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PubMed1998

The role of tenascin-C and related glycoproteins in early chondrogenesis.

A number of large multidomain extracellular matrix glycoproteins, including fibronectin and members of the tenascin and thrombospondin families, are expressed in locations that suggest they may be involved in the process of chondrogenesis. During early limb morphogenesis, tenascin-C is selectively associated with condensing chondrogenic mesenchyme. With progressive development of endochondral bones, tenascin-C is absent from the matrix surrounding proliferating and hypertrophic chondrocytes, but remains in a restricted distribution in peripheral epiphyseal cartilage. During long bone development, patterns of expression of tenascin-C splice variants differ between chondrogenic and osteogenic regions, suggesting that different isoforms may have different functional roles. Tenascin-C presented as a substratum for chick wing bud mesenchymal cells induces chondrogenic differentiation. In early studies, fibronectin was found to inhibit chondrogenesis, despite being abundant in early chondrogenic mesenchyme. Recent studies showing differential effects of fibronectin splice variants on prechondrogenic mesenchymal condensation may explain this paradox. Members of the thrombospondin gene family are expressed in chondrogenic tissues at different stages, suggesting that they each play a unique role in cartilage development.

Alternative Splicing↗
PubMed2000

Associations of FGF-3 and FGF-10 with signaling networks regulating tooth morphogenesis.

The morphogenesis and cell differentiation in developing teeth is governed by interactions between the oral epithelium and neural crest-derived ectomesenchyme. The fibroblast growth factors FGF-4, -8, and -9 have been implicated as epithelial signals regulating mesenchymal gene expression and cell proliferation during tooth initiation and later during epithelial folding morphogenesis and the establishment of tooth shape. To further evaluate the roles of FGFs in tooth development, we analyzed the roles of FGF-3, FGF-7, and FGF-10 in developing mouse teeth. In situ hybridization analysis showed developmentally regulated expression during tooth formation for Fgf-3 and Fgf-10 that was mainly restricted to the dental papilla mesenchymal cells. Fgf-7 transcripts were restricted to the developing bone surrounding the developing tooth germ. Fgf-10 expression was observed in the presumptive dental epithelium and mesenchyme during tooth initiation, whereas Fgf-3 expression appeared in the dental mesenchyme at the late bud stage. During the cap and bell stage, both Fgf-3 and Fgf-10 were intensely expressed in the dental papilla mesenchymal cells both in incisors and molars. It is of interest that Fgf-3 expression was also observed in the primary enamel knot, a putative signaling center of the tooth, whereas no transcripts were seen in the secondary enamel knots that appear in the tips of future cusps of the bell stage tooth germs. Down-regulation of Fgf-3 and Fgf-10 expression in postmitotic odontoblasts correlated with the terminal differentiation of the odontoblasts and the neighboring ameloblasts. In the incisors, mesenchymal cells of the cervical loop area showed partially overlapping expression patterns for all studied Fgfs. In vitro analyses showed that expression of Fgf-3 and Fgf-10 in the dental mesenchyme was dependent on dental epithelium and that epithelially expressed FGFs, FGF-4 and -8 induced Fgf-3 but not Fgf-10 expression in the isolated dental mesenchyme. Beads soaked in Shh, BMP-2, and TGF-beta 1 protein did not induce either Fgf-3 or Fgf-10 expression. Cells expressing Wnt-6 did not induce Fgf-10 expression. Furthermore, FGF-10 protein stimulated cell proliferation in the dental epithelium but not in the mesenchyme. These results suggest that FGF-3 and FGF-10 have redundant functions as mesenchymal signals regulating epithelial morphogenesis of the tooth and that their expressions appear to be differentially regulated. In addition, FGF-3 may participate in signaling functions of the primary enamel knot. The dynamic expression patterns of different Fgfs in dental epithelium and mesenchyme and their interactions suggest existence of regulatory signaling cascades between epithelial and mesenchymal FGFs during tooth development.

3T3 Cells↗
PubMed1988

Ultrastructure of the osteogenesis of acellular vertebral bone in the Japanese medaka, Oryzias latipes (Teleostei, Cyprinidontidae).

An ultrastructural study by transmission electron microscopy (TEM) of the vertebrae of embryonic, larval, juvenile and mature medaka shows that each vertebra consists of a core of notochordal cells surrounded by a sheath of bone. The vertebral bone lacks either fully or partially embedded cells in the matrix throughout development. Bone matrix is secreted by a layer of cells that lies over the outer surface of the vertebral bone. During the early stages of osteogenesis, these cells secrete bone matrix all around themselves. However, because of the gradual flow of the newly synthesized bone matrix through intercellular spaces, matrix-producing cells do not become trapped in their own secretion. In later stages of osteogenesis, these cells secrete matrix only toward the already-deposited bone. This polarized matrix secretion allows the osteoblasts to stay always on the bone surface and never to become trapped in the matrix as osteocytes.

Animals↗
PubMed1989

Ultrastructural features of the developing eosinophils in bone marrow and spleen of the musk shrew, Suncus murinus.

Eosinophilopoiesis in the musk shrew, Suncus murinus, a representative of the order Insectivora, was studied by light and electron microscopy. To examine biochemical features of cytoplasmic granules, extraction with proteolytic enzymes was carried out on ultrathin sections of bone marrow. In this species, eosinophils are produced in the same manner in both spleen and bone marrow. Developing eosinophils were distinguished as belonging to four stages, recognized by ultrastructural changes in cytoplasmic organelles as well as the eosinophilic granules during maturation. Granulogenesis began by budding of vacuoles containing flocculent material from the concave face of the Golgi apparatus, in the promyelocyte to myelocyte stage. The matrix of developing granules transformed into a finely granular structure, and the large spherical granules of mature eosinophils were homogeneous without crystalline cores. It was shown by proteolytic enzyme extraction that the proteinaceous cores of mature granules were uniformly removed; there was no evidence that they contained crystalloid inclusions. These results indicate that shrew eosinophils can be regarded as cells that retain a prototype of eosinophil granules, probably like those of ancestral mammals rather than those of higher living Mammalia.

Animals↗
PubMed1995

Selective expression of fos- and jun-related genes during osteoblast proliferation and differentiation.

Developmental studies of oncogene expression and transgenic animal studies implicate c-fos and other fos and jun family members in the regulation of bone tissue formation. Therefore, to initiate experimental examination of the hypothesis that expression of fos- and jun-related genes is functionally coupled to modulation of gene expression which supports bone development, we determined levels of expression of the principle fos and jun family members during progressive differentiation of normal rat calvaria-derived osteoblasts within two contexts. First, cellular mRNA levels were quantitated under conditions where expression of serum-induced early response genes had returned to basal levels. Our findings demonstrate high levels of c-fos, c-jun, and jun B mRNA transcripts during the proliferative period of osteoblast development, while expression of fra-1 and fra-2 is enhanced during the differentiation period. jun D is constitutively expressed during the time course exhibiting only a 30% decline in levels postproliferatively, and fos B mRNA is undetectable by Northern blot analyses. Late in the developmental sequence, apoptosis is evident. At this time, fra-1 expression is completely downregulated, while c-fos, fra-2, c-jun, jun B, and jun D show a dramatic enhancement in expression. Second, we addressed differential expression of fos and jun family members in relation to serum responsiveness as a function of stages of phenotypic development. Proliferating cells exhibit a prolonged induction of fos and jun family members in response to serum. While in differentiated cells, which are refractory to growth stimulus even when exposed to fresh serum every 2 days, a spike in fos and jun expression is observed. Thus, our data demonstrate significant differences in basal and serum responsiveness of fos and jun family members over the course of osteoblast differentiation. These findings are consistent with multiple lines of evidence linking activity of these early response genes to regulation of cell growth and development of the bone tissue phenotype.

Animals↗
PubMed2006

Bone strength and its determinants in pre- and early pubertal boys and girls.

Higher fracture rates in women than men may be related to a sex difference in bone strength that is thought to emerge during growth. However, sexual dimorphism in bone strength and the determinants of bone strength in boys and girls are not well understood. Thus, our objectives were to (1) compare tibial bone strength and its components (geometry and density) between pre- and early pubertal boys and girls and (2) identify the contribution of muscle cross-sectional area and other modulating factors to bone outcomes. We used pQCT to assess the distal tibia (8%) and tibial midshaft (50%) in 424 Asian and Caucasian pre- and early pubertal boys and girls. Our primary outcomes were bone strength index (BSI, mg2/mm(4)) at the distal tibia and strength strain index (SSI, mm3) at the midshaft. We also assessed components of bone strength including bone geometry [total (ToA) and cortical (CoA) cross-sectional areas, mm2] and total (ToD, mg/cm3) and cortical (CoD, mg/cm3) density. We used ANCOVA to compare bone outcomes between boys and girls in each maturity group (PRE or EARLY pubertal by Tanner stage) and multiple regression to evaluate the contribution of muscle cross-sectional area (MCSA, mm2 by pQCT), maturity, ethnicity, physical activity, dietary calcium, and vertical jump height to bone outcomes. After adjusting for tibial length and MCSA, bone strength indices were 6-15% (P < 0.05) greater in PRE and EARLY boys compared with PRE and EARLY girls. The sex difference in bone strength was due largely to greater bone areas (4-6%) in boys. At the distal tibia ToD was significantly greater in PRE boys (6%, P < 0.001) compared with PRE girls and at the midshaft CoD was slightly greater in both PRE and EARLY girls (1%, P = 0.01). After adjusting for tibial length, MCSA was the primary explanatory variable of tibial bone geometry and strength in both sexes accounting for 10-16% of the variance. The influence of maturity, ethnicity, physical activity, and dietary calcium on pQCT bone outcomes was small and was both site- and sex-specific. Sexual dimorphism in tibial bone strength is evident in prepuberty. Our results are consistent with a functional model of bone development in which bone adapts its geometry and strength to withstand challenges from muscle forces during growth.

Bone Density↗
PubMed2004

Thyroid disease: pathophysiology and diagnosis.

The thyroid is a butterfly-shaped gland that is located in the front of the neck just above the trachea; it weighs approximately 15 g to 20 g in the adult human. The thyroid produces and releases into the circulation at least two potent hormones, thyroxine (T4) and triiodothyronine (T3), that influence basal metabolic processes or enhance oxygen consumption in nearly all body tissues. Thyroid hormones also influence linear growth; brain function, including intelligence and memory; neural development; dentition; and bone development.

Humans↗
PubMed2005

Speed of sound: relation to geometric characteristics of bone in children, adolescents, and adults.

OBJECTIVES: To investigate the relation between volumetric bone mineral density (vBMD) and speed of sound (SOS). STUDY DESIGN: Total and trabecular vBMD were measured by peripheral quantitative computed tomography at the forearm in a population of 216 individuals of a pediatric outpatient clinic. Moreover, SOS was measured by a quantitative ultrasound device (QUS) at the thumb, patella, and os calcis. RESULTS: Linear regression analysis revealed that the prediction of SOS by vBMD is relatively weak (R2 < 0.1). Moreover, body height and measures of bone size have a stronger influence on SOS than vBMD. The influence of bone size on SOS also depends on the location of measurement (highest prediction of SOS by body height at patella with R2 = 0.56). Anthropometric characteristics have a stronger influence on SOS than measures of bone mineral density at the thumb and patella in comparison to os calcis (body height predicts SOS at os calcis, with R2 = 0.03). Conclusions QUS is not a suitable method to assess bone density. If QUS is applied for the assessment of bone development and of bone fracture risk, the measurement should be performed with consideration of anthropometric measurements.

Adolescent↗
PubMed2000

Relationships between bone protein and mineral in developing porcine long bone and calvaria.

Several proteins in the bone matrix have been implicated in the regulation of mineral crystal formation and growth. To investigate the relationships between these proteins and the mineral phase at various stages of mineral maturation, fetal porcine calvariae and long bones were fragmented and the particles (20 microm) separated by density gradient sedimentation into fractions of increasing density (1.8 to >2.2 g/cm3). Samples from each fraction were analyzed by X-ray diffraction to obtain the average crystal size/strain and chemical composition. Other samples were sequentially extracted, first with 4.0 mol/L guanidium hydrochloride (GuHCl) (G1), then with 0.5 mol/L ethylene-diamine tetraacetic acid (EDTA) (E), and again with 4.0 mol/L Gu-HCI (G2), for analysis of proteins in different tissue compartments. Based on the mineral density distribution and crystal size, fetal porcine bone protein content was determined for tissue residue and each extract and the protein composition analyzed by sodium dodecyl-polyacrylamide gel electrophoresis (SDS-PAGE). Although the insoluble organic matrix decreased with mineral density the collagen and protein content remained fairly constant, representing approximately 10% of the tissue weight, except in the highest density fraction. Whereas the total extractable protein, representing predominantly noncollagenous proteins, did not show density-related differences, differences were observed for individual proteins on SDS-PAGE. Consistent with their presence in osteoid, the content of bone sialoprotein (BSP), tyrosine-rich acidic matrix protein (TRAMP), and a series of small proteins with cell attachment properties in the G1 extract decreased with mineral density, whereas TRAMP and BSP were increased in G2 extracts. Mineral-associated proteins, including alpha2HS-glycoprotein, BSP, osteopontin (OPN), and osteocalcin, increased with mineral density, whereas secreted protein acidic and rich in cysteine (SPARC)/osteonectin, and some minor proteins, appeared to decrease. Differences of individual proteins within and between the calvarial and long bones could be related to the role of these proteins in the formation and maturation of hydroxyapatite crystals. Collectively, these studies demonstrate mineral density-associated changes in protein composition that reflect a rapid maturation of mineral crystals in embryonic porcine bones.

Animals↗
PubMed1992

The influence of testosterone substitution on bone mineral density in patients with Klinefelter's syndrome.

The aim of this study was to clarify the extent of bone mineral deficiency in patients with Klinefelter's syndrome on the premise that testosterone substitution could prevent this deficiency. Bone mineral density was measured by single-photon absorptiometry in 42 patients with Klinefelter's syndrome, (21 patients without therapy, 10 with testosterone substitution before the age of 20 and 11 patients with testosterone substitution beginning after the age of 20). We found significantly lower bone mineral density in patients without therapy and in patients when the therapy began later compared to normal individuals. Patients with early therapy showed a high proportion of normal values of bone mineral density. We found a positive correlation between bone mineral density and plasma testosterone and a negative correlation between plasma testosterone and age for patients without therapy. These findings suggest that low testosterone levels before or during puberty cause inadequate bone development and low bone mineral density in Klinefelter's syndrome. Only early testosterone substitution may prevent bone mineral deficiency. Later substitution no longer affects bone mineral density.

Adult↗
PubMed2006

Bone healing and graft resorption of autograft, anorganic bovine bone and beta-tricalcium phosphate. A histologic and histomorphometric study in the mandibles of minipigs.

OBJECTIVE: The purpose was to qualitatively and quantitatively compare the bone formation and graft resorption of two different bone substitutes used in both orthopedic and oral surgery, with autogenous bone as a positive control. MATERIALS AND METHODS: Three standardized bone defects were prepared in both mandibular angles of 12 adult minipigs. The defects were grafted with either autograft, anorganic bovine bone (ABB), or synthetic beta-tricalcium phosphate (beta-TCP). Sacrifice was performed after 1, 2, 4, and 8 weeks for histologic and histomorphometric analysis. RESULTS: At 2 weeks, more new bone formation was seen in defects filled with autograft than with ABB (P approximately 0.0005) and beta-TCP (P approximately 0.002). After 4 weeks, there was no significant difference between beta-TCP and the two other materials. Defects grafted with ABB still exhibited less bone formation as compared with autograft (P approximately 0.004). At 8 weeks, more bone formation was observed in defects grafted with autograft (P approximately 0.003) and beta-TCP (P approximately 0.00004) than with ABB. No difference could be demonstrated between beta-TCP and autograft. beta-TCP resorbed almost completely over 8 weeks, whereas ABB remained stable. CONCLUSION: Both bone substitutes seemed to decelerate bone regeneration in the early healing phase as compared with autograft. All defects ultimately regenerated with newly formed bone and a developing bone marrow. The grafting materials showed complete osseous integration. Both bone substitutes may have a place in reconstructive surgery where different clinical indications require differences in biodegradability.

Animals↗
PubMed2003

Stimulation of Fos- and Jun-related genes during distraction osteogenesis.

Bone cells respond to mechanical stimulation by gene expression. The molecular events involved in the translation of mechanical stimulation into cell proliferation and bone formation are not yet well understood. We looked for the expression of early-response genes of the AP-1 transcription factor complex in an in vivo bone regeneration system subjected to mechanical forces because these genes were found to be related to mechanotransduction and important for bone development. Sheep maxillary bone was distracted daily for 15 days. c-Jun and c-Fos were evaluated by Northern blotting analysis and immunohistochemistry in biopsy specimens removed at 8 and 15 days and were compared with post-osteotomy but not distracted repair tissue. Elevated levels of c-Jun and c-Fos mRNA were found after 8 days of distraction. Likewise, mesenchyme-like and fibroblast-like cells composing the 8-day distracted regeneration tissue showed increases in the intensity of immunostaining compared to cells in the corresponding non-distracted fracture repair tissue. After 15 days of distraction, when bone trabeculae start to form distally and proximally in the distracted regeneration tissue, mostly preosteoblasts and osteoblasts retained c-Fos and c-Jun immunoreactivity, similar to bone-associated cells in control non-distracted fracture repair tissue. We propose that the elevated expression of c-Jun and c-Fos is related to mechanical stimulation in this in vivo bone regeneration system.

Animals↗
PubMed2004

Parathyroid hormone-related peptide is required for increased trabecular bone volume in parathyroid hormone-null mice.

We investigated the relative contributions of PTH and PTHrP to the skeletal phenotype of mice deficient in PTH (PTH(-/-)). PTH(-/-) mice and PTH(-/-) mice lacking one allele encoding PTHrP (PTH(-/-)PTHrP(+/-)) were compared. Both mutants displayed similar biochemical abnormalities of hypoparathyroidism, but skeletal PTHrP mRNA and protein were decreased in PTH(-/-)PTHrP(+/ -) mice. PTH(-/-) mice had increased trabecular bone volume with diminished bone turnover. PTHrP haploinsufficiency reduced trabecular bone of the PTH(-/-) mice to levels below those in wild-type animals by decreasing osteoprogenitor cell recruitment, enhancing osteoblast apoptosis, and diminishing bone formation. The results show that the increased trabecular bone volume in PTH-deficient mice is due to diminished PTH-induced osteoclastic bone resorption and persistent PTHrP-stimulated osteoblastic bone formation. They also illustrate the changing role of PTHrP during bone development, demonstrate its bone- forming function in the postnatal state, and support its pharmacological potential as an anabolic agent.

Animals↗
PubMed2004

Type 2 iodothyronine selenodeiodinase is expressed throughout the mouse skeleton and in the MC3T3-E1 mouse osteoblastic cell line during differentiation.

Thyroid hormone affects multiple aspects of bone metabolism, but little is known about thyroid hormone deiodination in bone cells except that cultures of skeletal cells and bone organ express types 1 and 2 iodothyronine deiodinases (D1 and D2) mRNAs. In the present study, outer ring deiodination (ORD) activity was detected in bone extracts of multiple sites of the mouse skeleton, bone marrow, and the MC3T3-E1 osteoblastic cell line. In all tissues, ORD was detected using 125I-rT3 or 125I-T4 as substrates and was found to be 6-n-propylthiouracil insensitive, display a Michaelis constant (T4) of approximately 1 nM, increase about 3-fold in hypo- and virtually disappear in thyrotoxicosis. Extracts of calvaria had the lowest ORD activity, whereas tibial and femoral extracts had roughly three times as much. The absence of ORD activity in bone extracts from mice with targeted disruption of the Dio2 gene confirms the principal role of D2 in this tissue. In the MC3T3-E1 osteoblasts, D2 activity increased in a time-dependent manner after plating, and with the content of selenium in the media, reaching a maximum 5-7 d later as cells attained more than 90% confluence. In these cells D2 half-life is about 30-40 min, which is further accelerated by exposure to substrate and stabilized by the proteasome inhibitor, MG132. Treatment with vitamin D [1,25(OH)2VD]-induced D2 activity by 2- to 3-fold as early as 24 h, regardless of the level of cell confluence, but estradiol, PTH, forskolin, leptin, TNFalpha, TGFbeta, and dexamethasone did not affect D2. Given the role of D2 in other cell types and processes, it is likely that bone ORD not only plays a role in bone development and adult bone T3 homeostasis but also contributes to extrathyroidal T3 production and maintenance of serum T3.

Animals↗
PubMed2001

Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation.

Indian hedgehog (Ihh), one of the three mammalian hedgehog (Hh) proteins, coordinates proliferation and differentiation of chondrocytes during endochondral bone development. Smoothened (Smo) is a transmembrane protein that transduces all Hh signals. In order to discern the direct versus indirect roles of Ihh in cartilage development, we have used the Cre-loxP approach to remove Smo activity specifically in chondrocytes. Animals generated by this means develop shorter long bones when compared to wild-type littermates. In contrast to Ihh mutants (Ihh(n)/Ihh(n)), chondrocyte differentiation proceeds normally. However, like Ihh(n)/Ihh(n) mice, proliferation of chondrocytes is reduced by about 50%, supporting a direct role for Ihh in the regulation of chondrocyte proliferation. Moreover, by overexpressing either Ihh or a constitutively active Smo allele (Smo*) specifically in the cartilage using the bigenic UAS-Gal4 system, we demonstrate that activation of the Ihh signaling pathway is sufficient to promote chondrocyte proliferation. Finally, expression of cyclin D1 is markedly downregulated when either Ihh or Smo activity is removed from chondrocytes, indicating that Ihh regulates chondrocyte proliferation at least in part by modulating the transcription of cyclin D1. Taken together, the present study establishes Ihh as a key mitogen in the endochondral skeleton.

Animals↗