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PubMed1989

Hematopoiesis on cellulose ester membranes. XI. Induction of new bone and a hematopoietic microenvironment by matrix factors secreted by marrow stromal cells.

Cellulose ester membranes (CEM) were coated with stromal cells from bone marrow (BM) or bone and implanted intraperitoneally (IP) in CAF1 mice for intervals of 1 to 6 months. Previous studies indicated that matrix factors [glycoproteins (GPs), proteoglycans (PGs), and glycosaminoglycans (GAGs)] were secreted by the regenerating stromal cells and adsorbed by the CEM. After 1 to 6 months, the CEMs were removed, scraped free of adherent cells, and irradiated in vitro with 40 Gy. The scraped and irradiated CEMs were then reimplanted IP or subcutaneously (SC) for periods of 1 to 6 months in secondary syngeneic murine hosts. They were then removed for histologic study. CEMs reimplanted in SC sites developed bone and hematopoiesis as early as 1 month after implantation. Maximum hematopoiesis and bone formation was observed after 3 months. CEMs coated during the initial implantation with bone-derived stromal cells contained more bone and hematopoietic cells than did CEMs coated with marrow-derived stromal cells after SC implementation. Neither the CEMs coated with bone stromal cells nor those coated with marrow stromal cells developed new bone or trilineal hematopoiesis after being implanted IP. A few CEMs contained small foci of granulopoiesis only. We conclude that noncellular matrix substances deposited on CEMs by bone, and to a lesser degree by marrow cells, can induce prestromal cells in the SC tissues to produce a microenvironment suitable for trilineal hematopoiesis.

Animals↗
PubMed2003

Some aspects of the fetal doses given in ICRP Publication 88.

The International Commission on Radiological Protection (ICRP) has recently published dose coefficients (dose per unit intake, Sv Bq(-1)) for the offspring of women exposed to radionuclides during or before pregnancy. These dose estimates include in utero doses to the embryo and fetus and doses delivered postnatally to the newborn child from radionuclides retained at birth. This paper considers the effect on doses of the time of radionuclide intake and examines the proportion of dose delivered in utero and postnatally for different radionuclides. Methods used to calculate doses to the fetal skeleton are compared. For many radionuclides, doses are greatest for intakes early in pregnancy but important exceptions, for which doses are greatest for intakes later in pregnancy, are iodine isotopes and isotopes of the alkaline earth elements, including strontium. While radionuclides such as 131I deliver dose largely in utero, even for intakes late in pregnancy, others such as 239Pu deliver dose largely postnatally, even for intakes early during pregnancy. For alpha emitters deposited in the skeleton, the assumption made is of uniform distribution of the radionuclide and of target cells for leukaemia and bone cancer in utero; that is, the developing bone structure is not considered. However, for beta emitters, the bone structure was considered. Both approaches can be regarded as reasonably conservative, given uncertainties in particular in the location of the target cells and the rapid growth and remodelling of the skeleton at this stage of development.

Aging↗
PubMed1987

Pathogenesis of osteoporosis.

Five major risk factors for osteoporosis have been identified: age, initial bone density, the menopause, bioavailability of calcium, and sporadic factors. Age appears to be the major determinant of bone mass. During a lifetime, a woman will typically lose 50% of her trabecular bone and 35% of her cortical bone. Bone density is affected by the amount of bone developed during growth, as well as by the subsequent rate of loss. Strong evidence has shown that loss of ovarian function leads to an accelerated phase of bone loss. Bone turnover rates increase, but resorption occurs faster than formation. This acceleration slows with time, reaching the level of the underlying slower phase of bone loss approximately 10 years after the onset of menopause. The role of calcium intake in preventing osteoporosis remains a matter of debate. Other factors shown to affect the risk of osteoporosis include low weight, smoking, alcohol intake, and degree of physical activity. The fact that not all postmenopausal women develop osteoporosis suggests that other, as-yet-undetermined factors may play a role in this condition.

Aged↗
PubMed2000

Involvement of Ets transcription factors and targets in osteoblast differentiation and matrix mineralization.

The osteoblast-like MC3T3-E1 cell line provides an excellent in vitro model of bone development. This system undergoes three orderly time-dependent phases characterized by proliferating preosteoblasts, matrix accumulation by postmitotic differentiating osteoblasts, and mineralization of the matrix, which results in the formation of multilayered bone nodules. The Ets family transcription factors regulate genetic programs that affect the proliferation and differentiation of osteoblasts. Of the eight Ets family transcription factors examined by our laboratory, only Etsl and Ets2 were found to be expressed at significant levels in this osteogenic system. Etsl is expressed in proliferating preosteoblastic cells, whereas Ets2, silent during this phase, is expressed by differentiating and mature osteoblasts. In addition, the expression of Etsl can be induced in MC3T3-E1 and fetal rat calvaria cells by retinoic acid (RA) which is known to exert profound effects on skeletal growth and development and bone turnover and induce specific cellular responses in bone cells. Thus, the multiple functions of RA in bone cells are likely to be mediated in part by Etsl. We show that the expression of Ets2 precedes and then parallels osteopontin expression and that the OPN promoter contains Ets binding sites and is a transcriptional target of Ets2. In order to identify other potential Ets target genes, we analyzed promoter regions of genes revealed by serial analysis of gene expression as present in the differentiation stage. The functional analysis of these genes has the potential to provide much needed information as to their function in osteogenesis and mineralization of the extracellular matrix and in bone-related diseases.

Animals↗
PubMed1999

New Treatment Strategy for Bone Metastases from Breast Cancer.

Breast cancer patients frequently develop bone metastasis. Parathyroid hormone-related protein, an osteoclast activating factor, might be necessary for tumorto erode bone and grow at skeletal site. Bisphosphonates have an affinity for bone and are potent inhibitors of osteoclastic bone resorption. In light of this,53 patients with bone metastasis from breast cancer were treated with chemoendocrine(mainly high-dose medroxyprogesterone acetate as the endocrine therapy) therapy + bisphosphonate (pamidronate, Aredia (R)). During the previous 6 years (median 27 months), 53 breast cancer patients with bone metastasis were treated with pamidronate + chemoendocrine therapy. The regimen consisting of pamidronate + chemoendocrine agent was administered to 27 patients as a post relapse first-line regimen and to the remaining 26 cases, which failed first- or second-line treatment as a second or third line regimen. As a result of the combination therapy, sclerotic changes were observed in the osteolytic lesions in 31 of the 53 patients (59%). The effect on the osteolytic lesions did not correlate with the duration of disease free interval, estrogen receptor (ER) status, presence/absence of previous therapy or number of " hot spot(s) ] on bone scintigraphy. Lessening of pain from the bone metastasis was achieved in 83% of the patients after 3 months of pamidronate administration. Pamidronate + chemoendocrine therapy seems highly promising.

Journal Article↗
PubMed2000

Prevention of metastasis by a polyamine synthesis inhibitor in an animal bone metastasis model.

In order to better understand the development of skeletal metastases, we developed an appropriate animal model, as the natural progression of metastases in humans cannot be studied on the cellular level. In this study, we established a new animal model which developed bone metastasis in a bone grafted subcutaneously. C57BL/6 mice, which had received a bone (femur or tibia) transplanted in the dorsal subcutis, were injected with B16 melanoma cells into the left heart ventricle. Metastasis was found in approximately 70% of the extraskeletal bones. Using this model, the antimetastatic effect of a polyamine synthesis inhibitor was investigated. Inhibitors of the polyamine biosynthetic pathway have received considerable attention for their potential use in the treatment of cancer as they are responsible for the greatly increased production of the polyamines putrescine, spermidine, and spermine. A polyamine synthesis inhibitor, methylglyoxal-bis(cyclopentylamidinohydrazone) MGBCP, was investigated for its inhibitory effects on bone metastases. MGBCP (20 mg/kg) was administered intraperitoneally every day for 4 weeks and demonstrated strong inhibitory effects on bone metastases. MGBCP inhibited angiogenesis in the transplanted bone and the growth of B16 melanoma cells, thus suggesting a preventive mechanism in bone metastasis. No remarkable adverse effects of MGBCP were observed in any animal throughout the experimental period. Our results indicate that MGBCP has a strong potential for use as an anti-metastatic drug.

Animals↗
PubMed1999

Growth retardation in children with chronic renal failure.

Growth retardation is a major obstacle to full rehabilitation of children with chronic renal failure (CRF). Several factors have been identified as contributors to impaired linear growth and they include protein and calorie malnutrition, metabolic acidosis, growth hormone resistance, anemia, and renal osteodystrophy. Although therapeutic interventions such as the use of recombinant human growth hormone, recombinant human erythropoietin, and calcitriol have made substantial contributions, the optimal therapeutic strategy remains to be defined. Indeed, growth failure persists in a substantial proportion of children with renal failure and those treated with maintenance dialysis. In addition, the increasing prevalence of adynamic lesions of renal osteodystrophy and its effect on growth have raised concern about the continued generalized use of calcitriol in children with CRF. Recent studies have shown the critical roles of parathyroid hormone-related protein (PTHrP) and the PTH/PTHrP receptor in the regulation of endochondral bone formation. The PTH/PTHrP receptor mRNA expression has been shown to be down-regulated in kidney and growth plate cartilage of animals with renal failure. Differences in the severity of secondary hyperparathyroidism influence not only growth plate morphology but also the expression of selected markers of chondrocyte proliferation and differentiation in these animals. Such findings suggest potential molecular mechanisms by which cartilage and bone development may be disrupted in children with CRF, thereby contributing to diminished linear growth.

Bone Development↗
PubMed1975

The development of vertebral bone marrow of human fetuses.

The development of the bone marrow of the thoracic vertebrae in seven human fetuses ranging from 95 to 150 mm in crown-rump length (CRL) was studied using light and electron microscopy. In the 95-mm CRL, hypertrophy of the chondrocytes occurred in the central region of the vertebrae, and blood vessels penetrated there from dorsal and ventral sides of the vertebral body. The primary marrow was represented by liberated cartilage lacunnae, occupied by the thin-walled blood vessels and a few mesenchymal cells and mononuclear cells containing granules or vacuoles (GMC). In the 99-mm CRL, chondroclasts were active in removing the cartilage near the central region of the vertebrae. Consequently, a large cavity was formed and occupied by a dilated sinus. GMC were numerous. Osteoblasts and osteocytes were increased in number. Reticular cells with long processes containing large amounts of glycogen began to appear in the extravascular space and formed the loosely arranged cellular meshwork of the hematopoietic compartment. Bundles of collagen fibrils were scattered in the meshwork. Hematopoietic cells were recognizable only in the 105-mm-CRL fetus and increased in number in the 120-mm-CRL fetus. The sinus endothelium was very thin and continuous without apertures except where blood cells crossed the wall. The developing blood cells lying against the outside of the sinus endothelium indented it. At points, collagen fibrils attached to the outside of endothelial cells and appeared to function as the anchoring filaments of lymphatics. The physiologic implications of the association of stromal cells, vascular sinuses, and hematopoietic cells are discussed in relationship to the microhematopoietic environment of the bone marrow.

Bone Marrow↗
PubMed2006

T-lymphoid, megakaryocyte, and granulocyte development are sensitive to decreases in CBFbeta dosage.

The family of core-binding factors includes the DNA-binding subunits Runx1-3 and their common non-DNA-binding partner CBFbeta. We examined the collective role of core-binding factors in hematopoiesis with a hypomorphic Cbfb allelic series. Reducing CBFbeta levels by 3- or 6-fold caused abnormalities in bone development, megakaryocytes, granulocytes, and T cells. T-cell development was very sensitive to an incremental reduction of CBFbeta levels: mature thymocytes were decreased in number upon a 3-fold reduction in CBFbeta levels, and were virtually absent when CBFbeta levels were 6-fold lower. Partially penetrant consecutive differentiation blocks were found among early T-lineage progenitors within the CD4- CD8- double-negative 1 and downstream double-negative 2 thymocyte subsets. Our data define a critical CBFbeta threshold for normal T-cell development, and situate an essential role for core-binding factors during the earliest stages of T-cell development.

Alleles↗
PubMed1994

Immunohistology of bone proteins, bone quality, and bone turnover.

The role played by noncollagenous proteins in bone metabolism, originally conceived as mainly related to the promotion and regulation of matrix mineralization, probably involves a number of regulatory functions. Local composition of the bone matrix may affect cell responses to regulatory agents in different ways, which include binding of growth factors within the pericellular environment, and integrins on the cell surface. The focus of studies on the expression and localization of bone proteins in intact tissues should therefore move towards a detailed dissection of heterogeneity of matrix locales throughout bone development, growth, and postnatal remodeling. So far, such studies have provided valuable information on the diverse phenotypic profiles of maturational stages of bone cells, and more recently, on actual differences in secretory output of cells otherwise comprised in the 'mature' osteoblastic compartment. Still, a main gap in current information is represented by the paucity of data on bone protein expression and deposition during post-natal remodeling and its diseases. Filling this gap will require a more focused interest in post-natal (trabecular) bone, and the development of appropriate protocols of tissue preparation (noncollagenous) proteins in bone physiology.

Bone Matrix↗
PubMed2005

[Examination of infant bone status with quantitative ultrasound at birth].

OBJECTIVE: Quantitative ultrasound (QUS) is a new method of evaluating Children's bone status, including bone mineral density and bone strength. The bone nutrition during fetal and early neonatal period is very important for the human bone development of whole life. The objective of this study was to evaluate the clinical application of QUS for newborn infants and to obtain the QUS data for normal neonates including premature infants. METHODS: An ultrasound bone sonometer, Omnisense, produced by Sunlight company of Israel, was applied to measure the bone speed of sound (SOS) of tibia in 157 neonates including 68 premature infants in the first week of life. RESULTS: (1) No significant difference in SOS was found between male (n = 88, SOS = 2968 +/- 115 m/s) and female infants (n = 69, SOS = 2956 +/- 105 m/s) (P = 0.524). The SOS of premature infants (n = 68, mean gestational age 33.0 +/- 2.5 weeks) and full-term infants (n = 89, mean gestational age of 39.4 +/- 1.3 weeks) were 2935 +/- 96 m/s and 2984 +/- 116 m/s, respectively, at birth and there was significant difference between them (P = 0.005). (2) There were significant differences of SOS in neonates who were born in different seasons (F = 4.377, P = 0.005); the significant difference remained (F = 3.933, P = 0.010) after the influences of gestational age and birth weight were eliminated. The SOS in neonates born in spring (March, April and May) and summer (June, July and August) were significantly lower than that of those born in autumn (September, October and November) and winter (December, January and February). The SOS in neonates born in summer was about 2.3% (75/2999) was lower than that of those born in winter. (3) Significant difference of SOS was observed between neonates with different birth weight [< 1500 g (n = 11), SOS = 2968 +/- 115 m/s; and > 2500 g (n = 86), SOS = 2980 +/- 113 m/s; P = 0.042]. (4) Significant correlations were found between SOS and gestational age (r = 0.270, P = 0.005), and between bone SOS and birth weight (r = 0.232, P = 0.015) in appropriate for gestational age (AGA) infants (n = 109); however, no such significant correlations were found in small for gestational age (SGA) infants or large for gestational age (LGA) infants. Multiple regression analysis showed that gestational age and the birth season were two important factors which may contribute to bone SOS of neonates at birth (n = 157, F = 8.515, P < 0.001, adjusted R(2) = 0.141), when the analysis was carried out with SOS as dependent variable and gestational age, birth weight, chronological age, calf length and the birth season as independent variables. CONCLUSION: QUS is a new method which is suitable for evaluating the bone status of neonates and it is free of radiation, non-invasive, the machine is portable and easy to manipulate at infant bed side. The present study suggests the need for particular care for the bone status in premature infants and supplement of vitamin D in pregnant women.

Bone Density↗
PubMed1997

Influence of electromagnetic fields on bone mass and growth in developing rats: a morphometric, densitometric, and histomorphometric study.

The effect of electromagnetic fields on bone is debated. In an experimental study of this effect, we compared two lots of growing female rates (both lots n = 15, age 3 weeks, average weight 23.2 +/- 3.3 g), one of which was exposed to a 3-mT, 100-Hz, Helmholtz-type electromagnetic field for 24 hours a day for 30 days, and the other of which served as the control. Bone development and bone mass were evaluated by morphometry, densitometry, and histomorphometry. The rats were killed at 30 days and weighed. The right femurs were dissected, measured, and weighed; bone densitometry was used to determine femoral bone mineral content (BMC) and density (BMD), and histomorphometry of the nondecalcified bone was used to determine trabecular bone volume (Cn-BV-TV%), number (Tb-N mm) and thickness (Tb-Th microm), intertrabecular space (Tb-Sp microm) and growth cartilage thickness (Gc-Th microm). In the rats exposed to the electromagnetic field, BMC and BMD (P = 0.019 and P = 0.002, respectively) and Cn-BV-TV, Tb-N, Tb-Th (P = 0.005, P = 0.036, and P = 0.027, respectively) all were decreased, whereas Tb-Sp was increased (P = 0.002). There were no significant differences in initial and final body weight, or in final femur weight, femur length, and GC-Th. These findings indicate that electromagnetic fields of the type used here reduced bone formation and increased bone resorption without affecting bone development in rats.

Absorptiometry, Photon↗
PubMed2005

Gene disruption of Spred-2 causes dwarfism.

The impact of the fibroblast growth factor receptor 3 (FGFR3)-mediated signaling pathway on bone growth has been demonstrated by various genetic approaches. Overexpression of fibroblast growth factors (FGFs), several gain-of-function mutations in the FGFR3, and constitutive activation of mitogen-activated protein kinase (MAPK) kinase (MEK1) in chondrocytes have been shown to cause dwarfism in mice by activation of the MAPK signaling pathway. To investigate the previously reported inhibitory role of Spred in the FGFR3/MAPK pathway, we generated mice with a trapped Spred-2 gene. Here we show that lack of functional Spred-2 protein in mice caused a dwarf phenotype, similar to achondroplasia, the most common form of human dwarfism. Spred-2(-/-) mice showed reduced growth and body weight, they had a shorter tibia length, and showed narrower growth plates as compared with wild-type mice. We detected promoter activity and protein expression of Spred-2 in chondrocytes, suggesting an important function of Spred-2 in chondrocytes and bone development. Stimulation of chondrocytes with different FGF concentrations showed earlier and augmented ERK phosphorylation in Spred-2(-/-) chondrocytes in comparison to Spred-2(+/+) chondrocytes. Our observations suggest a model in which loss of Spred-2 inhibits bone growth by inhibiting chondrocyte differentiation through up-regulation of the MAPK signaling pathway.

Animals↗
PubMed2003

Bone metastases in breast cancer.

Patients with advanced breast cancer who develop bone metastases suffer from long-term skeletal morbidity. Complications of bone metastases include pain, pathologic fractures, and spinal cord compression, which have a significant impact on the quality of life of patients. Treatment options for patients with bone metastases include surgery, radiation, and analgesics to reduce bone pain and to prevent or repair fractures. Intravenous bisphosphonates can delay the onset of bone metastasis and reduce the percentage of patients who experience skeletal complications of bone metastasis, thus reducing skeletal morbidity. For the past 6 years, pamidronate disodium (90 mg administered by 2-hour intravenous infusion) has been the treatment of choice for the prevention of skeletal complications of bone metastases in patients with breast cancer. However, a more potent bisphosphonate, zoledronic acid (4 mg administered by 15-minute intravenous infusion), was approved for use and has improved efficacy in patients with bone metastases. Because of the increased efficacy and more convenient infusion time, zoledronic acid may become the new standard of care for the treatment and prevention of skeletal complications secondary to bone metastases in patients with breast cancer. Phase III clinical trials have shown that patients with an existing skeletal complication are more likely to develop subsequent complications compared with patients who have not experienced a complication. Therefore, zoledronic acid therapy should be initiated when the patient is diagnosed with bone metastasis.

Antineoplastic Agents↗
PubMed1985

Type X collagen synthesis by chick sternal cartilage and its relationship to endochondral development.

Our morphological studies have demonstrated that the appearance of localized, paired zones of primary calcification on either side of the midline of the 19-d embryonic chick sternum is heralded by the development of paired, translucent zones 2 d previously. Histological studies demonstrated that the majority of chondrocytes within these translucent zones are hypertrophic, and that the zones are surrounded by a margin of flattened nonhypertrophic cells. The discrete localization of these paired areas of hypertrophic chondrocytes and subsequent endochondral bone development allows for the direct correlation of the histological and biochemical characteristics of the zones sequentially during development and makes it possible to precisely match the synthetic activity to the cellular morphology, thereby eliminating possible minor but critical variations in developmental staging that could otherwise arise. Our studies have demonstrated that there is a direct spatial and temporal correlation between the degree of cellular maturation and the synthesis of type X collagen, and that the sudden and profound initiation of type X collagen synthesis on days 16-17 of development occurs concurrently with the attainment of hypertrophic characteristics by the majority of cells within the translucent zone. Before acquisition of these hypertrophic characteristics, the cells of this precalcification zone synthesize only type II and the minor cartilage collagens. Chondrocytes isolated from these regions in more immature sternae (i.e., 11+ d embryos) were found to synthesize high levels of type X collagen within 4 d of culture within collagen gels even though hypertrophic development and type X collagen synthesis by cells within this region would not normally have been apparent in ovo for several more days. These data indicate that there is a direct correlation between the development of hypertrophic characteristics and the synthesis of type X collagen, and that the maturation of chondrocytes in precalcification zones may be regulated by matrix components and/or stimulated by culture within collagen gels.

Age Factors↗
PubMed2005

IL-1 receptor-associated kinase M is a central regulator of osteoclast differentiation and activation.

Osteoporosis is a serious problem worldwide; it is characterized by bone fractures in response to relatively mild trauma. Osteoclasts originate from the fusion of macrophages and they play a central role in bone development and remodeling via the resorption of bone. Therefore, osteoclasts are important mediators of bone loss that leads, for example, to osteoporosis. Interleukin (IL)-1 receptor (IL-1R)-associated kinase M (IRAK-M) is only expressed in cells of the myeloid lineage and it inhibits signaling downstream of IL-1R and Toll-like receptors (TLRs). However, it lacks a functional catalytic site and, thus, cannot function as a kinase. IRAK-M associates with, and prevents the dissociation of, IRAK-IRAK-4-TNF receptor-associated factor 6 from the TLR signaling complex, with resultant disruption of downstream signaling. Thus, IRAK-M acts as a dominant negative IRAK. We show here that mice that lack IRAK-M develop severe osteoporosis, which is associated with the accelerated differentiation of osteoclasts, an increase in the half-life of osteoclasts, and their activation. Ligation of IL-1R or TLRs results in hyperactivation of NF-kappaB and mitogen-activated protein kinase signaling pathways, which are essential for osteoclast differentiation. Thus, IRAK-M is a key regulator of the bone loss that is due to osteoclastic resorption of bone.

Animals↗
PubMed1994

The effects of the inflammatory response on bone growth.

The inflammatory response is a process which forms a defence against the effects of trauma or invasion by foreign organisms or substances. Inflammation is mediated by local and systemic changes in expression of its activators and inhibitors. Many of these regulators of inflammation are also the controllers of normal cellular activity, so the effects of inflammation are due to changes in the amounts, ratios and timings of their expression, rather than de novo expression of specific mediators of inflammation. The effects of inflammation on bone growth are two-fold. Firstly, systemic inflammatory effects have consequences on hormone, mineral and nutrient metabolism which affect bone growth. Secondly, cytokine mediators of inflammation cause local changes in cell regulation to influence both endochondral processes in the growth plate, and modelling and remodelling activity associated with appositional growth. The complexity of the osteotropic influences responsible for maintaining normal bone development mean that inflammatory process will have different and unpredictable effects on linear growth at different times, and under different nutritional, biochemical, physical and psychological circumstances. This review will examine the effects of systemic and local changes in inflammation which have effects on bone growth and remodelling, focusing on systemic effects of the acute phase response, and the local actions of the eicosanoids and three cytokines with particularly potent actions on the metabolism of cells in bone and cartilage.

Adolescent↗