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  1. Article ; Online: Reproductive hormones and bone.

    Nicks, Kristy M / Fowler, Tristan W / Gaddy, Dana

    Current osteoporosis reports

    2010  Volume 8, Issue 2, Page(s) 60–67

    Abstract: Hypothalamic gonadotropin-releasing hormone (GnRH) stimulates secretion of pituitary luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which directly regulate ovarian function. Pituitary FSH can modulate osteoclast development, and thereby ...

    Abstract Hypothalamic gonadotropin-releasing hormone (GnRH) stimulates secretion of pituitary luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which directly regulate ovarian function. Pituitary FSH can modulate osteoclast development, and thereby influence bone turnover. Pituitary oxytocin and prolactin effects on the skeleton are not merely limited to pregnancy and lactation; oxytocin stimulates osteoblastogenesis and bone formation, whereas prolactin exerts skeletal effects in an age-dependent manner. Cyclic levels of inhibins and estrogen suppress FSH and LH, respectively, and also suppress bone turnover via their suppressive effects on osteoblast and osteoclast differentiation. However, continuous exposure to inhibins or estrogen/androgens is anabolic for the skeleton in intact animals and protects against gonadectomy-induced bone loss. Alterations of one hormone in the hypothalamic-pituitary-gonadal (HPG) axis influence other bone-active hormones in the entire feedback loop in the axis. Thus, we propose that the action of the HPG axis should be extended to include its combined effects on the skeleton, thus creating the HPG skeletal (HPGS) axis.
    MeSH term(s) Bone Density/physiology ; Bone Remodeling/physiology ; Bone and Bones/metabolism ; Gonadal Hormones/metabolism ; Humans ; Hypothalamo-Hypophyseal System/metabolism ; Osteoporosis/metabolism ; Pituitary-Adrenal System/metabolism
    Chemical Substances Gonadal Hormones
    Language English
    Publishing date 2010-03-25
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2186581-4
    ISSN 1544-2241 ; 1544-1873
    ISSN (online) 1544-2241
    ISSN 1544-1873
    DOI 10.1007/s11914-010-0014-3
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  2. Article ; Online: Osteoprotection Through the Deletion of the Transcription Factor Rorβ in Mice.

    Farr, Joshua N / Weivoda, Megan M / Nicks, Kristy M / Fraser, Daniel G / Negley, Brittany A / Onken, Jennifer L / Thicke, Brianne S / Ruan, Ming / Liu, Hong / Forrest, Douglas / Hawse, John R / Khosla, Sundeep / Monroe, David G

    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

    2017  Volume 33, Issue 4, Page(s) 720–731

    Abstract: There is a clinical need to identify new molecular targets for the treatment of osteoporosis, particularly those that simultaneously inhibit bone resorption while stimulating bone formation. We have previously shown in overexpression studies that ... ...

    Abstract There is a clinical need to identify new molecular targets for the treatment of osteoporosis, particularly those that simultaneously inhibit bone resorption while stimulating bone formation. We have previously shown in overexpression studies that retinoic acid receptor-related orphan receptor β (Rorβ) suppresses in vitro osteoblast differentiation. In addition, the expression of Rorβ is markedly increased in bone marrow-derived mesenchymal stromal cells with aging in both mice and humans. Here we establish a critical role for Rorβ in regulating bone metabolism using a combination of in vitro and in vivo studies. We used Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 gene editing to demonstrate that loss of Rorβ in osteoblasts enhances Wnt signaling, specifically through increased recruitment of β-catenin to T-cell factor/lymphoid enhancer factor (Tcf/Lef) DNA binding sites in the promoters of the Wnt target genes Tcf7 and Opg. This resulted in increased osteogenic gene expression and suppressed osteoclast formation through increased osteoprotegerin (OPG) secretion in Rorβ-deficient cells. Consistent with our in vitro data, genetic deletion of Rorβ in both female and male mice resulted in preserved bone mass and microarchitecture with advancing age due to increased bone formation with a concomitant decrease in resorption. The improved skeletal phenotype in the Rorβ
    MeSH term(s) Animals ; Bone Resorption/genetics ; Bone Resorption/metabolism ; Bone Resorption/pathology ; Bone Resorption/prevention & control ; Cell Differentiation ; Cell Line ; Mice ; Mice, Knockout ; Nuclear Receptor Subfamily 1, Group F, Member 2/deficiency ; Osteoblasts/metabolism ; Osteoblasts/pathology ; Osteogenesis ; Wnt Signaling Pathway
    Chemical Substances Nuclear Receptor Subfamily 1, Group F, Member 2 ; Rorb protein, mouse
    Language English
    Publishing date 2017-12-27
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
    ZDB-ID 632783-7
    ISSN 1523-4681 ; 0884-0431
    ISSN (online) 1523-4681
    ISSN 0884-0431
    DOI 10.1002/jbmr.3351
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  3. Article ; Online: Ability of circulating human hematopoietic lineage negative cells to support hematopoiesis.

    Peris, Pilar / Roforth, Matthew M / Nicks, Kristy M / Fraser, Daniel / Fujita, Koji / Jilka, Robert L / Khosla, Sundeep / McGregor, Ulrike

    Journal of cellular biochemistry

    2014  Volume 116, Issue 1, Page(s) 58–66

    Abstract: Hematopoietic stem cell (HSC) self-renewal is regulated by osteoblast and/or endothelial cells within the hematopoietic niche. However, the true identity of the supporting cells and the nature of the secreted factors remain uncertain. We developed a ... ...

    Abstract Hematopoietic stem cell (HSC) self-renewal is regulated by osteoblast and/or endothelial cells within the hematopoietic niche. However, the true identity of the supporting cells and the nature of the secreted factors remain uncertain. We developed a novel mouse model and analyzed whether circulating human peripheral hematopoietic lineage negative/AP+ (lin-/AP+) cells support hematopoiesis in vivo. Thus, immunocompromised (Rag) mice expressing thymidine kinase (Tk) under the control of the 3.6Col1α1 promoter (Tk-Rag) were treated with ganciclovir, resulting in osteoblast progenitor cell ablation and subsequent loss of hematopoiesis (evaluated by measuring mouse Ter119+ erythroid cells). Following hematopoietic cell depletion, human bone marrow-derived marrow stromal cells (MSCs) or lin-/AP+ cells were infused into Tk-Rag mice and compared with saline infusions. Ganciclovir significantly reduced (7.4-fold) Ter119+ cells in the bone marrow of Tk-Rag mice compared to saline injections. Infusion of either MSCs or lin-/AP+ cells into ganciclovir-treated mice resulted in a 3.3-fold and 2.7-fold increase (P < 0.01), respectively, in Ter119+ cells compared to mice receiving saline. Relative to lin-/AP- cells, lin-/AP+ cells expressed high levels of mesenchymal, endothelial, and hematopoiesis supporting genes. Thus, human peripheral blood lin-/AP+ cells represent a novel cell type capable of supporting hematopoiesis in a manner comparable to MSCs.
    MeSH term(s) Animals ; Bone Marrow Cells/cytology ; Bone Marrow Cells/physiology ; Cell Lineage ; Female ; Flow Cytometry ; Ganciclovir/pharmacology ; Hematopoiesis/drug effects ; Hematopoiesis/genetics ; Hematopoiesis/physiology ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/metabolism ; Humans ; Mice
    Chemical Substances Ganciclovir (P9G3CKZ4P5)
    Language English
    Publishing date 2014-08-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 392402-6
    ISSN 1097-4644 ; 0730-2312
    ISSN (online) 1097-4644
    ISSN 0730-2312
    DOI 10.1002/jcb.24942
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  4. Article ; Online: Relationship of age to bone microstructure independent of areal bone mineral density.

    Nicks, Kristy M / Amin, Shreyasee / Atkinson, Elizabeth J / Riggs, B Lawrence / Melton, L Joseph / Khosla, Sundeep

    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

    2011  Volume 27, Issue 3, Page(s) 637–644

    Abstract: Previous studies using dual-energy X-ray absorptiometry (DXA) have demonstrated that age is a major predictor of bone fragility and fracture risk independent of areal bone mineral density (aBMD). Although this aBMD-independent effect of age has been ... ...

    Abstract Previous studies using dual-energy X-ray absorptiometry (DXA) have demonstrated that age is a major predictor of bone fragility and fracture risk independent of areal bone mineral density (aBMD). Although this aBMD-independent effect of age has been attributed to poor bone "quality," the structural basis for this remains unclear. Because high-resolution peripheral quantitative computed tomography (HRpQCT) can assess bone microarchitecture, we matched younger and older subjects for aBMD at the ultradistal radius and assessed for possible differences in trabecular or cortical microstructure by HRpQCT. From an age-stratified, random sample of community adults, 44 women aged <50 years (mean age 41.0 years) were matched to 44 women aged ≥50 years (mean age 62.7 years) by ultradistal radius aBMD (mean ± SEM, younger and older aBMD 0.475 ± 0.011 and 0.472 ± 0.011 g/cm², respectively), and 57 men aged <50 years (mean age 41.3 years) were matched to 57 men aged ≥50 years (mean age 68.1 years; younger and older aBMD both 0.571 ± 0.008 g/cm²). In these matched subjects, there were no sex-specific differences in trabecular microstructural parameters. However, significant differences were noted in cortical microstructure (all p < 0.05): Older women and men had increased cortical porosity (by 91% and 56%, respectively), total cortical pore volume (by 77% and 61%, respectively), and mean cortical pore diameter (by 9% and 8%, respectively) compared with younger subjects. These findings indicate that younger and older women and men matched for DXA aBMD have similar trabecular microarchitecture but clearly different cortical microstructure, at least at an appendicular site represented by the radius. Further studies are needed to define the extent to which this deterioration in cortical microstructure contributes to the aBMD-independent effect of age on bone fragility and fracture risk at the distal radius and other sites of osteoporotic fractures.
    MeSH term(s) Absorptiometry, Photon ; Adult ; Age Factors ; Aged ; Bone Density ; Bone and Bones/diagnostic imaging ; Bone and Bones/ultrastructure ; Female ; Humans ; Male ; Middle Aged ; Tomography, X-Ray Computed
    Language English
    Publishing date 2011-11-18
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 632783-7
    ISSN 1523-4681 ; 0884-0431
    ISSN (online) 1523-4681
    ISSN 0884-0431
    DOI 10.1002/jbmr.1468
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  5. Article ; Online: Deletion of Estrogen Receptor Beta in Osteoprogenitor Cells Increases Trabecular but Not Cortical Bone Mass in Female Mice.

    Nicks, Kristy M / Fujita, Koji / Fraser, Daniel / McGregor, Ulrike / Drake, Matthew T / McGee-Lawrence, Meghan E / Westendorf, Jennifer J / Monroe, David G / Khosla, Sundeep

    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

    2016  Volume 31, Issue 3, Page(s) 606–614

    Abstract: Although the role of ERα in regulating bone metabolism has been extensively studied, ERβ has been largely dismissed as a relevant modulator of bone mass. Previous studies examining ERβ utilized a germline knockout mouse expressing transcript variants of ... ...

    Abstract Although the role of ERα in regulating bone metabolism has been extensively studied, ERβ has been largely dismissed as a relevant modulator of bone mass. Previous studies examining ERβ utilized a germline knockout mouse expressing transcript variants of ERβ and displaying systemic hormonal changes that confounded interpretation of the skeletal phenotype. Thus, we used a conditional ERβ mouse model to achieve deletion of ERβ specifically in early osteoprogenitor cells using the Prx1-Cre driver. We observed marked increases in the trabecular bone volume fraction (of 58% [p < 0.003] and 93% [p < 0.0003] in 6- and 12-week-old female ERβ(Prx1-CKO) mice, respectively) but no changes in cortical bone. Serum estradiol and IGF-I levels were unaltered in ERβ(Prx1-CKO) mice. Bone formation and resorption indices by histomorphometry and serum assays were unchanged in these mice, suggesting that alterations in bone turnover may have occurred early in development. However, the ratio of colony-forming unit-osteoblasts (CFU-OBs) to CFU-fibroblasts (CFU-Fs) was increased in bone marrow cultures from ERβ(Prx1-CKO) compared with control mice, indicating increased differentiation of osteoblast precursor cells into osteoblasts in ERβ(Prx1-CKO) mice. Detailed quantitative polymerase chain reaction analyses of 128 genes in 16 prespecified pathways revealed significant downregulation of 11 pathways in ERβ(Prx1-CKO) mice. Thus, deletion of ERβ specifically in osteoblast lineage cells, in the absence of all splice variants, increases trabecular bone mass and modulates multiple pathways related to bone metabolism. These findings suggest that pharmacological inhibition of ERβ in bone may provide a novel approach to treat osteoporosis.
    MeSH term(s) Animals ; Bone and Bones/cytology ; Cancellous Bone/anatomy & histology ; Cell Differentiation ; Cell Line ; Colony-Forming Units Assay ; Cortical Bone/anatomy & histology ; Estrogen Receptor alpha/metabolism ; Estrogen Receptor beta/metabolism ; Female ; Gene Deletion ; Gene Expression Regulation ; Gene Knockdown Techniques ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Organ Size ; Osteoblasts/metabolism ; Ovariectomy ; Stem Cells/metabolism ; X-Ray Microtomography
    Chemical Substances Estrogen Receptor alpha ; Estrogen Receptor beta
    Language English
    Publishing date 2016-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 632783-7
    ISSN 1523-4681 ; 0884-0431
    ISSN (online) 1523-4681
    ISSN 0884-0431
    DOI 10.1002/jbmr.2723
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  6. Article ; Online: Tumor-derived syndecan-1 mediates distal cross-talk with bone that enhances osteoclastogenesis.

    Kelly, Thomas / Suva, Larry J / Nicks, Kristy M / MacLeod, Veronica / Sanderson, Ralph D

    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

    2010  Volume 25, Issue 6, Page(s) 1295–1304

    Abstract: Tumor-stimulated bone resorption fuels tumor growth and marks a dramatic decline in the health and prognosis of breast cancer patients. Identifying mechanisms that mediate cross-talk between tumor and bone remains a key challenge. We previously ... ...

    Abstract Tumor-stimulated bone resorption fuels tumor growth and marks a dramatic decline in the health and prognosis of breast cancer patients. Identifying mechanisms that mediate cross-talk between tumor and bone remains a key challenge. We previously demonstrated that breast cancer cells expressing high levels of heparanase exhibit enhanced shedding of the syndecan-1 proteoglycan. Moreover, when these heparanase-high cells are implanted in the mammary fat pad, they elevate bone resorption. In this study, conditioned medium from breast cancer cells expressing high levels of heparanase was shown to significantly stimulate human osteoclastogenesis in vitro (p < .05). The osteoclastogenic activity in the medium of heparanase-high cells was traced to the presence of syndecan-1, intact heparan sulfate chains, and heat-labile factor(s), including the chemokine interleukin 8 (IL-8). The enhanced osteoclastogenesis promoted by the heparanase-high cells results in a dramatic increase in bone resorption in vitro. In addition, the long bones of animals bearing heparanase-high tumors in the mammary fat pad had significantly higher numbers of osteoclasts compared with animals bearing tumors expressing low levels of heparanase (p < .05). Together these data suggest that syndecan-1 shed by tumor cells exerts biologic effects distal to the primary tumor and that it participates in driving osteoclastogenesis and the resulting bone destruction.
    MeSH term(s) Animals ; Bone Resorption/metabolism ; Bone Resorption/pathology ; Bone and Bones/drug effects ; Bone and Bones/metabolism ; Bone and Bones/pathology ; Breast Neoplasms/enzymology ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Culture Media, Conditioned/pharmacology ; Female ; Glucuronidase/metabolism ; Humans ; Interleukin-8/metabolism ; Mice ; Mice, SCID ; Osteoclasts/drug effects ; Osteoclasts/metabolism ; Osteoclasts/pathology ; Osteogenesis/drug effects ; Syndecan-1/metabolism
    Chemical Substances Culture Media, Conditioned ; Interleukin-8 ; Syndecan-1 ; heparanase (EC 3.2.1.-) ; Glucuronidase (EC 3.2.1.31)
    Language English
    Publishing date 2010-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 632783-7
    ISSN 1523-4681 ; 0884-0431
    ISSN (online) 1523-4681
    ISSN 0884-0431
    DOI 10.1002/jbmr.16
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  7. Article: A plasmid-cured Chlamydia muridarum strain displays altered plaque morphology and reduced infectivity in cell culture.

    O'Connell, Catherine M / Nicks, Kristy M

    Microbiology (Reading, England)

    2003  Volume 152, Issue Pt 6, Page(s) 1601–1607

    Abstract: A highly conserved cryptic plasmid is present in Chlamydia trachomatis yet naturally occurring plasmid-deficient isolates are very rare. This paper describes the isolation and characterization of a plasmid-deficient strain of C. muridarum, using ... ...

    Abstract A highly conserved cryptic plasmid is present in Chlamydia trachomatis yet naturally occurring plasmid-deficient isolates are very rare. This paper describes the isolation and characterization of a plasmid-deficient strain of C. muridarum, using novobiocin as a curing agent. Plasmid-deficient derivatives of C. muridarum strain Nigg were generated at high efficiencies (4-30%). Phenotypic characterization revealed that the cured derivative was unable to accumulate glycogen within intracytoplasmic inclusions. In addition, this strain formed small plaques at a reduced efficiency compared to the wild-type parent.
    MeSH term(s) Animals ; Anti-Bacterial Agents/pharmacology ; Cell Line ; Centrifugation ; Chlamydia muridarum/drug effects ; Chlamydia muridarum/genetics ; Chlamydia muridarum/growth & development ; Chlamydia muridarum/pathogenicity ; Glycogen/metabolism ; Mice ; Novobiocin/pharmacology ; Plasmids/genetics ; Polymerase Chain Reaction
    Chemical Substances Anti-Bacterial Agents ; Novobiocin (17EC19951N) ; Glycogen (9005-79-2)
    Language English
    Publishing date 2003-10-16
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1180712-x
    ISSN 1465-2080 ; 1350-0872
    ISSN (online) 1465-2080
    ISSN 1350-0872
    DOI 10.1099/mic.0.28658-0
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  8. Article ; Online: Three-dimensional structural analysis of the proximal femur in an age-stratified sample of women.

    Nicks, Kristy M / Amin, Shreyasee / Melton, L Joseph / Atkinson, Elizabeth J / McCready, Louise K / Riggs, B Lawrence / Engelke, Klaus / Khosla, Sundeep

    Bone

    2013  Volume 55, Issue 1, Page(s) 179–188

    Abstract: Introduction: Aging is associated with worsening bone structure and increasing risk of hip fracture. However, the commonly used clinical tool, dual-energy x-ray absorptiometry, does not provide information on changes with age or disease separately in ... ...

    Abstract Introduction: Aging is associated with worsening bone structure and increasing risk of hip fracture. However, the commonly used clinical tool, dual-energy x-ray absorptiometry, does not provide information on changes with age or disease separately in trabecular versus cortical bone or in bone geometry. Here we used 3D quantitative computed tomography (QCT) to analyze age-related changes in femoral volumetric bone mineral density (vBMD) and structure in a well characterized, population-based cohort of Rochester, Minnesota women.
    Methods: MIAF-Femur (MIAF: medical image analysis framework) was used for the analysis of CT datasets from 358 women age 20 to 97 years. Integral, "apparent" cortical (rather than true cortical vBMD, due to volume averaging effects) and trabecular vBMD, volume, and bone mineral content (BMC) as well as cortical thickness of the femur head, neck, trochanter, inter-trochanteric, and proximal shaft volumes of interest (VOIs) were measured. In addition, changes in vBMD in the superior, inferior, posterior and anterior quadrants of the femur neck were assessed.
    Results: Cross-sectional percent decreases in vBMD across life were 2- to 5-fold higher in trabecular versus cortical bone at all sites in the femur, although absolute changes in the trabecular and cortical bone were fairly similar. In addition, the slopes of the relationships of trabecular vBMD with age were generally similar in pre- and postmenopausal women, whereas apparent cortical vBMD in the femur neck, trochanter, inter-trochanteric region, and proximal shaft remained relatively stable in premenopausal women but decreased significantly with age following the menopause. Bone volume increased at all sites, more so in pre- compared to postmenopausal women. Age-related BMC changes were not significant in premenopausal women, but BMC losses were highly significant in postmenopausal women. Detailed analyses of femur neck cortical bone showed that percent apparent vBMD decreases in the superior quadrants were 2- to 3-fold greater than in the inferior quadrants; changes in absolute values were most different (~2-fold) between the superior-posterior and inferior-posterior quadrants.
    Conclusions: These data demonstrate that patterns of changes with age within the femur differ in the trabecular versus cortical bone. In the cortical compartment which, due to limitations in spatial resolution, contains some subcortical bone and should be regarded as an "apparent" cortical VOI, the superior quadrants in the femur neck undergo the greatest decreases. These findings may have important implications for understanding the structural basis for increased hip fracture risk with aging.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Aging/physiology ; Bone Density/physiology ; Female ; Femur/anatomy & histology ; Femur/diagnostic imaging ; Femur Neck/anatomy & histology ; Femur Neck/diagnostic imaging ; Femur Neck/physiology ; Humans ; Imaging, Three-Dimensional/methods ; Middle Aged ; Minnesota ; Tomography, X-Ray Computed ; Young Adult
    Language English
    Publishing date 2013-02-26
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 632515-4
    ISSN 1873-2763 ; 8756-3282
    ISSN (online) 1873-2763
    ISSN 8756-3282
    DOI 10.1016/j.bone.2013.02.009
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  9. Article ; Online: Effects of Age and Estrogen on Skeletal Gene Expression in Humans as Assessed by RNA Sequencing.

    Farr, Joshua N / Roforth, Matthew M / Fujita, Koji / Nicks, Kristy M / Cunningham, Julie M / Atkinson, Elizabeth J / Therneau, Terry M / McCready, Louise K / Peterson, James M / Drake, Matthew T / Monroe, David G / Khosla, Sundeep

    PloS one

    2015  Volume 10, Issue 9, Page(s) e0138347

    Abstract: Unlabelled: Precise delineation of the specific genes and pathways altered with aging and estrogen (E) therapy may lead to new skeletal biomarkers and the development of novel bone therapeutics. Previous human bone studies, however, have been limited by ...

    Abstract Unlabelled: Precise delineation of the specific genes and pathways altered with aging and estrogen (E) therapy may lead to new skeletal biomarkers and the development of novel bone therapeutics. Previous human bone studies, however, have been limited by only examining pre-specified genes and pathways. High-throughput RNA sequencing (RNAseq), on the other hand, offers an unbiased approach to examine the entire transcriptome. Here we present an RNAseq analysis of human bone samples, obtained from iliac crest needle biopsies, to yield the first in vivo interrogation of all genes and pathways that may be altered in bone with aging and E therapy in humans. 58 healthy women were studied, including 19 young women (mean age ± SD, 30.3 ± 5.4 years), 19 old women (73.1 ± 6.6 years), and 20 old women treated with 3 weeks of E therapy (70.5 ± 5.2 years). Using generally accepted criteria (false discovery rate [q] < 0.10), aging altered a total of 678 genes and 12 pathways, including a subset known to regulate bone metabolism (e.g., Notch). Interestingly, the LEF1 transcription factor, which is a classical downstream target of the Wnt/β-catenin signaling pathway, was significantly downregulated in the bones from the old versus young women; consistent with this, LEF1 binding sites were significantly enriched in the promoter regions of the differentially expressed genes in the old versus young women, suggesting that aging was associated with alterations in Wnt signaling in bone. Further, of the 21 unique genes altered in bone by E therapy, the expression of INHBB (encoding for the inhibin, beta B polypeptide), which decreased with aging (by 0.6-fold), was restored to young adult levels in response to E therapy. In conclusion, our data demonstrate that aging alters a substantial portion of the skeletal transcriptome, whereas E therapy appears to have significant, albeit less wide-ranging effects. These data provide a valuable resource for the potential identification of novel biomarkers associated with age-related bone loss and also highlight potential pathways that could be targeted to treat osteoporosis.
    Trial registration: ClinicalTrials.gov NCT02349113.
    MeSH term(s) Adult ; Age Factors ; Aged ; Aged, 80 and over ; Biomarkers ; Biopsy ; Bone Morphogenetic Proteins/blood ; Bone Morphogenetic Proteins/metabolism ; Bone and Bones/drug effects ; Bone and Bones/metabolism ; Bone and Bones/pathology ; Estrogens/metabolism ; Estrogens/pharmacology ; Female ; Gene Expression Profiling ; Gene Expression Regulation/drug effects ; Gene Regulatory Networks ; Genetic Markers ; High-Throughput Nucleotide Sequencing ; Humans ; Male ; Nucleotide Motifs ; Regulatory Sequences, Nucleic Acid ; Sequence Analysis, RNA ; Signal Transduction ; Transcriptome ; Young Adult
    Chemical Substances Biomarkers ; Bone Morphogenetic Proteins ; Estrogens ; Genetic Markers ; SOST protein, human
    Language English
    Publishing date 2015
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0138347
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Regulation of osteoblastogenesis and osteoclastogenesis by the other reproductive hormones, Activin and Inhibin.

    Nicks, Kristy M / Perrien, Daniel S / Akel, Nisreen S / Suva, Larry J / Gaddy, Dana

    Molecular and cellular endocrinology

    2009  Volume 310, Issue 1-2, Page(s) 11–20

    Abstract: There is both cellular and physiological evidence demonstrating that both Activins and Inhibins regulate osteoblastogenesis and osteoclastogenesis, and regulate bone mass in vivo. Although Activins and Inhibins were initially isolated from the gonad, ... ...

    Abstract There is both cellular and physiological evidence demonstrating that both Activins and Inhibins regulate osteoblastogenesis and osteoclastogenesis, and regulate bone mass in vivo. Although Activins and Inhibins were initially isolated from the gonad, Activins are also produced and stored in bone, whereas Inhibins exert their regulation on bone cell differentiation and metabolism via endocrine effects. The accumulating data provide evidence that reproductive hormones, distinct from classical sex steroids, are important regulators of bone mass and bone strength. Given the well described dominant antagonism of Inhibin over Activin, as well as over BMPs and TGFbeta, the gonadally derived Inhibins are important regulators of locally produced osteotrophic factors. Thus, the cycling Inhibins in females and diurnal changes in Inhibin B in males elicit temporal shifts in Inhibin levels (tone) that de-repress the pituitary. This fundamental action has the potential to de-repress locally stimulated changes in osteoblastogenesis and osteoclastogenesis, thereby altering bone metabolism.
    MeSH term(s) Activins/metabolism ; Animals ; Bone Remodeling ; Humans ; Inhibins/metabolism ; Osteoblasts/cytology ; Osteoblasts/metabolism ; Osteoclasts/cytology ; Osteoclasts/metabolism ; Osteogenesis
    Chemical Substances Activins (104625-48-1) ; Inhibins (57285-09-3)
    Language English
    Publishing date 2009-07-15
    Publishing country Ireland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
    ZDB-ID 187438-x
    ISSN 1872-8057 ; 0303-7207
    ISSN (online) 1872-8057
    ISSN 0303-7207
    DOI 10.1016/j.mce.2009.07.001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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