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PubMed1998

Expression of type 2 11beta-hydroxysteroid dehydrogenase and corticosteroid hormone receptors in early human fetal life.

In adult life, the type 2 isozyme of 11beta-hydroxysteroid dehydrogenase (11betaHSD2) protects the mineralocorticoid receptor (MR) from glucocorticoid by inactivating cortisol to cortisone. 11betaHSD2 activity has been reported in human fetal tissues, where glucocorticoids may impair fetal growth yet are also required for normal fetal development. Using digoxigenin-labeled complementary ribonucleic acid (RNA) probes and an in-house 11betaHSD2 antiserum, we have analyzed the expression of 11betaHSD2, MR, and glucocorticoid receptor (GR) in human fetal tissues of gestational age 6-17 weeks (n=15). 11BetaHSD2 expression was absent at gestational age 6+ weeks, but was expressed in abundance in many fetal tissues between 8-12 weeks. At this time, 11betaHSD2 colocalized with GR messenger RNA (mRNA) expression in metanephros, gut, muscle, spinal cord and dorsal root ganglia, periderm, sex chords of testis, and adrenal. In particular within fetal kidney, intense expression of 11betaHSD2 and GR mRNA was observed over Bowman's capsule and the vascular tufts of developing glomeruli as they migrated from the surface of the kidney to the inner cortex. Only lung and adrenal medullary rests demonstrated high levels of GR mRNA but low levels of 11betaHSD2. 11BetaHSD2 mRNA and immunoreactivity staining patterns were similar, with the exception of the fetal adrenal, where mRNA was localized to the outer definitive zone but immunoreactivity was localized to the inner fetal zone. Colocalization of 11betaHSD2 (and GR mRNA) with MR mRNA was observed principally within epithelial cells of collecting ducts, particularly after 16 weeks gestation when the pattern of distribution of 11betaHSD2 became more adult in nature. High levels of MR mRNA were observed within developing bone. The data indicate that 11betaHSD2 in fetal life principally modulates ligand access to the GR in most fetal tissues, notably glomeruli and tubules in the developing kidney, testis, and periderm, and this may be have ramifications for fetal sodium homeostasis and differentiation. The development of tissues previously shown to have a critical requirement for glucocorticoids, such as lung and adrenal medulla, is facilitated by the expression of GR mRNA, but not 11betaHSD2. The expression of MR mRNA in high abundance in bone suggests a role for corticosteroids in human bone development, and the low/absent expression of 11betaHSD2 at this site suggests that it is functionally acting as a GR.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2005

Endothelial cell modulation of bone marrow stromal cell osteogenic potential.

In the context of bone development and regeneration, the intimate association of the vascular endothelium with osteogenic cells suggests that endothelial cells (ECs) may directly regulate the differentiation of osteoprogenitor cells. To investigate this question, bone marrow stromal cells (BMSCs) were cultured: in the presence of EC-conditioned medium, on EC extracellular matrix, and in EC cocultures with and without cell contact. RNA and protein were isolated from ECs and analyzed by reverse transcriptase-polymerase chain reaction and Western blotting, respectively, for expression of bone morphogenetic protein 2 (BMP-2). In animal studies, BMSCs and ECs were cotransplanted into severe combined immunodeficient mice on biodegradable polymer matrices, and histomorphometric analysis was performed to determine the extent of new bone and blood vessel formation. ECs significantly increased BMSC osteogenic differentiation in vitro only when cultured in direct contact. ECs expressed BMP-2, and experiments employing interfering RNA inhibition confirmed its production as contributing to the increased BMSC osteogenic differentiation. In vivo, cotransplantation of ECs with BMSCs resulted in greater bone formation than did transplantation of BMSCs alone. These data suggest that ECs function not only to form the microvasculature that delivers nutrients to developing bone but also to modulate the differentiation of osteoprogenitor cells in vitro and in vivo.

Alkaline Phosphatase↗
PubMed2005

Reduced expression of platelet endothelial cell adhesion molecule-1 in bone marrow cells in mice after skeletal unloading.

UNLABELLED: One week of tail suspension significantly decreased the expression of PECAM-1 in mouse tibial bone marrow cells but not those of a number of other vascular factors. Anti-PECAM-1 antibody suppressed both ALP+ CFU-f formation and ALP production under co-culture of the osteoblastic cell line and the PECAM-1+ endothelial cell line. This study suggests that the reduced ALP activity after skeletal unloading is related to downregulation of PECAM-1 expression in bone marrow cells in mice. INTRODUCTION: Vascular factors play a role in bone development and regeneration. We tested the hypothesis that skeletal unloading reduces osteogenic potential by inhibiting the molecules related to angiogenesis and/or vasculogenesis in bone marrow cells. MATERIALS AND METHODS: Eight-week-old male mice were assigned to three groups after acclimatization for 1 week: ground control (GC), tail suspension (TS), and reloading after 7-day TS (RL). Bilateral tibial and humeral samples were used for analyses. MC3T3-E1, a mouse osteoblastic cell line, and EOMA and ISOS-1, mouse endothelial cell lines, were also used. RESULTS: Flow cytometric analysis revealed that 7-day TS significantly decreased the expression of platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) in tibial bone marrow cells, but not those of angiopoietin-1, angiopoietin-2, Flk-1 (vascular endothelial growth factor receptor-2), and vascular endothelial cadherin. The expression of PECAM-1 in tibial marrow cells was reduced at day 3 of TS to 80% and still showed significantly low levels at day 7 of TS to 72% of that at the respective days of GC. This decreased expression of PECAM-1 after 7-day TS showed the GC level at 5-day reloading after 7-day TS. However, the expression of PECAM-1 in humeral marrow cells (internal bone marrow control) after TS and RL remained unchanged and equivalent to that of GC. The expression level of PECAM-1 mRNA was significantly lower at day 7 of TS to 62% of that in GC. Double labeling analyses revealed that PECAM-1+ cells mostly consisted of endothelial cells and partially of granulocytes. In bone marrow cell cultures, the formation of alkaline phosphatase (ALP)+ colony forming units-fibroblastic was significantly reduced in the presence of anti-PECAM-1 antibody in the medium compared with the presence of immunoglobulin G (0.025 times as much as ALP production with immunoglobulin G). ALP production by cultured MC3T3-E1 was enhanced in combination with PECAM-1+ EOMA (1.8 times as much as ALP production by MC3T3-E1 alone), but not in combination with PECAM-1- ISOS-1. Anti-PECAM-1 antibody inhibited the increase in ALP production under co-culture with EOMA. CONCLUSIONS: Our data show that the reduced ALP activity after skeletal unloading is closely correlated with reduced expression of PECAM-1 in bone marrow cells. We speculate that the loss of osteogenic potential after skeletal unloading is caused by the suppression of PECAM-1 signaling on endothelial cellular surface.

3T3 Cells↗
PubMed2000

Osteogenesis from cultured chick periostea has a specific requirement for chloride.

Bone development, like embryonic development in general, depends on a particular internal electrical milieu. Ions are the carriers of currents that maintain this internal environment. In embryonic bone, chloride is a major carrier of such current. To explore the role chloride plays in embryonic bone development we performed several ion-removal experiments, using the chick periosteal osteogenesis (CPO) system as our model. We found that if chloride is reduced in the medium and replaced with a nontoxic anion, alkaline phosphatase (ALP) activity does not rise, nor does osteogenic development occur. However, acid phosphatase (AP) activity is not affected by level of chloride. Experiments using metabolic inhibitors showed that explants cultured in low chloride medium remain viable. Dose-response studies revealed that the response of ALP activity to chloride concentration is sigmoidal, with a [Cl-]0.5 of 45.9 mM. Reciprocal transfers of explants between complete and low chloride medium show that the rise in ALP activity depends on the length of time explants are cultured with chloride. In contrast, such transfer experiments show that osteogenesis requires chloride only during days 2-3 of culture.

Acid Phosphatase↗
PubMed1986

The origin of osteoclasts: an immunohistochemical study on macrophages and osteoclasts in embryonic rat bone.

The origin of osteoclasts was studied in embryonic rat bone primordia using a set of monoclonal antibodies (ED1, ED2, and ED3) that exclusively recognize monocytes and macrophage. ED1 recognizes monocytes and macrophages. Mononuclear phagocytes which were ED1 positive were found in the perichondrium/periosteum of developing bone. These cells started to infiltrate the primordia when the cartilage became hypertrophic. During bone formation, multinucleated ED1-positive cells with the morphological characteristics of osteoclasts were found in the developing bone marrow cavity and against the bone collar. The present findings support the notion that osteoclasts arise by fusion of mononuclear phagocytes derived from blood monocytes.

Animals↗
PubMed2006

Bone-directed treatments for prostate cancer.

Maintaining bone health in men who have advanced prostate cancer is an important goal of therapy. Low bone mass is prevalent in men who have prostate cancer, and long-term androgen deprivation therapy causes additional significant decreases in bone mineral density. The adverse effects of the disease and current treatment modalities on bone health are further compounded when patients develop bone metastases,which cause clinically significant skeletal morbidity. Treatment with bone-directed therapies, including intravenous bisphosphonates, radio-nuclides, and endothelin-1 antagonists, can provide palliative and therapeutic benefits for patients who have established bone metastases, and treatment with intravenous bisphosphonates may prevent the development of bone metastases.

Bone Neoplasms↗
PubMed2005

FGF signaling in the developing endochondral skeleton.

Mutations in fibroblast growth factor receptors (Fgfrs) are the etiology of many craniosynostosis and chondrodysplasia syndromes in humans. The phenotypes associated with these human syndromes and the phenotypes resulting from targeted mutagenesis in the mouse have defined essential roles for FGF signaling in both endochondral and intramembranous bone development. In this review, I will focus on the role of FGF signaling in chondrocytes and osteoblasts and how FGFs regulate the growth and development of endochondral bone.

Bone Development↗
PubMed2004

Zinc-deficient rats have more limited bone recovery during repletion than diet-restricted rats.

The objective of this study was to investigate the effects of dietary zinc deficiency and diet restriction on bone development in growing rats, and to determine whether any adverse effects could be reversed by dietary repletion. Weanling rats were fed either a zinc-deficient diet ad libitum (ZD; <1 mg zinc/kg) or nutritionally complete diet (30 mg zinc/kg) either ad libitum (CTL) or pair-fed to the intake of the ZD group (DR; diet-restricted) for 3 weeks (deficiency phase) and then all groups were fed the zinc-adequate diet ad libitum for 3, 7, or 23 days (repletion phase). Excised femurs were analyzed for bone mineral density (BMD) using dual-energy x-ray absorptiometry, and plasma was analyzed for markers of bone formation (osteocalcin) and resorption (Ratlaps). After the deficiency phase, ZD had lower body weight and reduced femur BMD, zinc, and phosphorus concentrations compared with DR; and these parameters were lower in DR compared with CTL. Femur calcium concentrations were unchanged among the groups. Reduced plasma osteocalcin in ZD and elevated plasma Ratlaps in DR suggested that zinc deficiency limits bone formation while diet restriction accelerates bone resorption activity. After 23 days of repletion, femur size, BMD, and zinc concentrations remained lower in ZD compared with DR and CTL. Body weight and femur phosphorus concentrations remained lower in both ZD and DR compared with CTL after repletion. There were no differences in plasma osteocalcin concentrations after the repletion phase, but the plasma Ratlaps concentrations remained elevated in DR compared with CTL. In summary, both ZD and DR lead to osteopenia during rapid growth, but the mechanisms appear to be due to reduced modeling in ZD and higher turnover in DR. Zinc deficiency was associated with a greater impairment in bone development than diet restriction, and both deficiencies limited bone recovery during repletion in growing rats.

Animals↗
PubMed1984

Influence of penicillamine and various analogs on matrix-induced bone formation in rats.

D-penicillamine and a variety of analogs have been tested for their ability to interfere with the various stages of bone development using a model for endochondral bone formation. At the highest dose tested (40 mg/rat/day), D-penicillamine inhibited mineralization, D-2-Amino-3-methyl-3-[(2-acetamidoethyl)dithio]butanoic acid (II), at a relatively low dose (10 mg/day), decreased the amount of insoluble collagen in skin, mesenchymal cell proliferation on Day 3, and inhibited bone formation on Day 14. Several other compounds tested, sodium 4-[(D-1, 1-dimethyl-2-amino-2-carboxyethyl)-dithio]butanesulfinate (IV), 2-acetamidoethyl-2-acetamidoethanethiolsulfonate (V), and sodium 4-mercaptobutanesulfinate trihydrate (VI), also inhibited osteogenesis on Day 14.

Animals↗
PubMed2006

Ameloblastin expression during craniofacial bone formation in rats.

Based on previous results showing the expression of ameloblastin (Ambn; amelin) in the formation of mesenchymal dental hard tissues, we investigated its presence during bone development. Immunohistochemistry (IHC), in situ hybridization (ISH), and reverse transcription-polymerase chain reaction (RT-PCR) were used to investigate the expression of ameloblastin protein and mRNA during craniofacial development in rats. Tissue samples were collected on embryonic day 18 and from days 2-28 postnatally. IHC revealed the expression of ameloblastin during bone formation at embryonic and early postnatal stages with different patterns of expression in intramembranous and endochondral ossification. In intramembranous ossification, ameloblastin expression was detected in the superficial layer of the condensed vascularized primitive connective tissue and in the cellular layer covering the surface of the newly formed woven bone. In endochondral ossification, ameloblastin was expressed within the extracellular matrix of the cartilage templates and in the perichondrium. Between days 2 and 28 the expression decreased markedly, concordant with the maturation of the bone, and disappeared after completion of bone remodeling. The results obtained by IHC were confirmed by ISH and RT-PCR, showing the expression of ameloblastin mRNA during craniofacial bone formation. This study indicates the expression of the putative dental protein ameloblastin during craniofacial bone development in rats.

Animals↗
PubMed2002

The role of the alphaVbeta3 integrin in the development of osteolytic bone metastases: a pharmacological target for alternative therapy?

Common cancers frequently develop bone metastases, which are often osteolytic in nature due to activation of osteoclast differentiation and bone resorption. This may result from direct stimulation of these cells by the metastasis, or may be due to indirect enhancement of osteoclast activity by osteoblasts. A further feature of the bone metastasis is an extensive medullary angiogenesis which supports tumor growth. The alphaVbeta3 integrin is highly expressed in bone metastatic cells, as well as in osteoclasts and in the activated endothelium, where it plays a major role in cell function. In contrast, this receptor is barely expressed in other cell types. Our hypothesis is that inhibition of this mechanism, which is not widespread in most tissues and at the same time is common to several steps of cancer-induced osteolysis (i.e., homing, growth, and survival of metastatic cells, osteoclast bone resorption, and angiogenesis), should represent a suitable target to block the development of bone spreading of metastatic tumors. We extend this hypothesis to downstream signalling molecules activated by ligation of the alphaVbeta3 integrin, some of which (i.e., Src, PYK2, and Shc) could have similar specific roles in tumor cells, activated endothelium and osteoclasts, but not in other cell types.

Antineoplastic Agents↗
PubMed1999

Osteoblasts are a new target for prolactin: analysis of bone formation in prolactin receptor knockout mice.

Bone development is a multistep process that includes patterning of skeletal elements, commitment of hematopoietic and/or mesenchymental cells to chondrogenic and osteogenic lineages, and further differentiation into three specialized cell types: chondrocytes in cartilage and osteoblasts and osteoclasts in bone. Although PRL has a multitude of biological actions in addition to its role in the mammary gland, very little is known about its effect on bone. Mice carrying a germline null mutation for the PRL receptor gene have been produced in our laboratory and used to study the role of PRL in bone formation. In -/- embryos, we observed an alteration in bone development of calvaria. In adults, histomorphometric analysis showed that the absence of PRL receptors leads to a decrease in bone formation rate using double calcein labeling and a reduction of bone mineral density, measured by dual energy x-ray absorptiometry. In addition, serum estradiol, progesterone, testosterone, and PTH levels were analyzed. We also established that osteoblasts, but not osteoclasts, express PRL receptors. This suggests that an effect of PRL on osteoblasts could be required for normal bone formation and maintenance of bone mass. Thus, the PRL receptor knockout mouse model provides a new tool to investigate the involvement of PRL in bone metabolism.

Absorptiometry, Photon↗
PubMed1981

Maturation-linked expression of C3b and C3b' receptors on developing human bone marrow and peripheral blood granulocytes.

The sequential expression of granulocyte membrane receptors for C3b, C3b' and C3d have been investigated in normal human bone marrow and peripheral blood. In particular the relationship between receptor expression and morphological characteristics of granulocyte maturation has been assessed. The result indicate that C3b receptor development precedes that of the Fc-IgG receptor and is present on all neutrophil precursors with the exception of the agranular myeloblast. Furthermore, there is, in contrast to Fc-IgG receptors, no difference (P greater than 0.35) in C3b receptor expression between marrow and peripheral blood segmented neutrophils. An apparent subpopulation of granulocytes also appear to have receptors for C3b' whereas receptors for C3d were not detected at all during granulocyte maturation. The application of these findings to the normal in vivo functions of granulocytes and to the study of abnormal granulocyte populations in myeloproliferative disorders is discussed.

Adult↗
PubMed1987

Tenascin is associated with chondrogenic and osteogenic differentiation in vivo and promotes chondrogenesis in vitro.

The tissue distribution of the extracellular matrix glycoprotein, tenascin, during cartilage and bone development in rodents has been investigated by immunohistochemistry. Tenascin was present in condensing mesenchyme of cartilage anlagen, but not in the surrounding mesenchyme. In fully differentiated cartilages, tenascin was only present in the perichondrium. In bones that form by endochondral ossification, tenascin reappeared around the osteogenic cells invading the cartilage model. Tenascin was also present in the condensing mesenchyme of developing bones that form by intramembranous ossification and later was present around the spicules of forming bone. Tenascin was absent from mature bone matrix but persisted on periosteal and endosteal surfaces. Immunofluorescent staining of wing bud cultures from chick embryos showed large amounts of tenascin in the forming cartilage nodules. Cultures grown on a substrate of tenascin produced more cartilage nodules than cultures grown on tissue culture plastic. Tenascin in the culture medium inhibited the attachment of wing bud cells to fibronectin-coated substrates. We propose that tenascin plays an important role in chondrogenesis by modulating fibronectin-cell interactions and causing cell rounding and condensation.

Animals↗
PubMed1977

Engelmann's disease.

A 5-year-old boy with diaphyseal dysplasia who exhibited marked involvement of the cranial bones developed marked disk edema in a one-year period. We believed the optic canal was being rapidly compromised by bony proliferation and vision was threatened. Selective bone studies, including tetracycline labeling, demonstrated a rapid accretion of bone 1 1/2 to two times the expected rate for his age. We performed bilateral unroofing of the optic canals with additional temporal decompression of the left orbit. Limited unroofing of the right eye proved to be inadequate and only with additional extensive temporal decompression was the disk edema of the left eye reversed. Tomograms taken one year after surgery revealed regrowth of bone in the optic canal and orbital roof. The usefulness of bony decompression of the orbits in Engelmann's disease is requestionable.

Adolescent↗