138 results on '"Roschger A"'
Search Results
2. Curvature in Biological Systems: Its Quantification, Emergence, and Implications across the Scales
- Author
-
Schamberger, Barbara, primary, Ziege, Ricardo, additional, Anselme, Karine, additional, Ben Amar, Martine, additional, Bykowski, Michał, additional, Castro, André P. G., additional, Cipitria, Amaia, additional, Coles, Rhoslyn A., additional, Dimova, Rumiana, additional, Eder, Michaela, additional, Ehrig, Sebastian, additional, Escudero, Luis M., additional, Evans, Myfanwy E., additional, Fernandes, Paulo R., additional, Fratzl, Peter, additional, Geris, Liesbet, additional, Gierlinger, Notburga, additional, Hannezo, Edouard, additional, Iglič, Aleš, additional, Kirkensgaard, Jacob J. K., additional, Kollmannsberger, Philip, additional, Kowalewska, Łucja, additional, Kurniawan, Nicholas A., additional, Papantoniou, Ioannis, additional, Pieuchot, Laurent, additional, Pires, Tiago H. V., additional, Renner, Lars D., additional, Sageman‐Furnas, Andrew O., additional, Schröder‐Turk, Gerd E., additional, Sengupta, Anupam, additional, Sharma, Vikas R., additional, Tagua, Antonio, additional, Tomba, Caterina, additional, Trepat, Xavier, additional, Waters, Sarah L., additional, Yeo, Edwina F., additional, Roschger, Andreas, additional, Bidan, Cécile M., additional, and Dunlop, John W. C., additional
- Published
- 2023
- Full Text
- View/download PDF
3. Curvature in biological systems: its quantification, emergence and implications across the scales
- Author
-
Schamberger, B., Roschger, A., Ziege, R., Anselme, K., Amar, M.B., Bykowski, M., Castro, A.P.G., Cipitria, A., Coles, R., Dimova, R., Eder, M., Ehrig, S., Escudero, L.M., Evans, M.E., Fernandes, P.R., Fratzl, P., Geris, L., Gierlinger, N., Hannezo, E., Iglič, A., Kirkensgaard, J.J.K., Kollmannsberger, P., Kowalewska, Ł., Kurniawan, N.A., Papantoniou, I., Pieuchot, L., Pires, T.H.V., Renner, L., Sageman-Furnas, A., Schröder-Turk, G.E., Sengupta, A., Sharma, V.R., Tagua, A., Tomba, C., Trepat, X., Waters, S.L., Yeo, E., Bidan, C.M., and Dunlop, J.W.C.
- Subjects
Cardiovascular and Metabolic Diseases - Abstract
Surface curvature both emerges from, and influences the behavior of, living objects at length scales ranging from cell membranes to single cells to tissues and organs. The relevance of surface curvature in biology has been supported by numerous recent experimental and theoretical investigations in recent years. In this review, we first give a brief introduction to the key ideas of surface curvature in the context of biological systems and discuss the challenges that arise when measuring surface curvature. Giving an overview of the emergence of curvature in biological systems, its significance at different length scales becomes apparent. On the other hand, summarizing current findings also shows that both single cells and entire cell sheets, tissues or organisms respond to curvature by modulating their shape and their migration behavior. Finally, we address the interplay between the distribution of morphogens or micro-organisms and the emergence of curvature across length scales with examples demonstrating these key mechanistic principles of morphogenesis. Overall, this review highlights that curved interfaces are not merely a passive by-product of the chemical, biological and mechanical processes but that curvature acts also as a signal that co-determines these processes. This article is protected by copyright. All rights reserved.
- Published
- 2023
4. Synthesis and biological evaluation of new quinoline‐4‐carboxylic acid‐chalcone hybrids as dihydroorotate dehydrogenase inhibitors
- Author
-
Petrović, Milena M., primary, Roschger, Cornelia, additional, Lang, Kevin, additional, Zierer, Andreas, additional, Mladenović, Milan, additional, Trifunović, Snežana, additional, Mandić, Boris, additional, and Joksović, Milan D., additional
- Published
- 2022
- Full Text
- View/download PDF
5. Synthesis and biological evaluation of new quinoline-4-carboxylic acid-chalcone hybrids as dihydroorotate dehydrogenase inhibitors
- Author
-
Milena M. Petrović, Cornelia Roschger, Kevin Lang, Andreas Zierer, Milan Mladenović, Snežana Trifunović, Boris Mandić, and Milan D. Joksović
- Subjects
hDHODH inhibitors ,chalcones ,dihydroorotate dehydrogenase ,Drug Discovery ,quinoline‐4‐carboxylic acid ,Pharmaceutical Science - Abstract
Fourteen novel quinoline-4-carboxylic acid-chalcone hybrids were obtained via Claisen–Schmidt condensation and evaluated as potential human dihydroorotate dehydrogenase (hDHODH) inhibitors. The ketone precursor 2 was synthesized by the Pfitzinger reaction and used for further derivatization at position 3 of the quinoline ring for the first time. Six compounds showed better hDHODH inhibitory activity than the reference drug leflunomide, with IC50 values ranging from 0.12 to 0.58 μM. The bioactive conformations of the compounds within hDHODH were resolved by means of molecular docking, revealing their tendency to occupy the narrow tunnel of hDHODH within the N-terminus and to prevent ubiquinone as the second cofactor from easily approaching the flavin mononucleotide as a cofactor for the redox reaction within the redox site. The results of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that 4d and 4h demonstrated the highest cytotoxic activity against the A375 cell line, with IC50 values of 5.0 and 6.8 µM, respectively. The lipophilicity of the synthesized hybrids was obtained experimentally and expressed as logD7.4 values at physiologicalpH while the solubility assay was conducted to define physicochemical characteristics influencing the ADMET properties.
- Published
- 2023
6. Backbone distortions in lactam‐bridged helical peptides
- Author
-
Ali Moazzam, Vesna Stanojlovic, Arthur Hinterholzer, Christoph Holzner, Cornelia Roschger, Andreas Zierer, Markus Wiederstein, Mario Schubert, and Chiara Cabrele
- Subjects
Pharmacology ,Lactams ,Protein Conformation ,Circular Dichroism ,Organic Chemistry ,Valine ,General Medicine ,Peptides, Cyclic ,Biochemistry ,Protein Structure, Secondary ,Structural Biology ,Drug Discovery ,Tyrosine ,Molecular Medicine ,Isoleucine ,Peptides ,Molecular Biology - Abstract
Side-chain-to-side-chain cyclization is frequently used to stabilize the α-helical conformation of short peptides. In a previous study, we incorporated a lactam bridge between the side chains of Lys-i and Asp-i+4 in the nonapeptide 1Y, cyclo-(2,6)-(Ac-VKRLQDLQY-NH
- Published
- 2022
7. 3D Interrelationship between Osteocyte Network and Forming Mineral during Human Bone Remodeling
- Author
-
Ayoubi, Mahdi, primary, Tol, Alexander F., additional, Weinkamer, Richard, additional, Roschger, Paul, additional, Brugger, Peter C., additional, Berzlanovich, Andrea, additional, Bertinetti, Luca, additional, Roschger, Andreas, additional, and Fratzl, Peter, additional
- Published
- 2021
- Full Text
- View/download PDF
8. Backbone distortions in lactam‐bridged helical peptides
- Author
-
Moazzam, Ali, primary, Stanojlovic, Vesna, additional, Hinterholzer, Arthur, additional, Holzner, Christoph, additional, Roschger, Cornelia, additional, Zierer, Andreas, additional, Wiederstein, Markus, additional, Schubert, Mario, additional, and Cabrele, Chiara, additional
- Published
- 2022
- Full Text
- View/download PDF
9. Bone Matrix Mineralization in Patients With Gain-of-Function Calcium-Sensing Receptor Mutations Is Distinctly Different From that in Postsurgical Hypoparathyroidism
- Author
-
Paul Roschger, Rachel I Gafni, David W. Dempster, Diana Ovejero, Hua Zhou, Klaus Klaushofer, Barbara M. Misof, and Michael T. Collins
- Subjects
0301 basic medicine ,Bone mineral ,medicine.medical_specialty ,medicine.diagnostic_test ,Chemistry ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Bone tissue ,medicine.disease ,Resorption ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Endocrinology ,medicine.anatomical_structure ,Hypoparathyroidism ,Internal medicine ,Biopsy ,medicine ,Parathyroid hormone secretion ,Orthopedics and Sports Medicine ,Calcium-sensing receptor ,Primary Hypoparathyroidism - Abstract
The role of the calcium-sensing receptor (CaSR) as a regulator of parathyroid hormone secretion is well established, but its function in bone is less well defined. In an effort to elucidate the CaSR's skeletal role, bone tissue and material characteristics from patients with autosomal dominant hypocalcemia (ADH), a genetic form of primary hypoparathyroidism caused by CASR gain-of-function mutations, were compared to patients with postsurgical hypoparathyroidism (PSH). Bone structure and formation/resorption indices and mineralization density distribution (BMDD), were examined in transiliac biopsy samples from PSH (n = 13) and ADH (n = 6) patients by histomorphometry and quantitative backscatter electron imaging, respectively. Bone mineral density (BMD by DXA) and biochemical characteristics were measured at the time of the biopsy. Because both study groups comprised children and adults, all measured biopsy parameters and BMD outcomes were converted to Z-scores for comparison. Histomorphometric indices were normal and not different between ADH and PSH, with the exception of mineral apposition rate Z-score, which was higher in the ADH group. Similarly, average BMD Z-scores were normal and not different between ADH and PSH. Significant differences were observed for the BMDD: average Z-scores of mean and typical degree of mineralization (CaMean, CaPeak, respectively) were lower (p = 0.02 and p = 0.03, respectively), whereas the heterogeneity of mineralization (CaWidth) and percentage of lower mineralized areas (CaLow) were increased in ADH versus PSH (p = 0.01 and p = 0.002, respectively). The BMDD outcomes point toward a direct, PTH-independent role of the CaSR in the regulation of bone mineralization. © 2018 American Society for Bone and Mineral Research.
- Published
- 2019
10. Author response for 'Hypermineralization of hearing‐related bones by a specific osteoblast subtype'
- Author
-
Hidekazu Takano, Yukiko Kuroda, Paul Roschger, Koichi Matsuo, Katsuhiro Kawaai, Takayoshi Nakano, Yanlin Wu, Naoya Hatano, Stéphane Blouin, Takuya Ishimoto, and Atsushi Momose
- Subjects
medicine.medical_specialty ,Endocrinology ,medicine.anatomical_structure ,business.industry ,Internal medicine ,medicine ,Osteoblast ,business - Published
- 2021
11. Hypermineralization of Hearing‐Related Bones by a Specific Osteoblast Subtype
- Author
-
Kuroda, Yukiko, primary, Kawaai, Katsuhiro, additional, Hatano, Naoya, additional, Wu, Yanlin, additional, Takano, Hidekazu, additional, Momose, Atsushi, additional, Ishimoto, Takuya, additional, Nakano, Takayoshi, additional, Roschger, Paul, additional, Blouin, Stéphane, additional, and Matsuo, Koichi, additional
- Published
- 2021
- Full Text
- View/download PDF
12. Biomechanical and Bone Material Properties of Schnurri‐3 Null Mice
- Author
-
Hofstaetter, Jochen G, Misof, Barbara M, Jones, Dallas C, Zoehrer, Ruth, Blouin, Stéphane, Schueler, Christiane, Paschalis, Eleftherios P, Erben, Reinhold G, Weinkamer, Richard, Klaushofer, Klaus, and Roschger, Paul
- Subjects
Shn3‐NULL MICE ,Shn3‐DEFICIENCY ,BONE BIOMECHANICS ,BONE MATERIAL QUALITY ,Orthopedic surgery ,RC925-935 ,BONE MINERALIZATION ,DENSITY DISTRIBUTION ,Original Article ,Original Articles ,Diseases of the musculoskeletal system ,COLLAGEN CROSS‐LINK RATIO ,RD701-811 - Abstract
Schnurri‐3 (Shn3) is an essential regulator of postnatal skeletal remodeling. Shn3‐deficient mice (Shn3–/–) have high bone mass; however, their bone mechanical and material properties have not been investigated to date. We performed three‐point bending of femora, compression tests of L3 vertebrae. We also measured intrinsic material properties, including bone mineralization density distribution (BMDD) and osteocyte lacunae section (OLS) characteristics by quantitative backscatter electron imaging, as well as collagen cross‐linking by Fourier transform infrared microspectroscopy of femora from Shn3–/– and WT mice at different ages (6 weeks, 4 months, and 18 months). Moreover, computer modeling was performed for the interpretation of the BMDD outcomes. Femora and L3 vertebrae from Shn3–/– aged 6 weeks revealed increased ultimate force (2.2‐ and 3.2‐fold, p
- Published
- 2019
13. Novel PLS3 variants in X‐linked osteoporosis: Exploring bone material properties
- Author
-
Rory O'Sullivan, Mary Bull, Nicola Fa Peel, Paul Roschger, Rebecca Jones, Nick Bishop, Elizabeth Milne, Meena Balasubramanian, Klaus Klaushofer, Kath Smith, Nadja Fratzl-Zelman, and Rebecca C. Pollitt
- Subjects
Adult ,Male ,0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Genetic counseling ,Osteoporosis ,030209 endocrinology & metabolism ,Bone remodeling ,03 medical and health sciences ,Calcification, Physiologic ,0302 clinical medicine ,Genotype ,Genetics ,Humans ,Medicine ,Genetics (clinical) ,Reduction (orthopedic surgery) ,Genetic testing ,Hip fracture ,Membrane Glycoproteins ,medicine.diagnostic_test ,business.industry ,Microfilament Proteins ,Genetic Diseases, X-Linked ,Prognosis ,medicine.disease ,Pedigree ,Phenotype ,030104 developmental biology ,Mutation ,Etiology ,Female ,business - Abstract
BACKGROUND: Idiopathic Juvenile Osteoporosis (IJO) refers to significantly lower than expected bone mass manifesting in childhood with no identifiable aetiology. IJO classically presents in early pubertal period with multiple fractures including metaphyseal and vertebral crush fractures, and low bone-mass. METHODS: Here we describe two patients and provide information on their clinical phenotype, genotype and bone material analysis in one of the patients. RESULTS: Patient 1: 40-year old adult male diagnosed with IJO in childhood who re-presented with a hip fracture as an adult. Genetic analysis identified a pathogenic PLS3 hemizygous variant, c.1765del in exon 16. Patient 2: 15-year old boy with multiple vertebral fractures and bone biopsy findings suggestive of IJO who also has a diagnosis of autism spectrum disorder. Genetic analysis identified a maternally inherited PLS3 pathogenic c.1295T>A variant in exon 12. Analyses of the transiliac bone sample revealed severe reduction of trabecular volume and bone turnover indices and elevated bone matrix mineralisation. DISCUSSION: We propose that genetic testing for PLS3 should be undertaken in patients presenting with a current or previous history of IJO as this has implications for genetic counselling and cascade screening. The extensive evaluation of the transiliac biopsy sample of Patient 2 revealed a novel bone phenotype. CONCLUSION: This report includes a review of IJO and genetic causes of osteoporosis, and suggests that existing cases of IJO should be screened for PLS3. Through analysis of bone material properties in Patient 2, we can conclude that PLS3 does have a role in bone mineralisation.
- Published
- 2018
14. Mutations That Alter the Carboxy-Terminal-Propeptide Cleavage Site of the Chains of Type I Procollagen Are Associated With a Unique Osteogenesis Imperfecta Phenotype
- Author
-
Jyoti Rai, Bente L. Langdahl, Paul Roschger, Tim Cundy, Marta Szybowska, David R. Eyre, Michael Dray, Klaus Klaushofer, John W. Delahunt, Emma L. Duncan, Jannie Dahl Hald, Peter H. Byers, Ulrike Schwarze, Shehla Mohammed, Aideen M. McInerney-Leo, Patricia G Wheeler, Chumei Li, and MaryAnn Weis
- Subjects
0301 basic medicine ,Bone mineral ,medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Histology ,Achilles tendon calcification ,medicine.disease ,Phenotype ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Endocrinology ,Dysplasia ,Osteogenesis imperfecta ,Internal medicine ,medicine ,Orthopedics and Sports Medicine ,Haploinsufficiency ,business ,Type I collagen - Abstract
Osteogenesis imperfecta (OI) is a genetic bone disorder characterized by fractures, low bone mass, and skeletal fragility. It most commonly arises from dominantly inherited mutations in the genes COL1A1 and COL1A2 that encode the chains of type I collagen. A number of recent reports have suggested that mutations affecting the carboxyl-terminal propeptide cleavage site in the products of either COL1A1 or COL1A2 give rise to a form of OI characterized by unusually dense bones. We have assembled clinical, biochemical, and molecular data from 29 individuals from 8 families with 7 different mutations affecting the C-propeptide cleavage site. The phenotype was generally mild: The median height was ∼33th centile. Eighty percent of subjects had their first fracture by the age of 10 years, and one-third had a femoral or tibial fracture by the age of 25 years. Fractures continued into adulthood, though rates varied considerably. Healing was normal and rarely resulted in long bone deformity. One-third of subjects older than 15 years had scoliosis. The teeth and hearing were normal in most, and blue sclerae were not observed. Other features noted included fibro-osseous dysplasia of the mandible and Achilles tendon calcification. The mean spinal bone mineral density Z-score was +2.9 (SD 2.1) compared with -2.2 (0.7) in subjects with COL1A1 haploinsufficiency mutations. Bone mineral density distribution, assessed by quantitative backscattered electron imaging in bone showed higher levels of mineralization than found in any other disorder. Bone histology showed high trabecular volume and increased cortical thickness, with hyperosteoidosis and delayed mineralization. In vitro studies with cultured skin fibroblasts suggested that these mutations interfere with processing of the chain in which the sequence alteration occurs, but the C-propeptide is eventually cleaved (and detectable in blood), suggesting there are alternative sites of cleavage. The precise mechanism of the bony pathology is not yet clear. © 2018 American Society for Bone and Mineral Research.
- Published
- 2018
15. Hypophosphatemia, Severe Bone Pain, Gait Disturbance, and Fatigue Fractures After Iron Substitution in Inflammatory Bowel Disease: A Case Report
- Author
-
Shahin Zandieh, Attila Brehm, Johann Bartko, Paul Roschger, Klaus Klaushofer, and Jochen Zwerina
- Subjects
musculoskeletal diseases ,0301 basic medicine ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,urologic and male genital diseases ,Iliac crest ,Inflammatory bowel disease ,Gastroenterology ,Bone remodeling ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Insufficiency fracture ,medicine ,Orthopedics and Sports Medicine ,Osteomalacia ,Crohn's disease ,business.industry ,nutritional and metabolic diseases ,medicine.disease ,Surgery ,030104 developmental biology ,medicine.anatomical_structure ,Zoledronic acid ,business ,Hypophosphatemia ,medicine.drug - Abstract
Intravenous infusions of different iron formulations are recognized as a cause of hypophosphatemia. Chronic hypophosphatemia can alter bone metabolism and bone material structure. As a consequence, osteomalacia may develop and lead to bone fragility. Herein, we report a patient with Crohn's disease presenting with persistent hypophosphatemia and insufficiency fractures while receiving regular iron infusions due to chronic gastrointestinal bleeding. Previously, the patient regularly received vitamin D and also zoledronic acid. The patient underwent bone biopsy of the iliac crest that showed typical signs of osteomalacia with dramatically increased osteoid volume and decreased bone formation. Analysis of the bone mineralization density distribution (BMDD) revealed a more complex picture: On the one hand, there was a shift to higher matrix mineralization, presumably owing to low bone turnover; on the other hand, a broadening of the BMDD indicating more heterogeneous mineralization due to osteomalacia was also evident. This is the first report on changes of bone histomorphometry and bone matrix mineralization in iron-induced osteomalacia. © 2017 American Society for Bone and Mineral Research.
- Published
- 2017
16. Melorheostotic Bone Lesions Caused by Somatic Mutations in MAP2K1 Have Deteriorated Microarchitecture and Periosteal Reaction
- Author
-
Fratzl‐Zelman, Nadja, primary, Roschger, Paul, additional, Kang, Heeseog, additional, Jha, Smita, additional, Roschger, Andreas, additional, Blouin, Stéphane, additional, Deng, Zuoming, additional, Cabral, Wayne A, additional, Ivovic, Aleksandra, additional, Katz, James, additional, Siegel, Richard M, additional, Klaushofer, Klaus, additional, Fratzl, Peter, additional, Bhattacharyya, Timothy, additional, and Marini, Joan C, additional
- Published
- 2019
- Full Text
- View/download PDF
17. PLS3Deletions Lead to Severe Spinal Osteoporosis and Disturbed Bone Matrix Mineralization
- Author
-
Sonja Gamsjaeger, Anna Lindstrand, Corinna Grasemann, Eleftherios P. Paschalis, Outi Mäkitie, Anders Kämpe, Alice Costantini, Leonid Zeitlin, Paul Roschger, Matthias Hövel, Hong Jiao, Fulya Taylan, Yael Levy-Shraga, Klaus Klaushofer, and Annick Raas-Rothschild
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Osteoid ,business.industry ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,030209 endocrinology & metabolism ,medicine.disease ,Bone tissue ,Bone remodeling ,03 medical and health sciences ,Exon ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Primary bone ,Osteogenesis imperfecta ,medicine ,PLS3 ,Orthopedics and Sports Medicine ,business - Abstract
Mutations in the PLS3 gene, encoding Plastin 3, were described in 2013 as a cause for X-linked primary bone fragility in children. The specific role of PLS3 in bone metabolism remains inadequately understood. Here we describe for the first time PLS3 deletions as the underlying cause for childhood-onset primary osteoporosis in 3 boys from 2 families. We carried out thorough clinical, radiological, and bone tissue analyses to explore the consequences of these deletions and to further elucidate the role of PLS3 in bone homeostasis. In family 1, the 2 affected brothers had a deletion of exons 4-16 (NM_005032) in PLS3, inherited from their healthy mother. In family 2, the index patient had a deletion involving the entire PLS3 gene (exons 1-16), inherited from his mother who had osteoporosis. The 3 patients presented in early childhood with severe spinal compression fractures involving all vertebral bodies. The 2 brothers in family 1 also displayed subtle dysmorphic facial features and both had developed a myopathic gait. Extensive analyses of a transiliac bone biopsy from 1 patient showed a prominent increase in osteoid volume, osteoid thickness, and in mineralizing lag time. Results from quantitative backscattered electron imaging and Raman microspectroscopy showed a significant hypomineralization of the bone. Together our results indicate that PLS3 deletions lead to severe childhood-onset osteoporosis resulting from defective bone matrix mineralization, suggesting a specific role for PLS3 in the mineralization process. © 2017 American Society for Bone and Mineral Research.
- Published
- 2017
18. Targeting of a Helix-Loop-Helix Transcriptional Regulator by a Short Helical Peptide
- Author
-
Thomas Verwanger, Cornelia Roschger, Mario Schubert, Barbara Krammer, Brigitta Elsässer, Chiara Cabrele, Nicole Maeding, and Saskia Neukirchen
- Subjects
0301 basic medicine ,Cell Survival ,Cellular differentiation ,Peptide ,Biology ,Peptides, Cyclic ,Biochemistry ,Protein Structure, Secondary ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Drug Discovery ,Transcriptional regulation ,Humans ,Protein Interaction Domains and Motifs ,Amino Acid Sequence ,Viability assay ,General Pharmacology, Toxicology and Pharmaceutics ,Transcription factor ,Pharmacology ,chemistry.chemical_classification ,Helix-Loop-Helix Motifs ,Organic Chemistry ,Cell Differentiation ,Cell cycle ,Cell biology ,030104 developmental biology ,Microscopy, Fluorescence ,chemistry ,030220 oncology & carcinogenesis ,Cancer cell ,MCF-7 Cells ,Molecular Medicine ,Alpha helix ,Protein Binding ,Transcription Factors - Abstract
The Id proteins (Id1-4) are cell-cycle regulators that play a key role during development, in cancer and vascular disorders. They contain a conserved helix-loop-helix (HLH) domain that folds into a parallel four-helix bundle upon self- or hetero-association with basic-HLH transcription factors. By using such protein-protein interactions, the Id proteins inhibit cell differentiation and promote cell-cycle progression. Accordingly, their supporting role in cancer has been convincingly demonstrated, which makes these proteins interesting therapeutic targets. Herein we present a short peptide containing an (i,i+4)-lactam bridge and a hydrophobic (Φ) three-residue motif Φ(i)-Φ(i+3)-Φ(i+6), which adopts a helical conformation in water, shows Id protein binding in the low-micromolar range, penetrates into breast (MCF-7 and T47D) and bladder (T24) cancer cells, accumulates in the nucleus, and decreases cell viability to ∼50 %. Thus, this cyclopeptide is a promising scaffold for the development of Id protein binders that impair cancer cell viability.
- Published
- 2017
19. Hypermineralization and High Osteocyte Lacunar Density in Osteogenesis Imperfecta Type V Bone Indicate Exuberant Primary Bone Formation
- Author
-
Nadja Fratzl-Zelman, Stéphane Blouin, Paul Roschger, Frank Rauch, Francis H. Glorieux, Klaus Klaushofer, and Joan C. Marini
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Dentinogenesis imperfecta ,Chemistry ,Ossification ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,medicine.disease ,Bone tissue ,Bone remodeling ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Endocrinology ,Primary bone ,Forearm ,Osteogenesis imperfecta ,Internal medicine ,Osteocyte ,medicine ,Orthopedics and Sports Medicine ,medicine.symptom - Abstract
In contrast to "classical" forms of osteogenesis imperfecta (OI) types I to IV, caused by a mutation in COL1A1/A2, OI type V is due to a gain-of-function mutation in the IFITM5 gene, encoding the interferon-induced transmembrane protein 5, or bone-restricted interferon-inducible transmembrane (IFITM)-like protein (BRIL). Its phenotype distinctly differs from OI types I to IV by absence of blue sclerae and dentinogenesis imperfecta, by the occurrence of ossification disorders such as hyperplastic callus and forearm interosseous membrane ossification. Little is known about the impact of the mutation on bone tissue/material level in untreated and bisphosphonate-treated patients. Therefore, investigations of transiliac bone biopsy samples from a cohort of OI type V children (n = 15, 8.7 ± 4 years old) untreated at baseline and a subset (n = 8) after pamidronate treatment (2.6 years in average) were performed. Quantitative backscattered electron imaging (qBEI) was used to determine bone mineralization density distribution (BMDD) as well as osteocyte lacunar density. The BMDD of type V OI bone was distinctly shifted toward a higher degree of mineralization. The most frequently occurring calcium concentration (CaPeak) in cortical (Ct) and cancellous (Cn) bone was markedly increased (+11.5%, +10.4%, respectively, p < 0.0001) compared to healthy reference values. Treatment with pamidronate resulted in only a slight enhancement of mineralization. The osteocyte lacunar density derived from sectioned bone area was elevated in OI type V Ct and Cn bone (+171%, p < 0.0001; +183.3%, p < 0.01; respectively) versus controls. The high osteocyte density was associated with an overall immature primary bone structure ("mesh-like") as visualized by polarized light microscopy. In summary, the bone material from OI type V patients is hypermineralized, similar to other forms of OI. The elevated osteocyte lacunar density in connection with lack of regular bone lamellation points to an exuberant primary bone formation and an alteration of the bone remodeling process in OI type V. © 2017 American Society for Bone and Mineral Research.
- Published
- 2017
20. Impact of the amino acid sequence on the conformation of side chain lactam-bridged octapeptides
- Author
-
Cornelia Roschger, Mario Schubert, Chiara Cabrele, Viktoria Krieger, Saskia Neukirchen, and Brigitta Elsässer
- Subjects
Pharmacology ,chemistry.chemical_classification ,Circular dichroism ,010405 organic chemistry ,Stereochemistry ,Chemistry ,Organic Chemistry ,Protein primary structure ,Peptide ,General Medicine ,010402 general chemistry ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Amino acid ,chemistry.chemical_compound ,Structural Biology ,Drug Discovery ,Lactam ,Side chain ,Molecular Medicine ,Molecular Biology ,Peptide sequence ,Protein secondary structure - Abstract
Synthetic helical peptides are valuable scaffolds for the development of modulators of protein-protein interactions involving helical motifs. Backbone-to-side chain or side chain-to-side chain constraints have been and still are intensively exploited to stabilize short α-helices. Very often, these constraints have been combined with backbone modifications induced by Cα-tetrasubstituted, β-, or γ-amino acids, which facilitate the α-peptide or α/β/γ-peptide adopting an α-helical conformation. In this work, we investigated the helical character of octapeptides that were cyclized by a Lys-Asp-(i,i + 4)-lactam bridge. We started with two sequences extracted from the helix-loop-helix region of the Id proteins, which are inhibitors of cell differentiation during development and in cancer. Nineteen analogs containing the lactam bridge at different positions and displaying different amino acid core triads (i + 1,2,3) as well as outer residues were prepared by solid-phase methodology. Their conformation in water and water/2,2,2-trifluoroethanol mixtures was investigated by circular dichroism (CD) spectroscopy. The cyclopeptides could be grouped in helix-prone and non-helix-prone structures. Both the amino acid core triad (i + 1,2,3) and the pendant residues positively or negatively affected the formation of a helical structure. Computational studies based on the NMR-derived helical structure of a cyclopeptide containing Aib at position (i + 2) of the triad were generally in agreement with the secondary structure propensity of the cyclopeptides observed by CD spectroscopy. In conclusion, the Lys-Asp-(i,i + 4)-lactam bridge may succeed or fail in the stabilization of short helices, depending on the primary structure. Moreover, computational methods may be valuable tools to discriminate helix-prone from non-helix-prone peptide-based macrolactams. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.
- Published
- 2017
21. Fkbp10 Deletion in Osteoblasts Leads to Qualitative Defects in Bone
- Author
-
Hao Ding, Joohyun Lim, Klaus Klaushofer, Peter Fratzl, Paul Roschger, Brendan Lee, David R. Eyre, Nadja Fratzl-Zelman, Caressa Lietman, Douglas R. Keene, Deborah Krakow, Ingo Schmidt, Jyoti Rai, Yuqing Chen, Xiaohong Bi, Catherine G. Ambrose, Wolfgang Wagermaier, Ingo Grafe, and MaryAnn Weis
- Subjects
0301 basic medicine ,medicine.medical_specialty ,X-ray microtomography ,Bone density ,Bone disease ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Anatomy ,medicine.disease ,Tendon ,03 medical and health sciences ,Hydroxylysine ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Endocrinology ,chemistry ,N-terminal telopeptide ,Osteogenesis imperfecta ,Internal medicine ,medicine ,Orthopedics and Sports Medicine ,Bruck syndrome - Abstract
Osteogenesis imperfecta (OI), also known as brittle bone disease, displays a spectrum of clinical severity from mild (OI type I) to severe early lethality (OI type II), with clinical features including low bone mass, fractures, and deformities. Mutations in the FK506 Binding Protein 10 (FKBP10), gene encoding the 65-kDa protein FKBP65, cause a recessive form of OI and Bruck syndrome, the latter being characterized by joint contractures in addition to low bone mass. We previously showed that Fkbp10 expression is limited to bone, tendon, and ligaments in postnatal tissues. Furthermore, in both patients and Fkbp10 knockout mice, collagen telopeptide hydroxylysine crosslinking is dramatically reduced. To further characterize the bone specific contributions of Fkbp10, we conditionally ablated FKBP65 in Fkbp10fl/fl mice (Mus musculus; C57BL/6) using the osteoblast-specific Col1a1 2.3-kb Cre recombinase. Using μCT, histomorphometry and quantitative backscattered electron imaging, we found minimal alterations in the quantity of bone and no differences in the degree of bone matrix mineralization in this model. However, mass spectroscopy (MS) of bone collagen demonstrated a decrease in mature, hydroxylysine-aldehyde crosslinking. Furthermore, bone of mutant mice exhibits a reduction in mineral-to-matrix ratio and in crystal size as shown by Raman spectroscopy and small-angle X-ray scattering, respectively. Importantly, abnormalities in bone quality were associated with impaired bone biomechanical strength in mutant femurs compared with those of wild-type littermates. Taken together, these data suggest that the altered collagen crosslinking through Fkbp10 ablation in osteoblasts primarily leads to a qualitative defect in the skeleton. © 2017 American Society for Bone and Mineral Research.
- Published
- 2017
22. Abnormally High and Heterogeneous Bone Matrix Mineralization After Childhood Solid Organ Transplantation: A Complex Pathology of Low Bone Turnover and Local Defects in Mineralization
- Author
-
Paul Roschger, Renata C. Pereira, Helena Valta, Klaus Klaushofer, Katherine Wesseling-Perry, Nadja Fratzl-Zelman, Hannu Jalanko, Barbara M. Misof, and Outi Mäkitie
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Bone density ,business.industry ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Osteoporosis ,030209 endocrinology & metabolism ,Liver transplantation ,medicine.disease ,Bone remodeling ,Transplantation ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Osteocyte ,medicine ,Orthopedics and Sports Medicine ,Cortical bone ,business ,Kidney disease - Abstract
Chronic renal, liver, and heart failure in children associates with multiple skeletal complications. Increased fracture incidence often persists after transplantation and could be related to alterations in bone material properties. In the present cohort study we evaluated bone mineralization density distribution (BMDD) by quantitative backscattered electron imaging (qBEI) in 23 pediatric solid organ allograft recipients with suspected osteoporosis. We measured BMDD in the entire cross-sectional area of transiliac bone biopsies obtained from kidney (n = 9), liver (n = 9), and heart (n = 5) transplant recipients (aged 7.6 to 19.7 years; 6.0 ± 5.6 years posttransplantation, patients with a history of clinical fractures: n = 14). The BMDD findings were compared with age-appropriate references and with a previously presented cohort of children with chronic kidney disease on dialysis (CKD5D, n = 18). Furthermore, we related the BMDD parameters with patients' clinical and bone histomorphometric outcomes. Compared to healthy children, qBEI results for cancellous and cortical bone in transplant recipients revealed an increase in the most frequently occurring calcium concentration (+2.9%, p = 0.001; +3.5%, p = 0.014), in the portion of fully mineralized bone (fivefold; 10-fold, both p
- Published
- 2017
23. Sclerostin Deficiency Is Linked to Altered Bone Composition
- Author
-
Paul Roschger, Eleftherios P. Paschalis, Sonja Lueger, Antoon van Lierop, Michaela Kneissel, Sonja Gamsjaeger, Andreas Roschger, Socrates E. Papapoulos, Klaus Klaushofer, Norbert Hassler, and Ina Kramer
- Subjects
Bone mineral ,medicine.medical_specialty ,biology ,Endocrinology, Diabetes and Metabolism ,Anatomy ,Bone tissue ,Mineralization (biology) ,Raman microspectroscopy ,chemistry.chemical_compound ,medicine.anatomical_structure ,Endocrinology ,Proteoglycan ,chemistry ,Density distribution ,Internal medicine ,medicine ,biology.protein ,Sclerostin ,Orthopedics and Sports Medicine ,Cortical bone - Abstract
High bone mass in animals and humans with sclerostin deficiency is associated with increased bone strength, which is not the case for all disorders with high bone mineral density, some of which are even associated with fragility fractures owing to unfavorable bone composition. In the current study we investigated whether alterations in bone composition may contribute to the bone strength characteristics associated with lack of sclerostin. We examined cortical bone of Sost-knockout (KO) mice (n = 9, 16 weeks old) and sclerosteosis patients (young [4 to 14 years], n = 4 and adults [24 and 43 years], n = 2) by quantitative backscattered electron imaging and Raman microspectroscopy and compared it to bone from wild-type mice and healthy subjects, respectively. In Sost-KO mice endocortical bone exhibited altered bone composition, whereas subperiosteal bone was unchanged. When comparing endocortical bone tissue of identical tissue age as defined by sequential dual fluorochrome labeling the average bone matrix mineralization was reduced -1.9% (p < 0.0001, younger tissue age) and -1.5% (p < 0.05, older tissue age), and the relative proteoglycan content was significantly increased. Similarly, bone matrix mineralization density distribution was also shifted toward lower matrix mineralization in surgical samples of compact bone of sclerosteosis patients. This was associated with an increase in mineralization heterogeneity in the young population. In addition, and consistently, the relative proteoglycan content was increased. In conclusion, we observed decreased matrix mineralization and increased relative proteoglycan content in bone subcompartments of Sost-KO mice-a finding that translated into sclerosteosis patients. We hypothesize that the altered bone composition contributes to the increased bone strength of patients with sclerostin deficiency.
- Published
- 2014
24. Differential Effects of Teriparatide and Zoledronic Acid on Bone Mineralization Density Distribution at 6 and 24 Months in the SHOTZ Study
- Author
-
Barbara M. Misof, Jahangir Alam, David W. Dempster, Eleftherios P. Paschalis, Paul Roschger, Kathleen A. Taylor, Hua Zhou, Klaus Klaushofer, and Valerie A Ruff
- Subjects
0301 basic medicine ,Bone mineral ,medicine.medical_specialty ,Bone density ,business.industry ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,Urology ,030209 endocrinology & metabolism ,medicine.disease ,Surgery ,Bone remodeling ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Zoledronic acid ,medicine ,Teriparatide ,Orthopedics and Sports Medicine ,Cortical bone ,business ,Cancellous bone ,medicine.drug - Abstract
The Skeletal Histomorphometry in Patients on Teriparatide or Zoledronic Acid Therapy (SHOTZ) study assessed the progressive effects of teriparatide (TPTD) and zoledronic acid (ZOL) on bone remodeling and material properties in postmenopausal women with osteoporosis. Previously, we reported that biochemical and histomorphometric bone formation indices were significantly higher in patients receiving TPTD versus ZOL. Here we report bone mineralization density distribution (BMDD) results based on quantitative backscattered electron imaging (qBEI). The 12-month primary study was randomized and double blind until the month 6 biopsy, then open label. Patients (TPTD, n = 28; ZOL, n = 31) were then eligible to enter a 12-month open-label extension with their original treatment: TPTD 20 μg/d (subcutaneous injection) or ZOL 5 mg/yr (intravenous infusion). A second biopsy was collected from the contralateral side at month 24 (TPTD, n = 10; ZOL, n = 10). In cancellous bone, ZOL treatment was associated at 6 and 24 months with significantly higher average degree of mineralization (CaMEAN, +2.2%, p = 0.018; +3.9%, p = 0.009, respectively) and with lower percentage of low mineralized areas (CaLOW , -34.6%, p = 0.029; -33.7%, p = 0.025, respectively) and heterogeneity of mineralization CaWIDTH (-12.3%, p = 0.003; -9.9%, p = 0.012, respectively), indicating higher mineralization density and more homogeneous mineral content versus TPTD. Within the ZOL group, significant changes were found in all parameters from month 6 to 24, indicating a progressive increase in mineralization density. In sharp contrast, mineralization density did not increase over time with TPTD, reflecting ongoing deposition of new bone. Similar results were observed in cortical bone. In this study, TPTD stimulated new bone formation, producing a mineralized bone matrix that remained relatively heterogeneous with a stable mean mineral content. ZOL slowed bone turnover and prolonged secondary mineralization, producing a progressively more homogeneous and highly mineralized bone matrix. Although both TPTD and ZOL increase clinical measures of bone mineral density (BMD), this study shows that the underlying mechanisms of the BMD increases are fundamentally different. © 2016 American Society for Bone and Mineral Research.
- Published
- 2016
25. Histomorphometry and Bone Matrix Mineralization Before and After Bisphosphonate Treatment in Boys With Duchenne Muscular Dystrophy: A Paired Transiliac Biopsy Study
- Author
-
Hugh J. McMillan, Barbara M. Misof, Paul Roschger, Frank Rauch, Klaus Klaushofer, Jinhui Ma, and Leanne M Ward
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Bone density ,medicine.diagnostic_test ,business.industry ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Duchenne muscular dystrophy ,030209 endocrinology & metabolism ,Bisphosphonate ,medicine.disease ,Bone tissue ,Bone remodeling ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Endocrinology ,Internal medicine ,Biopsy ,medicine ,Orthopedics and Sports Medicine ,Cortical bone ,business ,Cancellous bone - Abstract
Duchenne muscular dystrophy (DMD) is a genetic disorder causing progressive muscle weakness. To prolong independent ambulation, DMD patients are treated with glucocorticoids, which, in turn, can increase bone fragility. In a cohort with vertebral fractures, intravenous bisphosphonate (iv BP) therapy stabilized vertebrae and reduced back pain. To characterize the effects of glucocorticoid therapy and bisphosphonate treatment on bone tissue and material properties, paired transiliac biopsy samples (before and after on average 2.4 years of iv BP) from 9 boys with DMD were studied for histomorphometry and bone mineralization density distribution (BMDD) and compared to reference values. Before iv BP, the boys had low cancellous bone volume (BV/TV) and cortical thickness (Ct.Wi) (both on average 56% of the healthy average, p
- Published
- 2016
26. Evidence for a Role for Nanoporosity and Pyridinoline Content in Human Mild Osteogenesis Imperfecta
- Author
-
Klaus Klaushofer, Peter Fratzl, Sonja Gamsjaeger, Nadja Fratzl-Zelman, Norbert Hassler, Admir Masic, Francis H. Glorieux, Frank Rauch, Eleftherios P. Paschalis, Paul Roschger, and Wolfgang Brozek
- Subjects
0301 basic medicine ,Connective Tissue Disorder ,Pathology ,medicine.medical_specialty ,Pyridinoline ,medicine.diagnostic_test ,Bone density ,business.industry ,Genetic heterogeneity ,Endocrinology, Diabetes and Metabolism ,Dentistry ,030209 endocrinology & metabolism ,medicine.disease ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,Osteogenesis imperfecta ,Raman band ,Biopsy ,Medicine ,Orthopedics and Sports Medicine ,business ,Haploinsufficiency - Abstract
Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous connective tissue disorder characterized by bone fragility that arises from decreased bone mass and abnormalities in bone material quality. OI type I represents the milder form of the disease and according to the original Sillence classification is characterized by minimal skeletal deformities and near-normal stature. Raman microspectroscopy is a vibrational spectroscopic technique that allows the determination of bone material properties in bone biopsy blocks with a spatial resolution of ∼1 µm, as a function of tissue age. In the present study, we used Raman microspectroscopy to evaluate bone material quality in transiliac bone biopsies from children with a mild form of OI, either attributable to collagen haploinsufficiency OI type I (OI-Quant; n = 11) or aberrant collagen structure (OI-Qual; n = 5), as a function of tissue age, and compared it against the previously published values established in a cohort of biopsies from healthy children (n = 54, ages 1 to 23 years). The results indicated significant differences in bone material compositional characteristics between OI-Quant patients and healthy controls, whereas fewer were evident in the OI-Qual patients. Differences in both subgroups of OI compared with healthy children were evident for nanoporosity, mineral maturity/crystallinity as determined by maxima of the v1 PO4 Raman band, and pyridinoline (albeit in different direction) content. These alterations in bone material compositional properties most likely contribute to the bone fragility characterizing this disease. © 2016 American Society for Bone and Mineral Research.
- Published
- 2016
27. Novel PLS3 variants in X-linked osteoporosis: Exploring bone material properties
- Author
-
Balasubramanian, M., Fratzl-Zelman, N., O'Sullivan, R., Bull, M., Fa Peel, N., Pollitt, R.C., Jones, R., Milne, E., Smith, K., Roschger, P., Klaushofer, K., and Bishop, N.J.
- Abstract
BACKGROUND: Idiopathic Juvenile Osteoporosis (IJO) refers to significantly lower than expected bone mass manifesting in childhood with no identifiable aetiology. IJO classically presents in early pubertal period with multiple fractures including metaphyseal and vertebral crush fractures, and low bone-mass. METHODS: Here we describe two patients and provide information on their clinical phenotype, genotype and bone material analysis in one of the patients. RESULTS: Patient 1: 40-year old adult male diagnosed with IJO in childhood who re-presented with a hip fracture as an adult. Genetic analysis identified a pathogenic PLS3 hemizygous variant, c.1765del in exon 16. Patient 2: 15-year old boy with multiple vertebral fractures and bone biopsy findings suggestive of IJO who also has a diagnosis of autism spectrum disorder. Genetic analysis identified a maternally inherited PLS3 pathogenic c.1295T>A variant in exon 12. Analyses of the transiliac bone sample revealed severe reduction of trabecular volume and bone turnover indices and elevated bone matrix mineralisation. DISCUSSION: We propose that genetic testing for PLS3 should be undertaken in patients presenting with a current or previous history of IJO as this has implications for genetic counselling and cascade screening. The extensive evaluation of the transiliac biopsy sample of Patient 2 revealed a novel bone phenotype. CONCLUSION: This report includes a review of IJO and genetic causes of osteoporosis, and suggests that existing cases of IJO should be screened for PLS3. Through analysis of bone material properties in Patient 2, we can conclude that PLS3 does have a role in bone mineralisation.
- Published
- 2018
28. Journal of Peptide Science / An explorative study towards the chemical synthesis of the immunoglobulin G1 Fc CH3 domain
- Author
-
Grassi, Luigi, Roschger, Cornelia, Stanojlović, Vesna, and Cabrele, Chiara
- Subjects
pseudoproline ,native chemical ligation ,Fc CH3 domain ,solid phase peptide synthesis - Abstract
Monoclonal antibodies, fusion proteins including the immunoglobulin fragment c (Ig Fc) CH2CH3 domains, and engineered antibodies are prominent representatives of an important class of drugs and drug candidates, which are referred to as biotherapeutics or biopharmaceuticals. These recombinant proteins are highly heterogeneous due to their glycosylation pattern. In addition, enzymeindependent reactions, like deamidation, dehydration, and oxidation of sensitive side chains, may contribute to their heterogeneity in a minor amount. To investigate the biological impact of a spontaneous chemical modification, especially if found to be recurrent in a biotherapeutic, it would be necessary to reproduce it in a homogeneous manner. Herein, we undertook an explorative study towards the chemical synthesis of the IgG1 Fc CH3 domain, which has been shown to undergo spontaneous changes like succinimide formation and methionine oxidation. We used Fmocsolidphase peptide synthesis (SPPS) and native chemical ligation (NCL) to test the accessibility of large fragments of the IgG1 Fc CH3 domain. In general, the incorporation of pseudoproline dipeptides improved the quality of the crude peptide precursors; however, sequences larger than 44 residues could not be achieved by standard stepwise elongation with FmocSPPS. In contrast, the application of NCL with cysteine residues, which were either native or introduced ad hoc, allowed the assembly of the Cterminal IgG1 Fc CH3 sequence 371 to 450. The syntheses reported here show advantages and limitations of the chemical approaches chosen for the preparation of the synthetic IgG1 Fc CH3 domain and will guide future plans towards the synthesis of both the native and selectively modified fulllength domain. (VLID)3106522
- Published
- 2018
29. Bone Matrix Mineralization in Patients With Gain-of-Function Calcium-Sensing Receptor Mutations Is Distinctly Different From that in Postsurgical Hypoparathyroidism
- Author
-
Ovejero, Diana, primary, Misof, Barbara M, additional, Gafni, Rachel I, additional, Dempster, David, additional, Zhou, Hua, additional, Klaushofer, Klaus, additional, Collins, Michael T, additional, and Roschger, Paul, additional
- Published
- 2019
- Full Text
- View/download PDF
30. FGF23 Regulates Bone Mineralization in a 1,25(OH)2D3and Klotho-Independent Manner
- Author
-
Ute Zeitz, Reinhold G. Erben, Klaus Klaushofer, Paul Roschger, Sathish K. Murali, and Olena Andrukhova
- Subjects
0301 basic medicine ,medicine.medical_specialty ,biology ,Chemistry ,Endocrinology, Diabetes and Metabolism ,urologic and male genital diseases ,Fibroblast growth factor ,Calcitriol receptor ,female genital diseases and pregnancy complications ,stomatognathic diseases ,03 medical and health sciences ,Paracrine signalling ,030104 developmental biology ,Endocrinology ,Downregulation and upregulation ,Internal medicine ,medicine ,biology.protein ,Alkaline phosphatase ,Orthopedics and Sports Medicine ,Osteopontin ,Autocrine signalling ,Klotho - Abstract
Fibroblast growth factor-23 (Fgf23) is a bone-derived hormone, suppressing phosphate reabsorption and vitamin D hormone (1,25(OH)2 D3 ) production in the kidney. It has long been an enigma why lack of Fgf23 or of Klotho, the coreceptor for Fgf23, leads to severe impairment in bone mineralization despite the presence of hypercalcemia and hyperphosphatemia. Using Fgf23(-/-) or Klotho(-/-) mice together with compound mutant mice lacking both Fgf23 or Klotho and a functioning vitamin D receptor, we show that in Klotho(-/-) mice the mineralization defect is solely driven by 1,25(OH)2 D3 -induced upregulation of the mineralization-inhibiting molecules osteopontin and pyrophosphate in bone. In Fgf23(-/-) mice, the mineralization defect has two components, a 1,25(OH)2 D3 -driven component similar to Klotho(-/-) mice and a component driven by lack of Fgf23, causing additional accumulation of osteopontin. We found that FGF23 regulates osteopontin secretion indirectly by suppressing alkaline phosphatase transcription and phosphate production in osteoblastic cells, acting through FGF receptor-3 in a Klotho-independent manner. Hence, FGF23 secreted from osteocytes may form an autocrine/paracrine feedback loop for the local fine-tuning of bone mineralization.
- Published
- 2015
31. PTH(1-84) Administration in Hypoparathyroidism Transiently Reduces Bone Matrix Mineralization
- Author
-
Barbara M. Misof, Mishaela R. Rubin, Hua Zhou, John P. Bilezikian, Paul Roschger, David W. Dempster, and Klaus Klaushofer
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Bone density ,business.industry ,Endocrinology, Diabetes and Metabolism ,Parathyroid hormone ,030209 endocrinology & metabolism ,Bone matrix ,medicine.disease ,Mineralization (biology) ,Bone remodeling ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Endocrinology ,Hypoparathyroidism ,Internal medicine ,medicine ,Orthopedics and Sports Medicine ,Cortical bone ,business ,Cancellous bone - Abstract
Patients with hypoparathyroidism have low circulating parathyroid (PTH) levels and higher cancellous bone volume and trabecular thickness. Treatment with PTH(1-84) was shown to increase abnormally low bone remodeling dynamics. In this work, we studied the effect of 1-year or 2-year PTH(1-84) treatment on cancellous and cortical bone mineralization density distribution (Cn.BMDD and Ct.BMDD) based on quantitative backscattered electron imaging (qBEI) in paired transiliac bone biopsy samples. The study cohort comprised 30 adult hypoparathyroid patients (14 treated for 1 year; 16 treated for 2 years). At baseline, Cn.BMDD was shifted to higher mineralization densities in both treatment groups (average degree of mineralization Cn.CaMean +3.9% and +2.7%, p
- Published
- 2015
32. Osteoporosis Caused by Mutations inPLS3: Clinical and Bone Tissue Characteristics
- Author
-
Somayyeh Fahiminiya, Francis H. Glorieux, John S. Mort, Jacek Majewski, Frank Rauch, Pierre Moffatt, Klaus Klaushofer, Hadil Al-Jallad, and Paul Roschger
- Subjects
musculoskeletal diseases ,Bone mineral ,Pathology ,medicine.medical_specialty ,medicine.diagnostic_test ,Osteoid ,business.industry ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,medicine.disease ,Bone tissue ,medicine.anatomical_structure ,Osteoclast ,Osteogenesis imperfecta ,medicine ,PLS3 ,Orthopedics and Sports Medicine ,Quantitative computed tomography ,business - Abstract
Mutations in PLS3 have been identified as a cause of bone fragility in children, but the bone phenotype associated with PLS3 mutations has not been reported in detail. PLS3 is located on the X chromosome and encodes the actin-binding protein plastin 3. Here we describe skeletal findings in 4 boys from 2 families with mutations in PLS3 (c.994_995delGA; p.Asp332* in family 1; c.1433T > C; p.Leu478Pro in family 2). When first evaluated between 4 and 8 years of age, these boys had a history of one to four long-bone fractures. Mild vertebral compression fractures were identified in each boy. No obvious extraskeletal disease manifestations were present. Lumbar spine areal bone mineral density (LS-aBMD) Z-scores ranged from –1.7 to –3.5, but height was normal. Iliac bone histomorphometry in 2 patients showed low trabecular bone volume and a low osteoid maturation time but normal bone formation rate and osteoclast surface. Quantitative backscattered electron imaging (qBEI) did not reveal a major abnormality in bone mineralization density distribution. The 2 boys from family 1 received oral alendronate for 6 years, which normalized LS-aBMD. The mothers of the 4 boys did not have a history of fractures and had normal LS-aBMD. However, one of these mothers had low bone mass at the distal radius, as measured by peripheral quantitative computed tomography (pQCT). In conclusion, hemizygous mutations in PLS3 are associated with osteoporosis and bone fragility in childhood, but in contrast to bone fragility caused by mutations in collagen type I encoding genes, there is no hypermineralization of mineralized bone matrix. © 2014 American Society for Bone and Mineral Research.
- Published
- 2014
33. Increased Heterogeneity of Bone Matrix Mineralization in Pediatric Patients Prone to Fractures: A Biopsy Study
- Author
-
Paul Roschger, Mervi K Mäyränpää, Barbara M. Misof, Heikki Kröger, Outi Mäkitie, Hanna Isaksson, Inari S. Tamminen, Klaus Klaushofer, and Mikael J. Turunen
- Subjects
Bone mineral ,medicine.medical_specialty ,Pathology ,Bone density ,medicine.diagnostic_test ,business.industry ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,Urology ,medicine.disease ,Mineralization (biology) ,Bone remodeling ,medicine.anatomical_structure ,Density distribution ,Biopsy ,Medicine ,Orthopedics and Sports Medicine ,Cortical bone ,business - Abstract
Idiopathic osteoporosis (IOP) in children is characterized by fragility fractures and/or low bone mineral density in otherwise healthy individuals. The aim of the present work was to measure bone mineralization density distribution (BMDD) based on quantitative backscattered electron imaging (qBEI) in children with suspected IOP. Entire cross-sectional areas of transiliac bone biopsy samples from children (n = 24, 17 boys; aged 6.7-16.6 years) with a history of fractures (n = 14 with at least one vertebral fracture) were analyzed for cancellous (Cn) and cortical (Ct) BMDD. Outcomes were compared with normal reference BMDD data and correlated with the patients' clinical characteristics and bone histomorphometry findings. The subjects had similar average degree but significantly higher heterogeneity of mineralization in both Cn and Ct bone (Cn.CaWidth +23%, Ct.CaWidth +15%, p
- Published
- 2014
34. Intravenous Treatment With Ibandronate Normalizes Bone Matrix Mineralization and Reduces Cortical Porosity After Two Years in Male Osteoporosis: A Paired Biopsy Study
- Author
-
Christian Muschitz, Sonja Gamsjaeger, Peter Pietschmann, Klaus Klaushofer, Heinrich Resch, Eleftherios P. Paschalis, Janina M. Patsch, Barbara M. Misof, Eva Prokop, and Paul Roschger
- Subjects
Bone mineral ,medicine.medical_specialty ,medicine.diagnostic_test ,biology ,business.industry ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,Urology ,medicine.disease ,Bone remodeling ,medicine.anatomical_structure ,Endocrinology ,Internal medicine ,Biopsy ,medicine ,Osteocalcin ,biology.protein ,Orthopedics and Sports Medicine ,business ,Cancellous bone ,Type I collagen ,Femoral neck - Abstract
The spectrum of therapeutic options and the amount of clinical trials for male osteoporosis (mOP) is lower than those for postmenopausal osteoporosis. Therefore, we examined the effects of 24 months of ibandronate (IBN) treatment (3 mg/3 mL intravenously every 3 months) on bone material quality in 19 subjects with mOP within an open-label, single-center, prospective phase III study (Eudract number 2006-006692-20). Patients (median age [25th, 75th percentiles] 53.0 [44.5; 57.0] years) were included if they had low bone mineral density (BMD) and/or at least one low trauma fracture and no secondary cause of osteoporosis. The primary endpoint was to evaluate IBN effects on cancellous (Cn.) and cortical (Ct.) bone mineralization density distribution (BMDD) based on quantitative backscattered electron imaging (qBEI) of paired transiliacal bone biopsies (baseline, 24 months). Secondary endpoints included changes in areal bone mineral density (BMD by dual-energy X-ray absorptiometry [DXA]) and serum markers of bone turnover including type I collagen peptides CrossLaps (CTX), procollagen type 1 amino-terminal propeptide (P1NP), and osteocalcin (OC). At baseline, cancellous bone matrix mineralization from mOP was lower than published reference data (mean degree of mineralization Cn.CaMean −1.8%, p
- Published
- 2014
35. Increased zinc accumulation in mineralized osteosarcoma tissue measured by confocal synchrotron radiation micro X-ray fluorescence analysis
- Author
-
Rauwolf, Mirjam, primary, Pemmer, Bernhard, additional, Roschger, Andreas, additional, Turyanskaya, Anna, additional, Smolek, Stephan, additional, Maderitsch, Angelika, additional, Hischenhuber, Peter, additional, Foelser, Martin, additional, Simon, Rolf, additional, Lang, Susanna, additional, Puchner, Stephan E., additional, Windhager, Reinhard, additional, Klaushofer, Klaus, additional, Wobrauschek, Peter, additional, Hofstaetter, Jochen G., additional, Roschger, Paul, additional, and Streli, Christina, additional
- Published
- 2016
- Full Text
- View/download PDF
36. Biomechanical and Bone Material Properties of Schnurri-3 Null Mice
- Author
-
Christiane Schueler, R. Zoehrer, Eleftherios P. Paschalis, Barbara M. Misof, Stéphane Blouin, Paul Roschger, Jochen G. Hofstaetter, Klaus Klaushofer, Richard Weinkamer, Dallas C. Jones, and Reinhold G. Erben
- Subjects
Null mice ,Bone material properties ,Chemistry ,Endocrinology, Diabetes and Metabolism ,Anatomy ,Mineralization (biology) ,Trabecular bone ,medicine.anatomical_structure ,Density distribution ,Osteocyte ,medicine ,Orthopedics and Sports Medicine ,Cortical bone ,Bone volume - Abstract
Schnurri-3 (Shn3) is an essential regulator of postnatal skeletal remodeling. Shn3-deficient mice (Shn3-/-) have high bone mass; however, their bone mechanical and material properties have not been investigated to date. We performed three-point bending of femora, compression tests of L3 vertebrae. We also measured intrinsic material properties, including bone mineralization density distribution (BMDD) and osteocyte lacunae section (OLS) characteristics by quantitative backscatter electron imaging, as well as collagen cross-linking by Fourier transform infrared microspectroscopy of femora from Shn3-/- and WT mice at different ages (6 weeks, 4 months, and 18 months). Moreover, computer modeling was performed for the interpretation of the BMDD outcomes. Femora and L3 vertebrae from Shn3-/- aged 6 weeks revealed increased ultimate force (2.2- and 3.2-fold, p < .01, respectively). Mineralized bone volume at the distal femoral metaphysis was about twofold (at 6 weeks) to eightfold (at 4 and 18 months of age) in Shn3-/- (p < .001). Compared with WT, the average degree of trabecular bone mineralization was similar at 6 weeks, but increased at 4 and 18 months of age (+12.6% and +7.7%, p < .01, respectively) in Shn3-/-. The analysis of OLS characteristics revealed a higher OLS area for Shn3-/- versus WT at all ages (+16%, +23%, +21%, respectively, p < .01). The collagen cross-link ratio was similar between groups. We conclude that femora and vertebrae from Shn3-/- had higher ultimate force in mechanical testing. Computer modeling demonstrated that in cases of highly increased bone volume, the average degree of bone matrix mineralization can be higher than in WT bone, which was actually measured in the older Shn3-/- groups. The area of 2D osteocyte lacunae sections was also increased in Shn3-deficiency, which could only partly be explained by larger remnant areas of primary cortical bone. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
- Published
- 2019
37. An explorative study towards the chemical synthesis of the immunoglobulin G1 Fc CH3 domain
- Author
-
Grassi, Luigi, primary, Roschger, Cornelia, additional, Stanojlović, Vesna, additional, and Cabrele, Chiara, additional
- Published
- 2018
- Full Text
- View/download PDF
38. Distinct Clinical and Pathological Features of Melorheostosis Associated With Somatic MAP2K1 Mutations
- Author
-
Jha, Smita, primary, Fratzl‐Zelman, Nadja, additional, Roschger, Paul, additional, Papadakis, Georgios Z, additional, Cowen, Edward W, additional, Kang, Heeseog, additional, Lehky, Tanya J, additional, Alter, Katharine, additional, Deng, Zuoming, additional, Ivovic, Aleksandra, additional, Flynn, Lauren, additional, Reynolds, James C, additional, Dasgupta, Abhijit, additional, Miettinen, Markku, additional, Lange, Eileen, additional, Katz, James, additional, Klaushofer, Klaus, additional, Marini, Joan C, additional, Siegel, Richard M, additional, and Bhattacharyya, Timothy, additional
- Published
- 2018
- Full Text
- View/download PDF
39. Mutations That Alter the Carboxy‐Terminal‐Propeptide Cleavage Site of the Chains of Type I Procollagen Are Associated With a Unique Osteogenesis Imperfecta Phenotype
- Author
-
Cundy, Tim, primary, Dray, Michael, additional, Delahunt, John, additional, Hald, Jannie Dahl, additional, Langdahl, Bente, additional, Li, Chumei, additional, Szybowska, Marta, additional, Mohammed, Shehla, additional, Duncan, Emma L, additional, McInerney‐Leo, Aideen M, additional, Wheeler, Patricia G, additional, Roschger, Paul, additional, Klaushofer, Klaus, additional, Rai, Jyoti, additional, Weis, MaryAnn, additional, Eyre, David, additional, Schwarze, Ulrike, additional, and Byers, Peter H, additional
- Published
- 2018
- Full Text
- View/download PDF
40. Reply: Hypophosphatemia, Severe Bone Pain, Gait Disturbance, and Fatigue Fractures After Iron Substitution in Inflammatory Bowel Disease: A Case Report
- Author
-
Bartko, Johann, primary, Roschger, Paul, additional, Zandieh, Shahin, additional, Brehm, Attila, additional, Zwerina, Jochen, additional, and Klaushofer, Klaus, additional
- Published
- 2018
- Full Text
- View/download PDF
41. Hypophosphatemia, Severe Bone Pain, Gait Disturbance, and Fatigue Fractures After Iron Substitution in Inflammatory Bowel Disease: A Case Report
- Author
-
Bartko, Johann, primary, Roschger, Paul, additional, Zandieh, Shahin, additional, Brehm, Attila, additional, Zwerina, Jochen, additional, and Klaushofer, Klaus, additional
- Published
- 2017
- Full Text
- View/download PDF
42. Annual intravenous zoledronic acid for three years increased cancellous bone matrix mineralization beyond normal values in the HORIZON biopsy cohort
- Author
-
Erik Fink Eriksen, Barbara M. Misof, Robert R. Recker, Eleftherios P. Paschalis, Jürg A. Gasser, Paul Roschger, Daniela Gabriel, and Klaus Klaushofer
- Subjects
medicine.medical_specialty ,Bone density ,Biopsy ,Endocrinology, Diabetes and Metabolism ,Urology ,Dentistry ,Placebo ,Zoledronic Acid ,Mineralization (biology) ,Bone remodeling ,Cohort Studies ,Placebos ,Bone Density ,Humans ,Medicine ,Orthopedics and Sports Medicine ,Infusions, Intravenous ,Bone Density Conservation Agents ,Diphosphonates ,medicine.diagnostic_test ,business.industry ,Imidazoles ,medicine.anatomical_structure ,Zoledronic acid ,Cortical bone ,business ,Cancellous bone ,medicine.drug - Abstract
The efficacy of 3 years of annual intravenous administration of zoledronic acid (ZOL) in reducing vertebral and nonvertebral fractures in postmenopausal osteoporosis has been shown by the HORIZON pivotal fracture trial. Histomorphometric analysis of transiliac bone biopsies from the HORIZON participants revealed significantly improved trabecular architecture and reduced bone remodeling for the ZOL-treated versus placebo-treated patients. The aim of our study was to evaluate the cancellous and cortical bone mineralization density distribution (BMDD) in these biopsies by quantitative backscattered electron imaging (qBEI). The study cohort comprised 82 patients on active treatment (ZOL, yearly doses of 5 mg) and 70 treated with placebo, and all received adequate Ca and VitD supplementation. Comparison of ZOL-treated versus placebo-treated cancellous (Cn.) and cortical (Ct.) BMDD-derived variables resulted in significantly higher average (Cn.CaMean + 3.2%, Ct.CaMean + 2.7%) and mode calcium concentrations (Cn.CaPeak + 2.1%, Ct.CaPeak + 1.5%), increased percentages of highly mineralized bone areas (Cn.CaHigh + 64%, Ct.CaHigh + 31%), lower heterogeneity of mineralization (Cn.CaWidth −14%, Ct.CaWidth −13%), and decreased percentages of low mineralized bone areas (Cn.CaLow −22%, Ct.CaLow −26%) versus placebo (all p
- Published
- 2013
43. Mineralization pattern of vertebral bone material following fragility fracture of the spine
- Author
-
Paul Roschger, Kamilla Nawrot-Wawrzyniak, Stefan G. Hofstaetter, Jochen G. Hofstaetter, Klemens Trieb, Josef G. Grohs, Helmut Hiertz, Reinhard Windhager, and Klaus Klaushofer
- Subjects
Male ,Biopsy ,Osteoporosis ,Dentistry ,Bone tissue ,Mineralization (biology) ,Calcification, Physiologic ,Fractures, Compression ,Humans ,Medicine ,Orthopedics and Sports Medicine ,Vertebral bone ,Aged ,Fracture Healing ,Fragility fracture ,Diphosphonates ,medicine.diagnostic_test ,business.industry ,Bone material properties ,Middle Aged ,medicine.disease ,Trabecular bone ,medicine.anatomical_structure ,Spinal Fractures ,Female ,business - Abstract
Little is known whether trabecular bone matrix mineralization is altered at the site of osteoporotic vertebral fractures. Bone mineralization density distribution (BMDD) was assessed in trabecular bone of acute, single-level compression fractures of the spine at various stages of fracture repair using quantitative backscattered electron imaging (qBEI). The grading of the repair stage was performed by histological methods. From 20 patients, who underwent either kyphoplasty (n = 18) or vertebroplasty (n = 2), a vertebral bone biopsy was taken prior to cement augmentation. Six patients took bisphosphonates (BP) prior to fracture. Three study groups were formed: N1 = early-, N2 = late-healing and B = BP treatment at late healing stage. In general, all groups had an altered BMDD when compared to historical normative reference data. Mean matrix mineralization (CaMean) was significantly (p
- Published
- 2012
44. Trabecular bone microstructure and local gene expression in iliac crest biopsies of men with idiopathic osteoporosis
- Author
-
Peter Pietschmann, Janina M. Patsch, Christian Muschitz, Thomas Kohler, Christian Bieglmayr, Andrea Berzlanovich, Heinrich Resch, and Paul Roschger
- Subjects
Adult ,Male ,musculoskeletal diseases ,Pathology ,medicine.medical_specialty ,Biopsy ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,Iliac crest ,Metabolic bone disease ,Ilium ,Image Processing, Computer-Assisted ,medicine ,Humans ,Orthopedics and Sports Medicine ,Aged ,biology ,medicine.diagnostic_test ,business.industry ,Osteoid ,Osteoblast ,Middle Aged ,medicine.disease ,Radiography ,medicine.anatomical_structure ,Gene Expression Regulation ,RANKL ,Osteocalcin ,biology.protein ,business ,Biomarkers ,Densitometry - Abstract
Male idiopathic osteoporosis (MIO) is a metabolic bone disease that is characterized by low bone mass, microstructural alterations, and increased fracture risk in otherwise healthy men. Although the detailed pathophysiology of MIO has yet to be clarified, evidence increasingly suggests an osteoblastic defect as the underlying cause. In this study we tested the hypothesis that the expression profile of certain osteoblastic or osteoblast-related genes (ie, WNT10B, RUNX2, Osterix, Osteocalcin, SOST, RANKL, and OPG) is different in iliac crest biopsies of MIO patients when compared with healthy controls. Furthermore, we investigated the relation of local gene expression characteristics with histomorphometric, microstructural, and clinical features. Following written informed consent and diligent clinical patient characterization, iliac crest biopsies were performed in nine men. While RNA extraction, reverse-transcription, and real-time polymerase chain reactions (PCRs) were performed on one biopsy, a second biopsy of each patient was submitted for histomorphometry and micro-computed tomography (µCT). Age-matched bone samples from forensic autopsies served as controls. MIO patients displayed significantly reduced WNT10B, RUNX2, RANKL, and SOST expression. Performing µCT for the first time in MIO biopsies, we found significant decreases in trabecular number and connectivity density. Trabecular separation was increased significantly, but trabecular thickness was similar in both groups. Histomorphometry revealed decreased BV/TV and osteoid volume and fewer osteoclasts in MIO. By providing evidence for reduced local WNT10B, RUNX2, and RANKL gene expression and histomorphometric low turnover, our data support the osteoblast dysfunction model discussed for MIO. Further, MIO seems to lead to a different microstructural pathology than age-related bone loss.
- Published
- 2011
45. Size and habit of mineral particles in bone and mineralized callus during bone healing in sheep
- Author
-
Yifei Liu, Inderchand Manjubala, Paul Roschger, Peter Fratzl, Georg N. Duda, Devakara R. Epari, and Hanna Schell
- Subjects
Bone mineral ,Sheep ,Chemistry ,Callus formation ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Bone healing ,Anatomy ,Osteotomy ,medicine.disease ,090300 BIOMEDICAL ENGINEERING ,Resorption ,Calcification, Physiologic ,Callus ,Microscopy, Electron, Scanning ,medicine ,Animals ,Scattering, Radiation ,Female ,Orthopedics and Sports Medicine ,Environmental scanning electron microscope ,Biomedical engineering ,Calcification - Abstract
Bone healing is known to occur through the successive formation and resorption of various tissues with different structural and mechanical properties. To get a better insight into this sequence of events, we used environmental scanning electron microscopy (ESEM) together with scanning small-angle X-ray scattering (sSAXS) to reveal the size and orientation of bone mineral particles within the regenerating callus tissues at different healing stages (2, 3, 6, and 9 weeks). Sections of 200 µm were cut from embedded blocks of midshaft tibial samples in a sheep osteotomy model with an external fixator. Regions of interest on the medial side of the proximal fragment were chosen to be the periosteal callus, middle callus, intercortical callus, and cortex. Mean thickness (T parameter), degree of alignment (ρ parameter), and predominant orientation (ψ parameter) of mineral particles were deduced from resulting sSAXS patterns with a spatial resolution of 200 µm. 2D maps of T and ρ overlapping with ESEM images revealed that the callus formation occurred in two waves of bone formation, whereby a highly disordered mineralized tissue was deposited first, followed by a bony tissue with more lamellar appearance in the ESEM and where the mineral particles were more aligned, as revealed by sSAXS. As a consequence, degree of alignment and mineral particle size within the callus increased with healing time, whereas at any given moment there were structural gradients, for example, from periosteal toward the middle callus.
- Published
- 2010
46. Effects of 1 year of daily teriparatide treatment on iliacal bone mineralization density distribution (BMDD) in postmenopausal osteoporotic women previously treated with alendronate or risedronate
- Author
-
Barbara M. Misof, Nadja Fratzl-Zelman, Klaus Klaushofer, Paul Roschger, Stéphane Blouin, and Eleftherios P. Paschalis
- Subjects
medicine.medical_specialty ,Anabolism ,business.industry ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Alendronic acid ,Osteoporosis ,Urology ,Bisphosphonate ,medicine.disease ,Endocrinology ,Internal medicine ,Risedronic acid ,medicine ,Teriparatide ,Orthopedics and Sports Medicine ,business ,medicine.drug ,Hormone ,Calcification - Abstract
Anabolic treatment with teriparatide of postmenopausal osteoporotic patients previously treated with bisphosphonates is a new therapeutic approach. However, its effects on the bone mineralization density distribution (BMDD) are unknown. We studied paired transiliac bone biopsy samples taken before and after 1 year of treatment with recombinant human parathyroid hormone peptide 1-34 (teriparatide) from 16 osteoporotic women treated with either alendronate (priorALN) or risedronate (priorRIS) for at least 2 years and subsequently treated for 12 months with teriparatide. Cancellous (Cn.) and cortical (Ct.) BMDD values were measured using quantitative backscattered electron imaging. At baseline, BMDD values of priorALN and priorRIS women were similar and within the normal range. One year of teriparatide treatment caused significant effects on the BMDD. Analyzing changes from baseline for each bisphosphonate group separately, priorALN patients revealed increases in the portion of low mineralized bone areas (Cn.CaLow +25.9%, Ct.CaLow +62.0%, both p
- Published
- 2010
47. Reply: Hypophosphatemia, Severe Bone Pain, Gait Disturbance, and Fatigue Fractures After Iron Substitution in Inflammatory Bowel Disease: A Case Report
- Author
-
Johann Bartko, Paul Roschger, Klaus Klaushofer, Jochen Zwerina, Shahin Zandieh, and Attila Brehm
- Subjects
medicine.medical_specialty ,Letter to the editor ,Gait Disturbance ,business.industry ,Endocrinology, Diabetes and Metabolism ,Fatigue fractures ,medicine.disease ,Inflammatory bowel disease ,Surgery ,medicine ,Orthopedics and Sports Medicine ,business ,Hypophosphatemia ,Severe bone pain - Published
- 2018
48. Effects of sodium fluoride and alendronate on the bone mineral in minipigs: A small-angle X-ray scattering and backscattered electron imaging study
- Author
-
Klaus Klaushofer, Marie-Helene Lafage, Peter Fratzl, Paul Roschger, Sabine Schreiber, and Gideon A. Rodan
- Subjects
Bone disease ,Swine ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Osteoporosis ,Biophysics ,Biophysical Phenomena ,Bone and Bones ,Bone resorption ,chemistry.chemical_compound ,Double-Blind Method ,Sodium fluoride ,Image Processing, Computer-Assisted ,medicine ,Animals ,Scattering, Radiation ,Orthopedics and Sports Medicine ,Bone mineral ,Analysis of Variance ,Minerals ,Alendronate ,Chemistry ,X-Rays ,Anatomy ,Bisphosphonate ,medicine.disease ,Transmission electron microscopy ,Microscopy, Electron, Scanning ,Sodium Fluoride ,Swine, Miniature ,Crystallization ,Fluoride ,Biomedical engineering - Abstract
Sodium fluoride (NaF), which stimulates bone formation, and bisphosphonates, which reduce bone resorption, are both used in the treatment of osteoporosis, and are binding to bone mineral. In this study, using small-angle X-ray scattering and backscattered electron imaging, we analyzed the bone mineral in the vertebrae of minipigs treated with fluoride, with the bisphosphonate alendronate (ALN), or with vehicle. All specimens were investigated blindly. A slight increase in the average thickness of the mineral crystals as well as changes in the structure of the mineral/collagen composite were found in the case of fluoride-treated animals. No differences were found between ALN-treated animals and controls. The changes produced by fluoride are in the same direction as seen in bones from patients treated with NaF, albeit much smaller. They also correlate quantitatively with the reduction in biomechanical properties of bone in fluoride-treated minipigs found in an earlier study with the same animals. These findings suggest that small changes in the structure of the mineral/collagen composite in bone may considerably affect its biomechanical properties. It also emphasizes the delicate balance between the increase of bone mass and deterioration of bone material properties for the effect of fluoride on the biomechanical properties of bone.
- Published
- 2009
49. Effect of Temporal Changes in Bone Turnover on the Bone Mineralization Density Distribution: A Computer Simulation Study
- Author
-
Richard Weinkamer, Roger J. Phipps, Peter Fratzl, Paul Roschger, Klaus Klaushofer, and Davide Ruffoni
- Subjects
Time Factors ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,Mineralogy ,Bone matrix ,Mineralization (biology) ,Bone and Bones ,Bone resorption ,Bone remodeling ,Bone Density ,Bone material ,medicine ,Humans ,Computer Simulation ,Orthopedics and Sports Medicine ,Models, Statistical ,Chemistry ,Etidronic Acid ,Models, Theoretical ,medicine.disease ,Kinetics ,Trabecular bone ,Density distribution ,Female ,Bone Remodeling ,Menopause ,Risedronic Acid ,Biomedical engineering - Abstract
The heterogeneous distribution of mineral content in trabecular bone reflects the continuous renewal of bone material in bone remodeling and the subsequent increase in mineral content in the newly formed bone packets. The bone mineralization density distribution (BMDD) is typically used to describe this nonuniform mineral content of the bone matrix. Our mathematical model describes changes of the BMDD of trabecular bone as a function of bone resorption and deposition rates and the mineralization kinetics in a newly formed bone packet. Input parameters used in the simulations were taken from experimental studies. The simulations of the time evolution of the BMDD after increase in bone turnover (perimenopausal period) resulted in a shift of the BMDD toward lower values of the mineral content. Transiently, there was a broadening of the BMDD configuration partly showing two peaks, which points to a strongly heterogeneous distribution of the mineral. Conversely, when the remodeling rate was reduced (antiresorptive therapy), the BMDD shifted toward higher values of the mineral content. There was a transient narrowing of the distribution before broadening again to reach the new steady state. Results from this latter simulation are in good agreement with measurements of the BMDD of patients after 3 and 5 yr of treatment with risedronate. Based on available experimental data on bone remodeling, this model gives reliable predictions of changes in BMDD, an important factor of bone material quality. With the availability of medications with a known effect on bone turnover, this knowledge opens the possibility for therapeutic manipulation of the BMDD.
- Published
- 2008
50. Front Cover: Targeting of a Helix-Loop-Helix Transcriptional Regulator by a Short Helical Peptide (ChemMedChem 18/2017)
- Author
-
Roschger, Cornelia, primary, Neukirchen, Saskia, additional, Elsässer, Brigitta, additional, Schubert, Mario, additional, Maeding, Nicole, additional, Verwanger, Thomas, additional, Krammer, Barbara, additional, and Cabrele, Chiara, additional
- Published
- 2017
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.