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Featured researches published by Björn Olsen.


Cell | 1997

Endostatin: An Endogenous Inhibitor of Angiogenesis and Tumor Growth

Michael S. O'Reilly; Thomas Boehm; Yuen Shing; Naomi Fukai; George Vasios; William S. Lane; Evelyn Flynn; James R Birkhead; Björn Olsen; Judah Folkman

We previously identified the angiogenesis inhibitor angiostatin. Using a similar strategy, we have identified endostatin, an angiogenesis inhibitor produced by hemangioendothelioma. Endostatin is a 20 kDa C-terminal fragment of collagen XVIII. Endostatin specifically inhibits endothelial proliferation and potently inhibits angiogenesis and tumor growth. By a novel method of sustained release, E. coli-derived endostatin was administered as a nonrefolded suspension. Primary tumors were regressed to dormant microscopic lesions. Immunohistochemistry revealed blocked angiogenesis accompanied by high proliferation balanced by apoptosis in tumor cells. There was no toxicity. Together with angiostatin data, these findings validate a strategy for identifying endogenous angiogenesis inhibitors, suggest a theme of fragments of proteins as angiogenesis inhibitors, and demonstrate dormancy therapy.


Cell | 1997

Cbfa1, a Candidate Gene for Cleidocranial Dysplasia Syndrome, Is Essential for Osteoblast Differentiation and Bone Development

Florian Otto; Anders P. Thornell; Tessa Crompton; Angela Denzel; Kimberly C Gilmour; Ian Rosewell; Gordon Stamp; Rosa Beddington; Stefan Mundlos; Björn Olsen; Paul B. Selby; Michael John Owen

We have generated Cbfa1-deficient mice. Homozygous mutants die of respiratory failure shortly after birth. Analysis of their skeletons revealed an absence of osteoblasts and bone. Heterozygous mice showed specific skeletal abnormalities that are characteristic of the human heritable skeletal disorder, cleidocranial dysplasia (CCD). These defects are also observed in a mouse Ccd mutant for this disease. The Cbfa1 gene was shown to be deleted in the Ccd mutation. Analysis of embryonic Cbfa1 expression using a lacZ reporter gene revealed strong expression at sites of bone formation prior to the earliest stages of ossification. Thus, the Cbfa1 gene is essential for osteoblast differentiation and bone formation, and the Cbfa1 heterozygous mouse is a paradigm for a human skeletal disorder.


Cell | 2001

LDL Receptor-Related Protein 5 (LRP5) Affects Bone Accrual and Eye Development

Gong Y; R. B. Slee; Naomi Fukai; Georges Rawadi; Sergio Roman-Roman; Anthony M. Reginato; Hong Wang; Tim Cundy; F. H. Glorieux; Dorit Lev; M. Zacharin; K. Oexle; Jose Marcelino; Wafaa M. Suwairi; Shauna Heeger; G. Sabatakos; Suneel S. Apte; W. N. Adkins; J. Allgrove; M. Arslan-Kirchner; J. A. Batch; Peter Beighton; Graeme C.M. Black; R. G. Boles; Laurence Boon; C. Borrone; Han G. Brunner; G. F. Carle; Bruno Dallapiccola; A. De Paepe

In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.


Cell | 1997

Mutations Involving the Transcription Factor CBFA1 Cause Cleidocranial Dysplasia

S Mundlos; Florian Otto; C Mundlos; John B. Mulliken; A.S. Aylsworth; S Albright; Dick Lindhout; W.G Cole; W Henn; J.H.M Knoll; Michael John Owen; R Mertelsmann; Bernhard Zabel; Björn Olsen

Cleidocranial dysplasia (CCD) is an autosomal-dominant condition characterized by hypoplasia/aplasia of clavicles, patent fontanelles, supernumerary teeth, short stature, and other changes in skeletal patterning and growth. In some families, the phenotype segregates with deletions resulting in heterozygous loss of CBFA1, a member of the runt family of transcription factors. In other families, insertion, deletion, and missense mutations lead to translational stop codons in the DNA binding domain or in the C-terminal transactivating region. In-frame expansion of a polyalanine stretch segregates in an affected family with brachydactyly and minor clinical findings of CCD. We conclude that CBFA1 mutations cause CCD and that heterozygous loss of function is sufficient to produce the disorder.


Journal of Virology | 2005

Characterization of a novel influenza A virus hemagglutinin subtype (H16) obtained from black-headed gulls

Ron A. M. Fouchier; Vincent J. Munster; Anders Wallensten; Theo M. Bestebroer; Sander Herfst; Derek J. Smith; Gus F. Rimmelzwaan; Björn Olsen; Albert D. M. E. Osterhaus

ABSTRACT In wild aquatic birds and poultry around the world, influenza A viruses carrying 15 antigenic subtypes of hemagglutinin (HA) and 9 antigenic subtypes of neuraminidase (NA) have been described. Here we describe a previously unidentified antigenic subtype of HA (H16), detected in viruses circulating in black-headed gulls in Sweden. In agreement with established criteria for the definition of antigenic subtypes, hemagglutination inhibition assays and immunodiffusion assays failed to detect specific reactivity between H16 and the previously described subtypes H1 to H15. Genetically, H16 HA was found to be distantly related to H13 HA, a subtype also detected exclusively in shorebirds, and the amino acid composition of the putative receptor-binding site of H13 and H16 HAs was found to be distinct from that in HA subtypes circulating in ducks and geese. The H16 viruses contained NA genes that were similar to those of other Eurasian shorebirds but genetically distinct from N3 genes detected in other birds and geographical locations. The European gull viruses were further distinguishable from other influenza A viruses based on their PB2, NP, and NS genes. Gaining information on the full spectrum of avian influenza A viruses and creating reagents for their detection and identification will remain an important task for influenza surveillance, outbreak control, and animal and public health. We propose that sequence analyses of HA and NA genes of influenza A viruses be used for the rapid identification of existing and novel HA and NA subtypes.


Cell | 1996

Vascular Dysmorphogenesis Caused by an Activating Mutation in the Receptor Tyrosine Kinase TIE2

Miikka Vikkula; Laurence M. Boon; Kermit L.Carraway; Jennifer T. Calvert; A.John Diamonti; Boyan C. Goumnerov; Krystyna A. Pasyk; Douglas A. Marchuk; Matthew L. Warman; Lewis C. Cantley; John B. Mulliken; Björn Olsen

Venous malformations (VMs), the most common errors of vascular morphogenesis in humans, are composed of dilated, serpiginous channels. The walls of the channels have a variable thickness of smooth muscle; some mural regions lack smooth muscle altogether. A missense mutation resulting in an arginine-to-tryptophan substitution at position 849 in the kinase domain of the receptor tyrosine kinase TIE2 segregates with dominantly inherited VM in two unrelated families. Using proteins expressed in insect cells, we demonstrate that the mutation results in increased activity of TIE2. We conclude that an activating mutation in TIE2 causes inherited VMs in the two families and that the TIE2 signaling pathway is critical for endothelial cell-smooth muscle cell communication in venous morphogenesis.


PLOS Pathogens | 2007

Spatial, Temporal, and Species Variation in Prevalence of Influenza A Viruses in Wild Migratory Birds

Vincent J. Munster; Chantal Baas; Pascal Lexmond; Jonas Waldenström; Anders Wallensten; Thord Fransson; Walter Beyer; Martin Schutten; Björn Olsen; Albert D. M. E. Osterhaus; Ron A. M. Fouchier

Although extensive data exist on avian influenza in wild birds in North America, limited information is available from elsewhere, including Europe. Here, molecular diagnostic tools were employed for high-throughput surveillance of migratory birds, as an alternative to classical labor-intensive methods of virus isolation in eggs. This study included 36,809 samples from 323 bird species belonging to 18 orders, of which only 25 species of three orders were positive for influenza A virus. Information on species, locations, and timing is provided for all samples tested. Seven previously unknown host species for avian influenza virus were identified: barnacle goose, bean goose, brent goose, pink-footed goose, bewicks swan, common gull, and guillemot. Dabbling ducks were more frequently infected than other ducks and Anseriformes; this distinction was probably related to bird behavior rather than population sizes. Waders did not appear to play a role in the epidemiology of avian influenza in Europe, in contrast to the Americas. The high virus prevalence in ducks in Europe in spring as compared with North America could explain the differences in virus–host ecology between these continents. Most influenza A virus subtypes were detected in ducks, but H13 and H16 subtypes were detected primarily in gulls. Viruses of subtype H6 were more promiscuous in host range than other subtypes. Temporal and spatial variation in influenza virus prevalence in wild birds was observed, with influenza A virus prevalence varying by sampling location; this is probably related to migration patterns from northeast to southwest and a higher prevalence farther north along the flyways. We discuss the ecology and epidemiology of avian influenza A virus in wild birds in relation to host ecology and compare our results with published studies. These data are useful for designing new surveillance programs and are particularly relevant due to increased interest in avian influenza in wild birds.


Science | 1996

Altered Growth and Branching Patterns in Synpolydactyly Caused by Mutations in HOXD13

Yasuteru Muragaki; Stefan Mundlos; Joseph Upton; Björn Olsen

Hox genes regulate patterning during limb development. It is believed that they function in the determination of the timing and extent of local growth rates. Here, it is demonstrated that synpolydactyly, an inherited human abnormality of the hands and feet, is caused by expansions of a polyalanine stretch in the amino-terminal region of HOXD13. The homozygous phenotype includes the transformation of metacarpal and metatarsal bones to short carpal- and tarsal-like bones. The mutations identify the polyalanine stretch outside of the DNA binding domain of HOXD13 as a region necessary for proper protein function.


Nature Medicine | 2010

Conversion of vascular endothelial cells into multipotent stem-like cells

Damian Medici; Eileen M. Shore; Vitali Y. Lounev; Frederick S. Kaplan; Raghu Kalluri; Björn Olsen

Mesenchymal stem cells can give rise to several cell types, but varying results depending on isolation methods and tissue source have led to controversies about their usefulness in clinical medicine. Here we show that vascular endothelial cells can transform into multipotent stem-like cells by an activin-like kinase-2 (ALK2) receptor–dependent mechanism. In lesions from individuals with fibrodysplasia ossificans progressiva (FOP), a disease in which heterotopic ossification occurs as a result of activating ALK2 mutations, or from transgenic mice expressing constitutively active ALK2, chondrocytes and osteoblasts expressed endothelial markers. Lineage tracing of heterotopic ossification in mice using a Tie2-Cre construct also suggested an endothelial origin of these cell types. Expression of constitutively active ALK2 in endothelial cells caused endothelial-to-mesenchymal transition and acquisition of a stem cell–like phenotype. Similar results were obtained by treatment of untransfected endothelial cells with the ligands transforming growth factor-β2 (TGF-β2) or bone morphogenetic protein-4 (BMP4) in an ALK2-dependent manner. These stem-like cells could be triggered to differentiate into osteoblasts, chondrocytes or adipocytes. We suggest that conversion of endothelial cells to stem-like cells may provide a new approach to tissue engineering.


The EMBO Journal | 1999

Endostatin inhibits VEGF-induced endothelial cell migration and tumor growth independently of zinc binding.

Noriko Yamaguchi; Bela Anand-Apte; Margaret S. Lee; Takako Sasaki; Naomi Fukai; Robert Shapiro; Ivo Que; Clemens W.G.M. Löwik; Rupert Timpl; Björn Olsen

Endostatin, produced as recombinant protein in human 293‐EBNA cells, inhibits the migration of human umbilical vein endothelial cells (HUVECs) in response to vascular endothelial growth factor (VEGF) in a dose‐dependent manner and prevents the subcutaneous growth of human renal cell carcinomas in nude mice at concentrations and in doses that are from 1000‐ to 100 000‐fold lower than those previously reported. The inhibition of migration is not affected by mutations which eliminate Zn or heparin binding and inhibition of tumor growth does not depend on Zn binding. The results of the migration assays suggest that endostatin causes a block at one or more steps in VEGF‐induced migration, while VEGF in turn can cause a block of the inhibition by endostatin of VEGF‐induced migration of HUVECs.

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Gunnar Gunnarsson

Kristianstad University College

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Matthew L. Warman

Howard Hughes Medical Institute

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Vincent J. Munster

National Institutes of Health

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