cost-effective, there is great interest in exploring the potential of biochemical assays that measure bone turnover activity. These markers may have value in measuring metastatic bone disease (MBD) progression and identifying patients at higher risk for metastases. Bone markers are also being evaluated as a possible guide to optimize treatment of bone complications. In the reports included in this supplement, experts at the frontiers of bone marker research offer insights on their progress.

Biomarkers, Tumor↗

PubMedDate not supplied

The toxic and teratogenic effect of aflatoxin B1 on the chick embryo development.

The embryotoxic and teratogenic effect of aflatoxin B1 was tested on the chick embryo. Aflatoxin B1 was injected into the embryonic area in doses of 1/100 ppm and 1/500 ppm in the 96th h of incubation. Aflatoxin B1 toxicity caused a rise in the mortality rate from 6.6% (controls) to 35% in the chicken injected with 1/100 ppm aflatoxin B1 and to 26% in the lot given 1/500 ppm. Several malformations were also noticed: spina bifida, anophthalmia, maxillary retrognathism, distorted legs and evisceration; the group receiving 1/100 ppm aflatoxin B1 also showed bone development retardation of the wing, leg, maxilla and mandible.

Abnormalities, Drug-Induced↗

PubMed1997

Parathyroid hormone-related protein and bone metastases.

Parathyroid hormone-related protein (PTH-rP) was purified and cloned 10 years ago as a factor responsible for the hypercalcemia associated with malignancy. Clinical evidence supports another important role for PTH-rP in malignancy as a mediator of the bone destruction associated with osteolytic metastasis. Patients with PTH-rP positive breast carcinoma are more likely to develop bone metastasis. In addition, breast carcinoma metastatic to bone expresses PTH-rP in >90% of cases, compared with only 17% of metastasis to nonbone sites. These observations suggest that PTH-rP expression by breast carcinoma cells may provide a selective growth advantage in bone due to its ability to stimulate osteoclastic bone resorption. Furthermore, growth factors such as transforming growth factor-beta (TGF-beta), which are abundant in bone matrix, are released and activated by osteoclastic bone resorption and may enhance PTH-rP expression and tumor cell growth. To investigate the role of PTH-rP in the pathophysiology of breast carcinoma metastasis to bone, the human breast carcinoma cell line MDA-MB-231 was studied in a murine model of human breast carcinoma metastasis to bone. A series of experiments were performed in which 1) PTH-rP secretion was altered, 2) the effects of PTH-rP were neutralized, or 3) the responsiveness to TGF-beta was abolished in MDA-MB-231 cells. Cultured MDA-MB-231 cells secreted low amounts of PTH-rP that increased fivefold in response to TGF-beta. Tumor cells inoculated into the left cardiac ventricle of nude mice caused osteolytic metastasis similar to that observed in humans with breast carcinoma. When PTH-rP was overexpressed in the tumor cells, bone metastases were increased. MDA-MB-231 cells transfected with the cDNA for human preproPTH-rP secreted a tenfold greater amount of PTH-rP and caused significantly greater bone metastases when inoculated into the left cardiac ventricle of female nude mice compared with parental cells. In contrast, when the biologic effects of PTH-rP were neutralized or its production was suppressed, such metastases were decreased. Treatment of mice with a neutralizing monoclonal antibody to human PTH-rP resulted in a decrease in the development and progression of bone metastasis due to the parental MDA-MB-231 cells. Similar results were observed when mice were treated with dexamethasone, a potent glucocorticoid that suppresses production of PTH-rP by the MDA-MB-231 cells in vitro. The role of bone-derived TGF-beta in the development and progression of bone metastasis was studied by transfecting MDA-MB-231 cells with a cDNA encoding a TGF-beta type II receptor lacking a cytoplasmic domain, which acts as a dominant negative to block the cellular response to TGF-beta. Stable clones expressing this mutant receptor (MDA/TbetaRIIdeltacyt) did not increase PTH-rP secretion in response to TGF-beta stimulation compared with controls of untransfected MDA-MB-231 or those transfected with the empty vector. Mice inoculated into the left cardiac ventricle with MDA/TbetaRIIdeltacyt had fewer and smaller bone metastases as assessed radiographically and histomorphometrically compared with controls. Taken together, these data suggest that PTH-rP expression by breast carcinoma cells enhance the development and progression of breast carcinoma metastasis to bone. Furthermore, TGF-beta responsiveness of breast carcinoma cells may be important for the expression of PTH-rP in bone and the development of osteolytic bone metastasis in vivo. These interactions define a critical feedback loop between breast carcinoma cells and the bone microenvironment that may be responsible for the alacrity with which breast carcinoma grows in bone.

Animals↗

PubMedDate not supplied

Postoperative PINP in serum reflects metastatic potential and poor survival in node-positive breast cancer.

The aim of this work was to evaluate the postoperative serum markers of type I collagen synthesis (PINP,PICP) and degradation (ICTP) and their possible potential for predicting the spread of disease and survival. 373 node-positive breast cancer patients were enrolled. 120 patients (32%) developed recurrent disease in the follow-up. The mean time to recurrence was 17 months and the mean follow-up time was 45 months. The mean level of PINP was significantly elevated in the patients who developed metastatic disease in the follow-up as compared with those without metastases. PINP was statistically significantly higher in all the patients who developed bone metastases than in those without metastases. When patients with only bone metastases or patients with bone and soft tissue and/or visceral metastases and patients with only visceral or soft tissue metastases were compared with those not exhibiting metastases, PINP was significantly higher in the group with recurrence in the bone, but there were no significant differences in serum PINP, PICP or ICTP values between the patients with only bone metastases and those who developed soft or visceral metastases during the follow-up. Postoperative high PINP was also a factor for poorer survivaL Tumor size, malignancy grade and progesterone receptors were shown in multivariate analysis to be predictors of recurrence and tumor size and PINP and progesterone receptors to be predictors of survivaL

Antineoplastic Agents, Hormonal↗

PubMed1987

[Influence of stromal cells on the development of allogeneic bone marrow grafts].

The development of long-term in vitro marrow culture techniques has allowed in vitro characterization of the cellular composition and functional attributes of the human bone marrow stromal microenvironment. Interest in these studies has increased because the interactions between hematopoiesis and the microenvironment through direct cellular contact or production of inhibiting or stimulating factors are better known. The role of the microenvironment in bone marrow transplantation needs further study. The main points of interest are: the role of the host microenvironment in sustaining engraftment, the influence of marrow manipulations on the microenvironment of the donor marrow inoculum, the role of the microenvironment on the establishment of complete chimerism and in the host-donor interactions.

Bone Marrow Cells↗

PubMed1994

Ethnic and genetic differences in susceptibility to osteoporotic fractures.

A plethora of investigations in recent years has demonstrated the occurrence of ethnic differences in bone mineral content, bone density and fracture rates. These findings indicate that genetic determinants exist both for bone development during growth and for bone loss during aging. Twin and parent-offspring studies have corroborated the existence of a hereditary component. It is most evident in the greater bone mass and lower fracture rate in blacks than in whites. Differences in bone mass between Asians and whites are less clear than between blacks and whites because of disparities in body size and other confounding factors. Black children and adults excrete less urinary calcium than whites on essentially the same diets and consequently retain more calcium in their skeletons. Better calcium retention is commensurate with the faster rate of bone growth of black children.

Adolescent↗

PubMed1995

Bone metabolic markers in bone metastases.

The efficacy and cost/performance benefit of radionuclide bone scintigraphy in monitoring metastatic bone activity remain controversial. Recently developed bone metabolic markers are expected to play an additional role in the diagnosis of bone metastasis. We measured osteoclastic and osteoblastic markers in 267 patients with breast cancer (100 with bone metastasis), 38 patients with prostatic cancer (25 with bone metastasis), 50 patients with lung cancer (12 with bone metastasis) and 33 patients with miscellaneous cancers (13 with bone metastasis) and compared the values in the presence and absence of bone metastasis. Bone metabolic markers, both osteoclastic and osteoblastic, increased significantly in patients with bone metastasis. In breast cancer (bone metastasis is mostly of the mixed type), osteoclastic markers were good in detecting bone metastasis. In prostatic cancer (bone metastasis is mostly osteoblastic), osteoclastic and osteoblastic markers were equally effective in detecting bone metastasis. In lung cancer (bone metastasis is mostly osteolytic), osteoclastic markers were elevated preferentially in bone metastasis. Over all, osteoclastic markers were more sensitive in the diagnosis of bone metastasis, and among osteoclastic markers, serum pyridionoline-cross-linked carboxyterminal telopeptide was the most efficient in both specificity (91.0%) and sensitivity (48.6%) for detecting bone metastasis.

Aged↗