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PubMed2005

Effect of osteoblast-targeted expression of bcl-2 in bone: differential response in male and female mice.

UNLABELLED: Transgenic mice (Col2.3Bcl-2) with osteoblast-targeted human Bcl-2 expression were established. Phenotypically, these mice were smaller than their wildtype littermates and showed differential effects of the transgene on bone parameters and osteoblast activity dependent on sex. The net effect was an abrogation of sex differences normally observed in wildtype mice and an inhibition of bone loss with age. Ex vivo osteoblast cultures showed that the transgene had no effect on osteoblast proliferation, but decreased bone formation. Estrogen was shown to stimulate endogenous Bcl-2 message levels. These studies suggest a link between Bcl-2 and sex regulation of bone development and age-related bone loss. INTRODUCTION: Whereas Bcl-2 has been shown to be an important regulator of apoptosis in development, differentiation, and disease, its role in bone homeostasis and development is not well understood. We have previously showed that the induction of glucocorticoid-induced apoptosis occurred through a dose-dependent decrease in Bcl-2. Estrogen prevented glucocorticoid-induced osteoblast apoptosis in vivo and in vitro by preventing the decrease in Bcl-2 in osteoblasts. Therefore, Bcl-2 may be an important regulator of bone growth through mechanisms that control osteoblast longevity and function. MATERIALS AND METHODS: Col2.3Bcl-2 mice were developed carrying a 2.3-kb region of the type I collagen promoter driving 1.8 kb of human Bcl-2 (hBcl-2). Tissue specific expression of hBcl-2 in immunoassays validated the transgenic animal model. Histomorphometry and DXA were performed. Proliferation, mineralization, and glucocorticoid-induced apoptosis were examined in ex vivo cultures of osteoblasts. The effect of estrogen on mouse Bcl-2 in ex vivo osteoblast cultures was assayed by RT-PCR and Q-PCR. RESULTS AND CONCLUSIONS: Two Col2.3Bcl-2 (tg/+) founder lines were established and appeared normal except that they were smaller than their nontransgenic wildtype (+/+) littermates at 1, 2, and 6 months of age, with the greatest differences at 2 months. Immunohistochemistry showed hBcl-2 in osteoblasts at the growth plate and cortical surfaces. Nontransgenic littermates were negative. Western blots revealed hBcl-2 only in type I collagen-expressing tissues. Histomorphometry of 2-month-old mice showed a significant decrease in tg/+ calvaria width with no significant differences in femoral trabecular area or cortical width compared with +/+. However, tg/+ males had significantly more trabecular bone than tg/+ females. Female +/+ mice showed increased bone turnover with elevated osteoblast and osteoclast parameters compared with +/+ males. Col2.3Bcl-2 mice did not show such significant differences between sexes. Male tg/+ mice had a 76.5 +/- 1.5% increase in ObS/BS with no significant differences in bone formation rate (BFR) or mineral apposition rate (MAR) compared with male +/+ mice. Transgenic females had a significant 48.4 +/- 0.1% and 20.1 +/- 5.8% decrease in BFR and MAR, respectively, compared with +/+ females. Osteoclast and osteocyte parameters were unchanged. By 6 months, femurs from female and male +/+ mice had lost a significant amount of their percent of trabecular bone compared with 2-month-old mice. There was little to no change in femoral bone in the tg/+ mice with age. Ex vivo cultures of osteoblasts from +/+ and Col2.3Bcl-2 mice showed a decrease in mineralization, no effect on proliferation, and an inhibition of glucocorticoid-induced apoptosis in Col2.3Bcl-2 cultures. Estrogen was shown to increase mouse Bcl-2 transcript levels in osteoblast cultures of wildtype mice, supporting a role for Bcl-2 in the sex-related differences in bone phenotype regulated by estrogen. Therefore, Bcl-2 differentially affected bone phenotype in male and female transgenic mice, altered bone cell activity associated with sex-related differences, and decreased bone formation, suggesting that apoptosis is necessary for mineralization. In addition, Bcl-2 targeted to mature osteoblasts seemed to delay bone development, producing a smaller transgenic mouse compared with wildtype littermates. These studies suggest that expression of Bcl-2 in osteoblasts is important in regulating bone mass in development and in the normal aging process of bone.

Absorptiometry, Photon↗
PubMed1997

Recombinant transforming growth factor-beta1 induces endochondral bone in the baboon and synergizes with recombinant osteogenic protein-1 (bone morphogenetic protein-7) to initiate rapid bone formation.

Several members of the bone morphogenetic protein (BMP) and transforming growth factor-beta (TGF-beta) families are molecular regulators of cartilage and bone regeneration, although their actual roles and combined interactions in skeletal repair are poorly understood. The presence of several molecular forms suggests multiple functions in vivo as well as synergistic interactions during both embryonic bone development and regeneration of cartilage and bone in postfetal life. Here we show for the first time that recombinant human transforming growth factor-beta1 (TGF-beta1) induces endochondral bone formation in extraskeletal sites of adult baboons. We also show that TGF-beta1 and recombinant human osteogenic protein-1 (OP-1, bone morphogenetic protein-7) synergize in inducing large ossicles in extraskeletal sites of the primate as early as 15 days after implantation. A single application of OP-1, in conjunction with an insoluble collagenous matrix as carrier (5, 25, and 125 microg/100 mg of carrier matrix) induced bone differentiation in the rectus abdominis of the baboon. This level of tissue induction was raised several-fold by the simultaneous addition of comparatively low doses of TGF-beta1 (0.5, 1.5, and 5 microg), which by itself induces bone formation in the rectus abdominis at doses of 5 microg/100 mg of carrier matrix. Combinations of OP-1 and TGF-beta1 yielded a 2- to 3-fold increase in cross-sectional area of the newly generated ossicles, with markedly elevated key parameters of bone formation, and corticalization of the newly formed bone by day 15, culminating in bone marrow generation by day 30. The tissue generated by the combined application of OP-1 and TGF-beta1 showed distinct morphological differences when compared with OP-1-treated specimens, with large zones of endochondral development and extensive bone marrow formation. At the doses tested, synergy was optimal at a ratio of 1:20 by weight of TGF-beta1 and OP-1, respectively. These results provide evidence for a novel function of TGF-beta1 in the primate and the scientific basis for synergistic molecular therapeutics for the rapid regeneration of cartilage and bone.

Animals↗
PubMed2001

The urokinase plasminogen activator receptor-associated protein/endo180 is coexpressed with its interaction partners urokinase plasminogen activator receptor and matrix metalloprotease-13 during osteogenesis.

The urokinase plasminogen activator receptor-associated protein/Endo180 (uPARAP/Endo180) is a newly discovered member of the macrophage mannose receptor family that was reported to interact with ligand-bound urokinase plasminogen activator receptor (uPAR), matrix metalloprotease-13 (MMP-13), and collagen V on the cell surface. We have determined the sites of expression of this novel receptor during murine postimplantation development. uPARAP/Endo180 was expressed in all tissues undergoing primary ossification, including the developing bones of the viscerocranium and calvarium that ossify intramembranously, and developing long bones undergoing endochondral ossification. uPARAP/Endo180 mRNA was expressed by both immature osteoblasts and by mature osteocalcin-producing osteoblasts-osteocytes, and was coexpressed with MMP-13. Interestingly, osteoblasts also expressed uPAR. Besides bone-forming tissues, uPARAP/Endo180 expression was detected only in a mesenchymal condensation of the midbrain and in the developing lungs. The data suggest a function of this novel protease receptor in bone development, possibly mediated through its interactions with uPAR, MMP-13, or collagen V.

Animals↗
PubMed1993

Genital and nongenital teratogenesis of prenatal progestogen therapy: the effects of 17 alpha-hydroxyprogesterone caproate on embryonic and fetal development and endochondral ossification in the C57B1/6J mouse.

OBJECTIVE: The current study assesses the effects of 17 alpha-hydroxyprogesterone caproate on embryo-fetal development, with a particular focus placed on intrauterine endochondral bone development and growth. STUDY DESIGN: Primigravid C57 BI/6J mice were administered 17 alpha-hydroxyprogesterone caproate by means of subdermal pellets designed to deliver doses of 0.5, 5.0, and 50.0 mg/kg/day on gestational days 7 through 19. Assuming a dosage regimen of 250 mg per 50 kg per week in humans for the treatment of threatened spontaneous abortion, the doses used were 0.7, 7.0, and 70.0 times the human dose equivalent. The time course of exposure encompassed the period of organogenesis through the late fetal period. RESULTS: No maternal toxicity was noted throughout the course of 17 alpha-hydroxyprogesterone caproate administration. Fetal weight at term and the percentage of resorptions, dead fetuses, male fetuses, and malformations at term were not significantly affected at any evaluated dose when compared with control group values. The steroid did not exert a significant influence on any assessed parameter of endochondral bone development or growth, even at a dosage concentration that far exceeded the human therapeutic dose equivalent. As would be expected, fetal weight was directly correlated with diaphyseal length and also influenced the relationship of cartilage to osseous tissue in both the humeri and femora. There were no 17 alpha-hydroxyprogesterone caproate dose and fetal sexual phenotype interactive effects noted with regard to any developmental or bone growth parameter measured, thus discounting any sexual phenotype-related toxic or teratogenic sensitivities. CONCLUSION: The data indicate that 17 alpha-hydroxyprogesterone caproate administered at doses of up to 70 times the human dose equivalent did not induce increases in the frequency of genital and, importantly, nongenital teratogenesis in spite of exposure during the critical period of organogenesis. Additionally, the steroid did not affect limb morphogenesis or endochondral ossification.

17 alpha-Hydroxyprogesterone Caproate↗
PubMed1996

Radiotherapy, alkylating agents, and risk of bone cancer after childhood cancer.

BACKGROUND: Individuals who had cancer in childhood are at higher risk of developing bone cancer than any other type of second primary cancer. PURPOSE: Using the population-based National Registry of Childhood Tumours in Britain, we investigated the incidence and etiology of second primary bone cancer after childhood cancer in a cohort study and in a case-control study. METHODS: A cohort study of 13,175 3-year survivors of childhood cancer diagnosed in Britain between 1940 and 1983 revealed 55 subsequent bone cancers. A largely nested case-control study comprised 59 case subjects developing second primary bone cancer, and 220 control subjects were selected and matched for sex, type of first cancer, age at first cancer, and interval between diagnosis of first cancer and subsequent bone cancer. Outcome measures were the incidence of bone cancer after childhood cancer, the cumulative dose of radiation received at the site of the second cancer in the case subject and at the corresponding anatomic site in the matched control subjects, and the cumulative dose of alkylating agents and vinca alkaloids received by case and control subjects. RESULTS: The percentage of 3-year survivors developing bone cancer within 20 years did not exceed 0.9%, except following heritable retinoblastoma (7.2%), Ewing's sarcoma (5.4%), and other malignant bone tumors (2.4%). The risk of bone cancer increased substantially with increased cumulative dose of radiation to the bone (P< .001, linear trend). At the highest levels of exposure, however, the risk appeared to decline somewhat (P=.065, nonlinearity). Exposure to less than 10 Gy was at worst, associated with only a small increased relative risk (RR) of bone cancer (RR= 0.7; 95% confidence interval = 0.2-2.2). The risk of bone cancer increased linearly (P= .04, one-tailed test) with increased cumulative dose of alkylating agents. IMPLICATIONS: This population-based study provides grounds for reassurance of the majority of survivors in that their risk of developing bone cancer within 20 years of 3-year survival did not exceed 0.9%. The higher risks found for bone cancer following the other specific rare types of childhood cancer provide a rational basis for surveillance. The RRs reported for bone cancer after specified levels of exposure to radiation should help in making decisions concerning future treatment protocols.

Adolescent↗
PubMed1996

Bone morphogenetic proteins in development.

The bone morphogenetic proteins (BMPs) constitute a large family of cytokines related to members of the transforming growth factor-beta superfamily. Recent evidence, in particular from gene targeting experiments in the mouse, indicates that BMPs are required for mesoderm formation and for the development and patterning of many different organ systems. Significant progress has also been made in understanding the role of BMPs in gastrulation and neurulation in Xenopus and in identifying genes regulating BMP expression and components of the downstream signaling pathways. Extracellular modifiers of BMP activity may constitute an opposing morphogenetic system.

Animals↗
PubMed1996

Effect of thyroid hormone on growth. Lessons from the syndrome of resistance to thyroid hormone.

Thyroid hormone deprivation results in deleterious effects on bone growth. The delayed bone development is mediated by a direct effect of thyroid hormone on bone and an indirect effect of the hormone on GH release and IGF-1 action. Both TR alpha and TR beta are expressed in bone cells. To examine the role of TR beta on bone, we have reviewed the growth abnormalities in the human syndrome of RTH caused by mutations in the TR beta gene. The mutant TR beta reduces the tissue responsiveness to thyroid hormone, producing in some tissues variable degrees of thyroid hormone deprivation. With regard to bone, relative thyroid hormone deficiency caused by the mutant TR beta produces short stature and delayed bone growth but does not attenuate growth to the extent that absolute thyroid hormone deficiency does. These observations indicate that an intact TR beta is required for normal bone development and growth.

Bone and Bones↗
PubMed1994

Role of vascular endothelial cells in bone biology.

Bone development and remodeling depend on complex interactions between bone-forming osteoblasts, bone-degrading osteoclasts, and other cells present within the bone microenvironment. Balanced control of bone formative and degradative processes is normally carefully maintained in the adult skeleton but becomes uncoupled in the course of aging or in various pathological disease states. Systemic regulators of bone metabolism and local mediators, including matrix molecules, cytokines, prostaglandins, leukotrienes, and other autocrine or paracrine factors, regulate the recruitment, differentiation, and function of cells participating in bone formation and turnover. Although some of these interactions are now understood, many yet remain to be elucidated. Recent studies have begun exploring in detail how vascular endothelial cells and their products function in bone physiology. The findings are revealing that bone vascular endothelial cells may be members of a complex communication network in bone which operates between endothelial cells, osteoblasts, osteoclasts, macrophages, stromal cells, and perhaps other cell types found in bone as well. Therefore, multiple systemic and locally produced signals may be received, transduced, and integrated by individual cells and then propagated by the release from these cells of further signals targeted to other members of the bone cell network. In this manner, bone cell activities may be continuously coordinated to afford concerted actions and rapid responses to physiological changes. The bone microvasculature may play a pivotal role in these processes, both in linking circulatory and local signals with cells of the bone microenvironment and in actively contributing itself to the regulation of bone cell physiology.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Matrix metalloproteinases and their inhibitors in bone: an overview of regulation and functions.

Matrix metalloproteinases (MMPs), a family of Zn2+-dependent endopeptidases, mediate different physiological processes by digesting components of the extracellular matrix. Nevertheless, overexpression of MMPs is implicated in the pathogenesis of various diseases. Different MMPs and tissue inhibitors of MMPs (TIMPs) are expressed in bone cells, and their biosynthesis is regulated by local and systemic hormones and factors. The levels of enzymatically active MMPs in bone are further controlled by secretion, activation of proenzymes, inhibition by TIMPs, cellular uptake and degradation. Members of the cysteine and serine family of proteinases also coordinate some of the biological activities of MMPs in bone. The functions of MMPs and TIMPs in bone include regulation of processes, such as degradation of collagen and other components of the bone matrix, migration and survival of bone cells, endochondral bone formation and bone resorption. Abnormal expression of MMPs may lead to pathological conditions affecting bone and cartilage. Various pharmacological agents can inhibit MMPs, and some of these inhibitors may be potential therapeutic agents for certain bone diseases. This review briefly describes the regulation and functions of different MMPs and TIMPs in bone, and provides an insight into the role of MMPs in bone development, remodeling and pathology.

Bone Development↗
PubMed1994

Reconstruction of resected mandibles using a hydroxyapatite veterinary bone graft.

A newly developed bone equivalent hydroxyapatite was derived from veterinary bone (VHAP). Sections of 1 cm of six rabbit mandibles were equally replaced by this VHAP graft. Radiological studies by X-ray were performed pre-operatively, immediately, and 1, 2 and 3 months post-operatively. The graft host-bone interface was examined periodically by scanning electron microscopy (SEM). Accompanying structural changes of the graft 3 months post-operatively were compared with the pre-operative findings by infra-red (IR) spectroscopic analysis. Complete union of the biomaterial to the host bone after 3 months was evidenced radiologically. SEM proved complete graft integration. This was accompanied by a decrease in optical density of the IR analysis of post-operative VHAP, indicating some leaching of the ions. Clinically, the graft was completely incorporated in the mandible without any complications. We discuss the use of VHAP in humans to reconstruct post-surgical mandibular defects.

Animals↗
PubMed1993

Effect of basic fibroblast growth factor on the growth and differentiation of adult stromal bone marrow cells: enhanced development of mineralized bone-like tissue in culture.

Rat stromal bone marrow cells (SBMC) were shown to produce mineralized bone-like tissue in culture in the presence of dexamethasone, ascorbic acid, and beta-glycerophosphate. The addition of 3 ng/ml of basic fibroblast growth factor (bFGF) resulted in a significant increase in formation of mineralized tissue. The present study was aimed at assessing the effect of bFGF on the proliferation and differentiation of SBMC and on the sequential development of mineralized bone-like tissue in culture. Transmission electron microscopy of bFGF-treated cultures demonstrated the development of a multilayered structure resembling mineralized bone tissue consisting of cell layers embedded within a heavy extracellular matrix. The matrix was rich in bundles of collagen fibers associated with extensive mineral deposits consisting of hydroxyapatite as determined by infrared spectrophotometry. The addition of 3 ng/ml of bFGF resulted in significant enhancement of [3H]thymidine and [3H]proline incorporation and protein accumulation by 12-, 2.5-, and 2.5-fold, respectively. bFGF treatment increased cAMP responsiveness, alkaline phosphatase activity, osteocalcin level, 45Ca2+ deposition, and mineralized-like tissue formation and induced the earlier expression of these markers in the treated culture. A biphasic sequence of events was observed during the development of mineralized bone-like tissue in bFGF-treated and control cultures. The first phase is characterized by cell proliferation and matrix accumulation and is reflected by a progressive increase in [3H]thymidine and [3H]proline incorporation until day 11. The second phase, which follows, is characterized by a sharp decline in cell proliferation and matrix accumulation and a concomitant expression of osteoblast differentiation as reflected by the progressive increase in alkaline phosphatase activity, mineral deposition, and osteocalcin expression. Treatment of cultures with bFGF accentuated this biphasic sequence of events. These results indicate that bFGF has the capacity to stimulate both the growth and the biochemical functions of SBMC obtained from a young adult animal.

Alkaline Phosphatase↗
PubMed2002

Stanniocalcin 1 (STC1) protein and mRNA are developmentally regulated during embryonic mouse osteogenesis: the potential of stc1 as an autocrine/paracrine factor for osteoblast development and bone formation.

STC1, a mammalian homologue of stanniocalcin (STC) which plays a major role in calcium/phosphate homeostasis in fish, has been recently isolated. We have characterized the spatiotemporal distribution of STC1 mRNA and protein during mouse embryonic development generally and osteogenesis specifically. Northern blotting analysis of whole embryos showed that STC1 mRNA is highly and differentially expressed during embryogenesis. By in situ hybridization, STC1 mRNA was detected early in mesenchymal condensations and was then found to be highly expressed in perichondrial cells, periosteal cells, and then osteoblasts during endochondral bone formation. In bones forming by intramembranous ossification, STC1 mRNA was not detected until osteogenic cells appeared. The cellular distribution of STC1 protein closely corresponded to that of its mRNA, but the protein was also detected in hypertrophic chondrocytes. In the MC3T3-E1 osteogenic cell model, STC1 protein and mRNA were detectable throughout proliferation and differentiation stages but levels were relatively higher late during nodule formation/mineralization phases. For comparison, STC1 mRNA was also found in epithelial cells of both embryonic and adult intestine that had not previously been described among tissues responsive to calcium/phosphate transport. These results suggest that STC1 is expressed in a time- and cell-specific manner and may play an autocrine/paracrine role during osteoblast development and bone formation.

Animals↗
PubMed1997

Development of bone marrow eosinophilia in mice induced by Aspergillus fumigatus antigens.

A model of allergic bronchopulmonary aspergillosis (ABPA) developed by exposing mice to Aspergillus fumigatus antigen (Af) exhibits peripheral blood (PB), lung, and bone marrow (BM) eosinophilia. Because the BM is a site of eosinophilopoiesis, we have investigated the role of Af in the induction of this process in the BM. Groups of mice were exposed intranasally (i.n.) or intraperitoneally (i.p.) to Af. BM cells from mice were cultured with either Af or allogenic spleen cell supernatant stimulated with Af. Eosinophil counts in different lymphoid compartments, eosinophil peroxidase (EPO), and mRNA for cytokines and IgE in BM cells were studied. Results indicate that the eosinophil numbers were significantly elevated in PB and BM of all Af-exposed mice. Lung lavage eosinophils increased only in the i.n. group. Af induced EPO activity only in BM cultures from Af-exposed mice. The EPO activity was further enhanced by supernatants from spleen cells from Af-exposed mice. mRNA transcription of IL-3 and IL-5 were measurable in BM cells of the ip exposed mice. These findings suggest that Af mediates eosinophil development in BM of mice and this process is promoted by hematopoietic factors generated within the BM and in other lymphoid tissue such as the spleen.

Animals↗
PubMed2006

Transglutaminases in mineralized tissues.

Bone development and formation during embryogenesis as well as postnatally during bone remodeling is a complex process controlled systemically and locally by hormones, growth factors and matrix molecules. Transglutaminases (TGases) are the protein cross-linking enzymes, which have long been implicated in bone development and formation. Two members of TGase family, TG2 (also called tissue transglutaminase) and FXIIIA (the enzymatic A subunit of coagulation factor XIII), are expressed in chondrocytes and osteoblasts. The results of analyses in vivo and in vitro accumulated to date indicate an important role of these enzymes in promoting chondrocyte and osteoblast differentiation and matrix mineralization. These effects could be mediated by protein cross-linking activity of TGases, by GTPase activity of TG2 or via non-catalytic signaling effects. The aim of this review is to summarize the available data regarding the expression, localization and activity of TG2 and FXIIIA in mineralizing tissues and to discuss a number of mechanisms by which TGases could exert their promineralizing effects.

Animals↗
PubMed2006

Endostatin inhibits VEGF-A induced osteoclastic bone resorption in vitro.

BACKGROUND: Endostatin is a C-terminal fragment of collagen XVIII which is a component of basement membranes with the structural properties of both collagens and proteoglycans. Endostatin has a major role in angiogenesis which is intimately associated with bone development and remodeling. Signaling between the endothelial cells and the bone cells, for example, may have a role in recruitment of osteoclastic precursor cells. Our study aims at exploring a possibility that endostatin, either as a part of basement membrane or as a soluble molecule, may control osteoclastogenesis and osteoclastic bone resorption in vitro. METHODS: Rat pit formation assay was employed in order to examine the effect of endostatin alone or in combination with vascular endothelial growth factor-A (VEGF-A) on bone resorption in vitro. Effect of these agents on osteoclast differentiation in vitro was also tested. Osteoclastogenesis and the number of osteoclasts were followed by tartrate resistant acid phosphatase (TRACP) staining and resorption was evaluated by measuring the area of excavated pits. RESULTS: Endostatin inhibited the VEGF-A stimulated osteoclastic bone resorption, whereas endostatin alone had no effect on the basal resorption level in the absence of VEGF-A. In addition, endostatin could inhibit osteoclast differentiation in vitro independent of VEGF-A. CONCLUSION: Our in vitro data indicate that collagen XVIII/endostatin can suppress VEGF-A induced osteoclastic bone resorption to the basal level. Osteoclastogenesis is also inhibited by endostatin. The regulatory effect of endostatin, however, is not critical since endostatin alone does not modify the basal bone resorption.

Acid Phosphatase↗
PubMed2004

Using focus groups to develop a bone health curriculum for after-school programs.

INTRODUCTION: Childhood behaviors influence peak bone mass and osteoporosis risk in later life. The after-school environment provides an opportunity to enrich a child's learning and experience. Our objective was to gain a better understanding of the knowledge of, attitudes and beliefs about, and barriers to achieving bone health among children, parents, and after-school program leaders from low-income, ethnically diverse communities. Findings led to the development, implementation, and evaluation of a bone health curriculum in the after-school setting. METHODS: Eight focus groups were conducted in three representative communities. Focus group participants included children aged six to eight years, parents of children aged six to eight, and after-school program staff. Transcripts and written notes from each session were reviewed and common themes were identified within each group. RESULTS: Most adults had some understanding of osteoporosis, but did not recognize that childhood behaviors had a role in developing the disease. Program leaders raised concerns about their ability to implement a health program and recommended a flexible format. Parents and program leaders recognized the importance of maintaining a fun atmosphere. CONCLUSION: It is feasible to create a curriculum for a bone health program that meets the unique needs and interests of children and program leaders in the after-school setting. Addressing the needs, interests, and common barriers of the target population is an essential first step in curriculum development.

Bone and Bones↗
PubMed2004

Experimental cholestatic liver disease through bile-duct ligation in rats results in skeletal fragility and impaired osteoblastogenesis.

BACKGROUND/AIMS: Patients with cholestatic liver disease have 'low-turnover' osteoporosis. Since we reported that bile-duct ligated (BDL) rats develop bone disease with low bone formation and mass, we examined whether their reduced bone mass results in skeletal fragility, and whether the reduction in osteoprogenitor cells could explain the depressed bone formation. METHODS: Four-week-old rats were pair-fed and subjected to BDL or sham surgery. After 4 weeks, ex vivo bone marrow stromal cell cultures were used to estimate the number of osteoprogenitors and tibial strength was measured by mechanical testing. The serum levels of albumin, bilirubin, alanine amino-transferase (ALT), alkaline phosphatase (ALP) and nitrite were measured. RESULTS: BDL rats had elevated levels of bilirubin, ALT, ALP and nitrite. Tibiae of BDL rats were weaker than those of sham rats, exhibiting lower maximal force (-34%) and stiffness (-37%). The number of mineralized bone-like nodules in cultures from BDL rats was 65% lower than that in cultures from sham-operated rats, attesting to a diminished number of osteoprogenitors. CONCLUSIONS: Skeletal fragility diminished osteoprogenitor pool and elevated plasma levels of nitrite are three additional characteristics of the bone disease that develops in BDL rats, thus increasing the validity of this animal model as representing the human bone disease in patients with cholestatic liver disease.

Animals↗