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PubMed1988

Cytological and functional studies of preosteoclasts and osteoclasts in the alveolar bones from neonatal rats using microperoxidase as a tracer.

Microperoxidase (MP) was used to investigate the cytological and functional features of preosteoclasts and osteoclasts during rat alveolar bone development. We observed mononuclear cells as preosteoclasts and multinuclear cells with and without ruffled borders (RB). In the bone facing multinuclear cells with RB as active osteoclasts, MP was extensively deposited along the external bone matrix undergoing resorption, and was phagocytosed with bone components into the vacuoles of osteoclasts. Neither preosteoclasts nor multinuclear cells without RB took up MP and bone components. Only multinuclear cells with RB seemed to resorb bone. Monocytes/macrophages (MMP) phagocytosed MP through all regions of the plasma membrane, whereas osteoclasts took up MP only through the RB which was a part of the plasma membrane. Endogenous peroxidase was detected in the MMP but not in preosteoclasts and osteoclasts. Thus, osteoclasts were considerably different from the MMP. The numbers of MMP were extremely few close to the osteoclasts, whereas moderate numbers of preosteoclasts were located close to the osteoclasts. Except for the nucleus and RB, there were many morphological similarities between preosteoclasts and osteoclasts. We therefore suggest that preosteoclasts, rather than MMP, are the precursors of osteoclasts during alveolar bone development of neonatal rats.

Alveolar Process↗
PubMed2006

Osteoblast differentiation and skeletal development are regulated by Mdm2-p53 signaling.

Mdm2 is required to negatively regulate p53 activity at the peri-implantation stage of early mouse development. However, the absolute requirement for Mdm2 throughout embryogenesis and in organogenesis is unknown. To explore Mdm2-p53 signaling in osteogenesis, Mdm2-conditional mice were bred with Col3.6-Cre-transgenic mice that express Cre recombinase in osteoblast lineage cells. Mdm2-conditional Col3.6-Cre mice die at birth and display multiple skeletal defects. Osteoblast progenitor cells deleted for Mdm2 have elevated p53 activity, reduced proliferation, reduced levels of the master osteoblast transcriptional regulator Runx2, and reduced differentiation. In contrast, p53-null osteoprogenitor cells have increased proliferation, increased expression of Runx2, increased osteoblast maturation, and increased tumorigenic potential, as mice specifically deleted for p53 in osteoblasts develop osteosarcomas. These results demonstrate that p53 plays a critical role in bone organogenesis and homeostasis by negatively regulating bone development and growth and by suppressing bone neoplasia and that Mdm2-mediated inhibition of p53 function is a prerequisite for Runx2 activation, osteoblast differentiation, and proper skeletal formation.

Animals↗
PubMed2001

A bone-seeking clone exhibits different biological properties from the MDA-MB-231 parental human breast cancer cells and a brain-seeking clone in vivo and in vitro.

Breast cancer has a predilection for spreading to bone. The mechanism of preferential metastasis of breast cancer to bone is unknown. We hypothesize that breast cancer cells that develop bone metastases have the capacity to facilitate their colonization in bone. To examine this hypothesis, we established bone-seeking (MDA-231BO) and brain-seeking (MDA-231BR) clones of the human breast cancer cell line MDA-MB-231 by repeated sequential passages in nude mice and in vitro of metastatic cells obtained from bone and brain metastases, respectively. These clones were examined for distinguishing biological characteristics and compared with the MDA-231 parental cells (MDA-231P) in vivo and in vitro. Both the MDA-231BR and the MDA-231BO showed identical tumorigenicity to MDA-231P at the orthotopic site. MDA-231P that was inoculated into the heart developed metastases in bone, brain, ovary, and adrenal glands. On the other hand, MDA-231BO exclusively metastasized to bone with larger osteolytic lesions than MDA-231P. MDA-231BR exclusively disseminated to brain and failed to develop bone metastases. In culture, MDA-231BO produced greater amounts of parathyroid hormone-related protein (PTH-rP) than MDA-231BR and MDA-231P in the absence or presence of transforming growth factor beta (TGF-beta). Furthermore, the anchorage-independent growth of MDA- 231BO in soft agar was not inhibited by TGF-beta, whereas TGF-beta profoundly inhibited the growth of MDA-231P and MDA-231BR. Insulin-like growth factor I (IGF-I) markedly promoted the anchorage-independent growth of MDA-231BO, whereas marginal or no stimulation was observed in MDA-231BR or MDA-231P, respectively. Our data suggest that these phenotypic changes allow breast cancer cells to promote osteoclastic bone resorption, survive, and proliferate in bone, which consequently leads to the establishment of bone metastases.

Agar↗
PubMed1996

Different effects of phagocytosable particles during bone formation versus remodeling.

Previously, small phagocytosable particles of high density polyethylene (HDPE) but not Ti6-Al4-V alloy, at a concentration of 10(8) particles/mL inhibited net bone formation in vivo after 3 weeks in the bone harvest chamber (BHC). These findings reflected the effects of particles during the phase of bone ingrowth. In this study, we tested whether these effects persisted or were different during the phase of bone maturation and remodeling. BHCs were bilaterally implanted in mature male NZW rabbits. After a 6-week period for osseointegration, the contents of the chamber were harvested and discarded. One percent sodium hyaluronate, the carrier, was then placed within the canal of the chambers bilaterally and the tissue within the chambers was harvested 3 weeks later. HDPE particles were then inserted unilaterally for a 3-week period, followed by Ti6-Al4-V for 3 weeks, HDPE for 6 weeks, and Ti6-Al4-V for 6 weeks. The side chosen for each treatment was switched consecutively; the nonimplanted, contralateral chamber served as a control. At 3 weeks the control treatments yielded trabeculae of woven bone in a fibrovascular stroma. By 6 weeks, the peripheral trabeculae were thicker, and a central marrow cavity was developing. Bone ingrowth was less with HDPE particles at 3 and 6 weeks compared to controls. Ti6-Al4-V particles did not inhibit bone ingrowth at 3 weeks but showed a trend at 6 weeks. The characteristics of particles affect the differentiation, maturation, and remodeling of mesenchymal tissue differently.

Alloys↗
PubMed1986

Structural differences between bone formed intramuscularly following the transplantation of isolated calvarial bone cells or chondrocytes.

Bone formed in intramuscular transplants of isolated syngeneic calvarial bone cells in mice, was compared with endochondral bone induced by cartilage produced by analogous transplants of isolated epiphyseal chondrocytes, as well as with parietal bones forming the bulk of the calvaria. Transplanted calvarial cells produced islands of bone, some of which contained intraosseous cavities. Osteoclasts inside these cavities were observed only in 14-day-old transplants and bone marrow cells in 28-day and older transplants. On the contrary, bone marrow appeared soon after formation of bone trabeculae in endochondral bone. The percentage area occupied by bone marrow in these specimens was about twentyfold larger than in the bone formed by transplanted bone cells. On the other hand, the bone marrow area in the latter type of bone was somewhat smaller but of similar order as in parietal bones. Moreover, both in parietal bones and in bone formed by isolated bone cells, the bone marrow was devoid of fat cells which were numerous in bone arising by endochondral ossification. It appears, therefore, that the ratio of bone marrow to the bone tissue area in parietal bones depends more on the intrinsic properties of osteoblasts than on the local factors in the environment of the developing bone. In the case of bone induced by cartilage, the bone marrow/bone tissue area could be determined both by the extent of cartilage resorption by vascularized tissue and by the properties of osteoblasts.

Animals↗
PubMed2001

Association between urinary potassium, urinary sodium, current diet, and bone density in prepubertal children.

BACKGROUND: Our understanding of the role of nutrients in bone development in children is limited. OBJECTIVE: We examined the associations between urinary potassium, urinary sodium, usual dietary intake, and bone mineral density (BMD) in prepubertal children. DESIGN: This was a cross-sectional study of 330 boys and girls aged 8 y. Urinary measures were assessed in a single, timed, overnight urine specimen. Usual diet was assessed with a food-frequency questionnaire completed by a parent or guardian. BMD at the femoral neck, lumbar spine, and total body was measured by dual-energy X-ray absorptiometry. RESULTS: Urinary potassium correlated significantly with BMD at all sites (femoral neck: r = 0.20, P < 0.001; lumbar spine: r = 0.19, P = 0.001; total body: r = 0.24, P < 0.001). After adjustment for confounders (primarily lean body mass), this association was lower in magnitude but remained significant at 2 sites with a consistent trend at the third (femoral neck: P = 0.15; lumbar spine: P = 0.046; total body: P = 0.028). Urinary sodium was not associated with BMD at any site. No nutrient or food intake estimate was associated with BMD, although urinary potassium correlated significantly with potassium intake (r = 0.14, P = 0.016) and fruit and vegetable intake (r = 0.12, P = 0.033). CONCLUSIONS: Urinary potassium was associated with both dietary intake and BMD independent of lean body mass in these well-nourished, calcium-replete young children. These findings should be confirmed in further longitudinal studies. Nevertheless, this association is likely to represent dietary intake of potassium and suggests that measurement of urinary potassium is superior to food-frequency questionnaires for assessing potassium intake in this age group.

Absorptiometry, Photon↗
PubMed1999

Matrix-degrading proteases and angiogenesis during development and tumor formation.

Embryonic development and tumor progression both require the exquisite coordination of programs for extracellular matrix (ECM) formation and remodeling, and those for angiogenesis and vascular development. Without a vascular supply the normal tissue or tumor is limited in size and organization. Without ECM remodeling the alteration of tissue and tumor boundaries and cellular migrations are limited. Recent insights into the molecular mechanisms regulating the extracellular environment of the growing embryonic tissue or tumors have implicated proteases, the matrix metalloproteinases (MMPs) in particular, in both the process of ECM remodeling and angiogenesis, and in a potential causal relationship between these processes. This review focuses on the roles that MMPs play in regulating three processes in which both proteolysis and vascular development are tightly coordinated: embryo implantation, bone development and tumor progression.

Animals↗
PubMed2005

Cell-cell interactions in regulating osteogenesis and osteoblast function.

Endochondral bone formation requires an elaborate interplay among autocrine, paracrine, and endocrine signals, positional cues, and cell-cell contacts to mediate the complex three-dimensional architecture and function of the skeleton. Embryonic bone development occurs by migration, aggregation, and condensation of immature mesenchymal progenitor cells to form the cartilaginous anlage. Upon vascular invasion, the cartilaginous scaffold is colonized and subsequently mineralized by osteoblasts. Likewise, bone remodeling in the adult skeleton is a dynamic process that requires coordinated cellular activities among osteoblasts, osteocytes, and osteoclasts to maintain bone homeostasis. This review examines the role of cell-cell interactions mediated by adherens junctions formed by cadherins and communicative gap junctions formed by connexins in regulating bone development and osteogenic function.

Bone Remodeling↗
PubMed2005

Therapy tolerance in selected patients with androgen-independent prostate cancer following strontium-89 combined with chemotherapy.

PURPOSE: Clinicians may have reservations about using strontium-89 for the treatment of bone metastases because of concerns that it may limit future use of chemotherapy. We assessed the rate of bone marrow failure in patients with prostate cancer who had received a dose of strontium-89. PATIENTS AND METHODS: This subgroup analysis involved 34 patients with androgen-independent prostate cancer who had been given a dose of strontium-89 and six weekly doses of doxorubicin after response to induction chemotherapy. We assessed subsequent hematotoxicity in terms of bone marrow failure and the ability to tolerate additional treatments during a median of 25 months (range, 7 to 76 months) after the strontium-89 was administered. RESULTS: No patients developed bone marrow failure within 6 months of receiving strontium-89. Five (15%) of 34 patients developed bone marrow failure at a median 23 months (range, 6 to 53 months) after the strontium-89 treatment. Bone marrow biopsy performed in two of these five patients showed complete replacement of the marrow by tumor. Thirty-one patients (91%) received subsequent cytotoxic treatments at a median 11 months (range, 1 to 33 months) after the strontium-89 treatment. CONCLUSION: This analysis demonstrated that a single dose of strontium-89 combined with chemotherapy did not affect the delivery of subsequent courses of chemotherapy in a select group of patients. However, a majority of these therapies were given off protocol and were administered at a dose schedule that might be considered inappropriate or inadequate. The clinical role and safety profile of radiopharmaceuticals combined with chemotherapy in prostate cancer therapy deserve further exploration.

Aged↗
PubMed2004

Lack of a fusion requirement for development of bone marrow-derived epithelia.

Analysis of developmental plasticity of bone marrow-derived cells (BMDCs) is complicated by the possibility of cell-cell fusion. Here we demonstrate that epithelial cells can develop from BMDCs without cell-cell fusion. We use the Cre/lox system together with beta-galactosidase and enhanced green fluorescent protein expression in transgenic mice to identify epithelial cells in the lung, liver, and skin that develop from BMDCs without cell fusion.

Animals↗
PubMed1999

The parathyroid hormone-related protein (PTHrP) gene: use of downstream TATA promotor and PTHrP 1-139 coding pathways in primary breast cancers vary with the occurrence of bone metastasis.

We analyzed the use of different promoters and the splicing patterns of the exons encoding 5'- and 3'-untranslated sequence amounts of parathyroid hormone-related protein (PTHrP) gene products in breast cancers. Tumor samples from 74 cases of primary breast cancer that had been followed from 1 to 14 years were selected retrospectively according to the occurrence of metastasis: 18 patients developed no metastasis (NM), 56 developed metastases (M), 22 of whom developed metastases in soft tissues (MB-) and 34 of whom developed bone metastases (MB+). The amount of the 1-139 isoform mRNA was much higher in the tumors of patients who later developed metastases (M: 0.29 +/- 0.03) than in those of patients who developed no metastases (NM, 0.13 +/- 0.03; p < 0.01). This isoform mRNA was also more abundant in breast tumors from patients who developed bone metastases (MB+, 0.39 +/- 0.04) than in those of patients who developed metastases in soft tissues (MB-, 0.15 +/- 0.03; p < 0. 0001). By contrast, the amounts of the 1-141 isoform mRNA in these three groups of tumors were similar, but its concentration was higher in the tumors of premenopausal women than in those of postmenopausal women (p < 0.05). Analysis with 5' untranslated regions-specific primers showed transcription from all three putative transcription start sites of PTHrP (P1, P2, and P3). The P3-initiated transcripts were more abundant in patients who developed metastases (M, 0.31 +/- 0.03) than in the nonmetastatic tumors (NM, 0.13 +/- 0.03; p < 0.01). The amount of P3 element did not differ with the site of metastasis (BM+, 0.32 +/- 0.05; BM-, 0. 28 +/- 0.05; NS). The same trend was observed for the P2 element. However, the use of P2-initiated messages was strongly associated with the absence of estrogen receptors from the breast tumors (p < 0. 01). We thus find a close association between the pattern of PTHrP gene expression and the outcome of breast cancer. The P3-initiated start site and the presence of PTHrP 139 mRNA could help identify patients at risk of developing metastases.

Adult↗
PubMed2002

Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188.

Vascular endothelial growth factor (VEGF)-mediated angiogenesis is an important part of bone formation. To clarify the role of VEGF isoforms in endochondral bone formation, we examined long bone development in mice expressing exclusively the VEGF120 isoform (VEGF120/120 mice). Neonatal VEGF120/120 long bones showed a completely disturbed vascular pattern, concomitant with a 35% decrease in trabecular bone volume, reduced bone growth and a 34% enlargement of the hypertrophic chondrocyte zone of the growth plate. Surprisingly, embryonic hindlimbs at a stage preceding capillary invasion exhibited a delay in bone collar formation and hypertrophic cartilage calcification. Expression levels of marker genes of osteoblast and hypertrophic chondrocyte differentiation were significantly decreased in VEGF120/120 bones. Furthermore, inhibition of all VEGF isoforms in cultures of embryonic cartilaginous metatarsals, through the administration of a soluble receptor chimeric protein (mFlt-1/Fc), retarded the onset and progression of ossification, suggesting that osteoblast and/or hypertrophic chondrocyte development were impaired. The initial invasion by osteoclasts and endothelial cells into VEGF120/120 bones was retarded, associated with decreased expression of matrix metalloproteinase-9. Our findings indicate that expression of VEGF164 and/or VEGF188 is important for normal endochondral bone development, not only to mediate bone vascularization but also to allow normal differentiation of hypertrophic chondrocytes, osteoblasts, endothelial cells and osteoclasts.

Animals↗
PubMed1985

Structural and histochemical study of the effect of 1,25-dihydroxyvitamin D3 on long-bone growth center in suckling mice.

The in vivo effects of 1 alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] on cellular structure and response, matrix metachromasia and mineralization have been studied in the epiphysis and growth plate of humeri in normal neonatal mice. A relatively low dose of the metabolite, 50 ng/kg body weight, significantly increased the overall size of humeral growth plate, the zone of proliferating cells and that of hypertrophic chondrocytes. The response of the tissue to the metabolite changed with the increase in dose administered so that it was only the zone of proliferation that still showed increases in size in comparison to untreated controls. 1,25 (OH)2D3 led to an increase in the metachromatic reaction of the cartilage matrix in the chondroblastic zone, and to marked increase in matrix mineralization in the hypertrophic zone. Qualitative changes were also noted in the structure of chondroblasts and hypertrophic chondrocytes. 1,25(OH)2D3 affected the osteoblastic and osteocytic populations of cells along the metaphysis and diaphysis of the humerus. High doses of 1,25(OH)2D3 brought about distinct atrophic changes in the above cells. Chondrocytes in the epiphysis were found to synthesize type I collagen and fibronectin. These findings indicate that excessive doses of 1,25(OH)2D3 in an intact growing animal affect the normal differentiative pathway of prechondroblasts and thereby affect long bone development.

Animals↗
PubMed2000

Is bone a target-tissue for the nervous system? New advances on the understanding of their interactions.

Bone cells respond in specific ways to various hormones and growth factors, but the biology of skeletal innervation and its physiologic significance in bone metabolism is poorly understood. With the introduction of immunohistochemical staining techniques and new molecular biology tools, the knowledge in this field has significantly improved. In this review, we update current understanding of the effects of neuropeptides on bone metabolism, specifically vasoactive intestinal peptide (VIP) and calcitonin-gene related peptide (CGRP). In addition, new information concerning the role of growth factors, such as neurotrophins, is also discussed. There is strong evidence to suggest that bone can be a target of the nervous system. Further investigations in this field will allow us to answer questions related to pre-natal development, bone growth, fracture healing, osteoporosis, osteoarthritis or neoplasias of mesoderm origin.

Bone Development↗
PubMed1976

Problems in the nutritional assessment of black individuals.

Nutritional assessment of American Negro (Black) individuals of largely-African ancestry is complicated by differences that transcend socioeconomic status (SES). These include smaller size at birth but greater size from 2 to 14 years, advanced skeletal development ("bone age"), advanced dental development, a larger skeletal mass and bone "density" and a lesser rate of adult bone loss in the Black female from age 40 on as shown in a variety of bone-losing situtations, including renal osteodystrophies. Thus, appropriate dimensional and radiographic and radiogrammetric measures must be employed. Differences in hemoglobin concentration approximating 1.0g/100ml and in hematocrit levels also indicate the need for population-specific standards, otherwise gross errors will be made in calculating the per cent "deficient" and "low". Since self-assignments to racial categories are commonly used, the problem of racial identification is minimal. Failure to employ appropriate standards will result in underestimating the dimensional, radiographic and radiogrammetric effects of undernutrition in Blacks after the 2nd year, underestimating adult bone loss to a large degree, but overestimating the severity of hematologic responses from the 1st year through the 9th decade.

Adolescent↗
PubMed1999

SDF-1 responsiveness does not correlate with CXCR4 expression levels of developing human bone marrow B cells.

Chemokines and their receptors are broadly expressed in different tissues and are involved in diverse biologic processes. Gene inactivation studies have shown that both stromal cell derived factor-1 (SDF-1) and chemokine receptor 4 (CXCR4) are essential for B lymphopoiesis. However, it is not yet clear by which mechanisms B lymphopoiesis is affected. In the present study, we have examined CXCR4 expression and function on primary B cells representing sequential stages of development (eg, pro-B, pre-B, immature, and mature B cells) in fetal and adult bone marrow. The expression of CXCR4 was observed to be sinusoidal. Expression was highest on pre-B cells, decreased as cells developed into immature B cells, and then increased again upon transition to the mature B-cell stage. The corresponding ligand SDF-1 was shown to trigger vigorous cell signaling and migration responses, which are restricted to early lineage B cells. The responsiveness to SDF-1 was markedly decreased for immature and mature B cells despite relatively high levels of CXCR4 expression. Thus, the diminished responsiveness to SDF-1 by more mature B cells was determined to be disproportionate to the level of CXCR4 expression. These findings raise the possibility that CXCR4 function is differentially controlled during B lymphopoiesis and may be relevant to the compartmentalization of B-cell precursors in the bone marrow.

Adult↗