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  • 1
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    Online Resource
    A Frame-Shift Mutation in the Type I Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Causing Blomstrand Lethal Osteochondrodysplasia
    The Endocrine Society ; 1999
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 10 ( 1999-10-01), p. 3713-3720
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 84, No. 10 ( 1999-10-01), p. 3713-3720
    Abstract: Blomstrand osteochondrodysplasia (BOCD) is a rare lethal skeletal dysplasia characterized by accelerated endochondral and intramembranous ossification. Comparison of the characteristics of BOCD with type I PTH/PTH-related peptide (PTHrP) receptor-ablated mice reveals striking similarities that are most prominent in the growth plate. In both cases, the growth plate is reduced in size due to a strongly diminished zone of resting cartilage and the near absence of columnar arrangement of proliferating chondrocytes. This overall similarity suggested that an inactivating mutation of the PTH/PTHrP receptor might be the underlying genetic defect causing BOCD. Indeed, inactivating mutations of the PTH/PTHrP receptor have been recently identified in two cases of BOCD. We describe here a novel inactivating mutation in the PTH/PTHrP receptor. Sequence analysis of all coding exons of the type I PTH/PTHrP receptor gene and complementary DNA of a case with BOCD identified a homozygous point mutation in exon EL2 in which one nucleotide (G at position 1122) was absent. The mutation was inherited from both parents, supporting the autosomal recessive nature of the disease. The missense mutation resulted in a shift in the open reading frame, leading to a truncated protein that completely diverged from the wild-type sequence after amino acid 364. The mutant receptor, therefore, lacked transmembrane domains 5, 6, and 7; the connecting intra- and extracellular loops; and the cytoplasmic tail. Functional analysis of the mutant receptor in COS-7 cells and of dermal fibroblasts obtained from the case proved that the mutation was indeed inactivating. Neither the transiently transfected COS-7 cells nor the dermal fibroblasts responded to a challenge with PTH or PTHrP with a rise in intracellular cAMP levels, in sharp contrast to control cells. Our results provide further evidence that BOCD is caused by inactivating mutations of the type I PTH/PTHrP receptor and underscore the importance of this receptor in mammalian skeletal development
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jcem.84.10.6033
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 1999
    detail.hit.zdb_id: 2026217-6
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  • 2
    Online Resource
    Online Resource
    Interleukin‐17: A New Bone Acting Cytokine In Vitro
    Wiley ; 1999
    In:  Journal of Bone and Mineral Research Vol. 14, No. 9 ( 1999-09), p. 1513-1521
    Details
    In: Journal of Bone and Mineral Research, Wiley, Vol. 14, No. 9 ( 1999-09), p. 1513-1521
    Abstract: Interleukin‐17 (IL‐17) is a recently cloned cytokine that is exclusively produced by activated T cells, but its receptor has been found on several cells and tissues. Like other proinflammatory cytokines produced by activated T cells, IL‐17 may affect osteoclastic resorption and thereby mediate bone destruction accompanying some inflammatory diseases. In the present study, we investigated whether osteogenic cells possess the receptor for IL‐17 (IL‐17R) and whether IL‐17 affects osteoclastic resorption. We found that IL‐17R mRNA is expressed both in mouse MC3T3‐E1 osteoblastic cells and fetal mouse long bones, suggesting that osteogenic cells may be responsive to IL‐17. In fetal mouse long bones, IL‐17 had no effect on basal and IL‐1β–stimulated osteoclastic bone resorption, but when given together with tumor necrosis factor‐α (TNF‐α) it increased bone resorption dose dependently in serum‐free conditions. In addition, IL‐17 increased TNF‐α–induced IL‐1α, IL‐1β, and IL‐6 mRNA expression in fetal mouse metatarsals and IL‐1α and IL‐6 mRNA expression in MC3T3‐E1 cells. In conclusion, IL‐17R mRNA was expressed by mouse osteoblastic cells and fetal mouse long bones, and IL‐17 in combination with TNF‐α, but not IL‐1β, increased osteoclastic resorption in vitro. IL‐17 may therefore affect bone metabolism in pathological conditions characterized by the presence of activated T cells and TNF‐α production such as rheumatoid arthritis and loosening of bone implants.
    Type of Medium: Online Resource
    ISSN: 0884-0431 , 1523-4681
    URL: Article
    DOI: 10.1359/jbmr.1999.14.9.1513
    RVK:
    XA 52230
    Language: English
    Publisher: Wiley
    Publication Date: 1999
    detail.hit.zdb_id: 2008867-X
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  • 3
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    Online Resource
    Downregulation of Wnt Signaling by Increased Expression of Dickkopf-1 and -2 is a Prerequisite for Late-Stage Osteoblast Differentiation of KS483 Cells
    Wiley ; 2005
    In:  Journal of Bone and Mineral Research Vol. 20, No. 10 ( 2005-06-26), p. 1867-1877
    Details
    In: Journal of Bone and Mineral Research, Wiley, Vol. 20, No. 10 ( 2005-06-26), p. 1867-1877
    Type of Medium: Online Resource
    ISSN: 0884-0431
    URL: Article
    DOI: 10.1359/JBMR.050614
    RVK:
    XA 52230
    Language: English
    Publisher: Wiley
    Publication Date: 2005
    detail.hit.zdb_id: 2008867-X
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  • 4
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    Novel Late Response Genes of PTHrP in Chondrocytes
    S. Karger AG ; 2007
    In:  Hormone Research in Paediatrics Vol. 67, No. 4 ( 2007), p. 159-170
    Details
    In: Hormone Research in Paediatrics, S. Karger AG, Vol. 67, No. 4 ( 2007), p. 159-170
    Abstract: To gain more insight into the downstream effectors of parathyroid hormone (PTH) related peptide (PTHrP) signaling in chondrocytes, we performed microarray analysis to identify late PTHrP response genes using the chondrogenic ATDC5 cell line and studied their response in the osteoblastic KS483 cell line and explanted metatarsals. At day 8 of micromass culture, ATDC5 cells have pre-hypertrophic-like characteristics and at this time point the cells were stimulated with PTHrP for 24 and 72 h and RNA was isolated. PTHrP treatment inhibited outgrowth of cartilage matrix and decreased the expression of Col10a1 mRNA, which is in line with the inhibitory effects of PTHrP on chondrocyte differentiation. Using cDNA microarray analysis, a list of 9 genes (p 〈 10 〈 sup 〉 –3 〈 /sup 〉 ) was generated, including 3 upregulated (IGFBP4, Csrp2, and Ecm1) and 6 downregulated (Col9a1, Col2a1, Agc, Hmgn2, Calm1, and Mxd4) response genes. Four out of 9 genes are novel PTHrP response genes and 2 out of 9 have not yet been identified in cartilage. Four out of 9 genes are components of the extra-cellular matrix and the remaining genes are involved in signal transduction and transcription regulation. The response to PTHrP was validated by quantitative PCR, using the same RNA samples as labeled in the microarray experiments and RNA samples isolated from a new experiment. In addition, we examined whether these genes also reacted to PTHrP in other PTHrP responsive models, like KS483 osteoblasts and explanted metatarsals. The expression of late PTHrP response genes varied between ATDC5 chondrocytes, KS483 osteoblasts and metatarsals, suggesting that the expression of late response genes is dependent on the cellular context of the PTHrP responsive cells.
    Type of Medium: Online Resource
    ISSN: 1663-2818 , 1663-2826
    URL: Article
    DOI: 10.1159/000096586
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2007
    detail.hit.zdb_id: 2540224-9
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  • 5
    Online Resource
    Online Resource
    IL‐1α, IL‐1β, IL‐6, and TNF‐α Steady‐State mRNA Levels Analyzed by Reverse Transcription‐Competitive PCR in Bone Marrow of Gonadectomized Mice
    Wiley ; 1998
    In:  Journal of Bone and Mineral Research Vol. 13, No. 2 ( 1998-02), p. 185-194
    Details
    In: Journal of Bone and Mineral Research, Wiley, Vol. 13, No. 2 ( 1998-02), p. 185-194
    Abstract: Loss of gonadal function in both females and males is associated with increased rates of bone loss by a yet unidentified mechanism. There is ample evidence that cytokines that are produced in the bone microenvironment and stimulate the activity and/or formation of osteoclasts are involved. In the present study, we examined whether gonadectomy increases cytokine production via increased transcription in the bone marrow of mice. For this, the in vivo steady‐state mRNA levels of multiple cytokines were determined in the central bone marrow compartment of mice at different time points following ovariectomy or orchidectomy by reverse transcription‐competitive polymerase chain reaction. The limit of detectable differences in mRNA expression was approximately 2‐fold. Bone marrow mRNA levels of the cytokines interleukin‐1α (IL‐1α), interleukin‐1β (IL‐1β), interleukin‐6 (IL‐6), and tumor necrosis factor‐α (TNF‐α) were elevated up to 30‐fold after treatment of mice with lipopolysaccharide. Following gonadectomy, there were no differences in the mRNA expression of these cytokines in bone marrow of female and male mice 4, 7, and 14 days after surgery. Gender steroid deficiency does not, therefore, increase steady‐state mRNA levels of IL‐1α, IL‐1β, IL‐6, and TNF‐α in cells of the central bone marrow compartment in mice. If changes have occurred these should have been less than 2‐fold or in a small cell population. These results do not preclude an important role of these cytokines in the induction of bone loss after gonadectomy. For example, bone marrow cells situated close to the bone surface or bone cells may be responsible for increased cytokine synthesis. Alternatively, the loss of gender steroids may alter post‐transcriptional events in cytokine synthesis and activity or may modify the responsiveness of target cells.
    Type of Medium: Online Resource
    ISSN: 0884-0431 , 1523-4681
    URL: Article
    DOI: 10.1359/jbmr.1998.13.2.185
    RVK:
    XA 52230
    Language: English
    Publisher: Wiley
    Publication Date: 1998
    detail.hit.zdb_id: 2008867-X
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  • 6
    Online Resource
    Online Resource
    Multiple Mechanisms Are Involved in Inhibition of Osteoblast Differentiation by PTHrP and PTH in KS483 Cells
    Wiley ; 2005
    In:  Journal of Bone and Mineral Research Vol. 20, No. 12 ( 2005-12), p. 2233-2244
    Details
    In: Journal of Bone and Mineral Research, Wiley, Vol. 20, No. 12 ( 2005-12), p. 2233-2244
    Abstract: We examined the mechanism by which PTHrP and PTH inhibit KS483 osteoblastic differentiation. We show that PTHrP and PTH inhibit differentiation downstream of early BMP signaling and downregulated components of the hedgehog (Hh) signaling cascade. In addition, PTHrP and PTH repressed RunX2 and osx expression. Overexpression of either gene, however, could not relieve PTHrP and PTH's inhibitory actions. Our data suggest that multiple parallel mechanisms are involved in the inhibition of osteoblast differentiation and matrix mineralization by PTHrP and PTH. Introduction : PTH‐related peptide (PTHrP) and PTH are potent inhibitors of osteoblast differentiation in vitro by as yet unexplained mechanisms. Materials and Methods : We treated murine bone marrow stromal cells and the mesenchymal progenitor cell line KS483 with PTHrP and PTH in combination with either BMPs or hedgehog (Hh) and measured early and late markers of osteoblast differentiation and studied the expression of RunX2 and Osterix (osx). In addition, we examined the PTHrP and PTH response in stable KS483 cells overexpressing either RunX2 or osx. Results : PTHrP and PTH inhibited BMP‐ and Hh‐induced osteogenesis downstream of early BMP signaling and by downregulation of components of the Hh signaling cascade. PTHrP and PTH prevented the upregulation of RunX2 expression associated with osteoblast differentiation in an indirect response. However, PTHrP and PTH could still inhibit differentiation, and particularly matrix mineralization, of cells expressing RunX2. In addition, PTHrP and PTH potently downregulated osx expression only in mature osteoblasts in an intermediate early response, but osx overexpression could not relieve the inhibitory effects of PTHrP and PTH on matrix mineralization. Conclusions : Our data suggest that, besides transcriptional repression of RunX2 and osx, other mechanisms in parallel with or downstream of RunX2 and osx are involved in the inhibition of osteoblast differentiation and matrix mineralization by PTHrP and PTH in vitro.
    Type of Medium: Online Resource
    ISSN: 0884-0431 , 1523-4681
    URL: Article
    DOI: 10.1359/JBMR.050821
    RVK:
    XA 52230
    Language: English
    Publisher: Wiley
    Publication Date: 2005
    detail.hit.zdb_id: 2008867-X
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  • 7
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    Online Resource
    Expression of the Parathyroid Hormone-Related Peptide Gene in Retinoic Acid-Induced Differentiation: Involvement of ETS and Sp1
    The Endocrine Society ; 1997
    In:  Molecular Endocrinology Vol. 11, No. 10 ( 1997-09-01), p. 1435-1448
    Details
    In: Molecular Endocrinology, The Endocrine Society, Vol. 11, No. 10 ( 1997-09-01), p. 1435-1448
    Abstract: Differentiation of P19 embryonal carcinoma (EC) and embryonal stem (ES)-5 cells with retinoic acid (RA) induces expression of PTH-related peptide (PTHrP) mRNA. In this study we have characterized a region between nucleotide (nt) −88 and −58 relative to the transcription start site in the murine PTHrP gene that was involved in this expression. Sequence analysis identified two partially overlapping binding sites for the Ets family of transcription factors and an inverted Sp1-binding site. Two major specific bands were detected in a bandshift assay using an oligonucleotide spanning nt −88 and −58 as a probe and nuclear extracts from both undifferentiated and RA-differentiated P19 EC cells. The lower complex consisted of Ets-binding proteins as demonstrated by competition with consensus Ets-binding sites, while the upper complex contained Sp1-binding activity as demonstrated by competition with consensus Sp1-binding sites. The observed bandshift patterns using nuclear extracts of undifferentiated or RA-differentiated P19 cells were indistinguishable, suggesting that the differentiation-mediated expression was not caused by the induction of expression of new transcription factors. Mutations in either of the Ets-binding sites or the Sp1-binding site completely abolished RA-induced expression of PTHrP promoter reporter constructs, indicating that the RA effect was dependent on the simultaneous action of both Ets- and Sp1-like activities. Furthermore, these mutations also abolished promoter activity in cells that constitutively expressed PTHrP mRNA, suggesting a central role for the Ets and Sp1 families of transcription factors in the expression regulation of the mouse PTHrP gene.
    Type of Medium: Online Resource
    ISSN: 0888-8809 , 1944-9917
    URL: Article
    DOI: 10.1210/mend.11.10.9997
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 1997
    detail.hit.zdb_id: 1492112-1
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  • 8
    Online Resource
    Online Resource
    Identification of a Retinoic Acid-Inducible Element in the Murine PTH/PTHrP (Parathyroid Hormone/Parathyroid Hormone-Related Peptide) Receptor Gene
    The Endocrine Society ; 1999
    In:  Molecular Endocrinology Vol. 13, No. 7 ( 1999-07), p. 1183-1196
    Details
    In: Molecular Endocrinology, The Endocrine Society, Vol. 13, No. 7 ( 1999-07), p. 1183-1196
    Type of Medium: Online Resource
    ISSN: 0888-8809 , 1944-9917
    URL: Article
    DOI: 10.1210/mend.13.7.0313
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 1999
    detail.hit.zdb_id: 1492112-1
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  • 9
    Online Resource
    Online Resource
    Full Length or Fragments in Hormone Studies?
    Wiley ; 2006
    In:  Journal of Bone and Mineral Research Vol. 21, No. 5 ( 2006-02-20), p. 802-802
    Details
    In: Journal of Bone and Mineral Research, Wiley, Vol. 21, No. 5 ( 2006-02-20), p. 802-802
    Type of Medium: Online Resource
    ISSN: 0884-0431
    URL: Article
    DOI: 10.1359/jbmr.060212
    RVK:
    XA 52230
    Language: English
    Publisher: Wiley
    Publication Date: 2006
    detail.hit.zdb_id: 2008867-X
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