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      Thalidomide‐induced teratogenesis: History and mechanisms

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          Abstract

          Nearly 60 years ago thalidomide was prescribed to treat morning sickness in pregnant women. What followed was the biggest man‐made medical disaster ever, where over 10,000 children were born with a range of severe and debilitating malformations. Despite this, the drug is now used successfully to treat a range of adult conditions, including multiple myeloma and complications of leprosy. Tragically, a new generation of thalidomide damaged children has been identified in Brazil. Yet, how thalidomide caused its devastating effects in the forming embryo remains unclear. However, studies in the past few years have greatly enhanced our understanding of the molecular mechanisms the drug. This review will look at the history of the drug, and the range and type of damage the drug caused, and outline the mechanisms of action the drug uses including recent molecular advances and new findings. Some of the remaining challenges facing thalidomide biologists are also discussed. Birth Defects Research (Part C) 105:140–156, 2015. © 2015 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc.

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          Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone.

          Anjali P. Kusumbe, Saravana K. Ramasamy, Ralf H. Adams (2014)
          The mammalian skeletal system harbours a hierarchical system of mesenchymal stem cells, osteoprogenitors and osteoblasts sustaining lifelong bone formation. Osteogenesis is indispensable for the homeostatic renewal of bone as well as regenerative fracture healing, but these processes frequently decline in ageing organisms, leading to loss of bone mass and increased fracture incidence. Evidence indicates that the growth of blood vessels in bone and osteogenesis are coupled, but relatively little is known about the underlying cellular and molecular mechanisms. Here we identify a new capillary subtype in the murine skeletal system with distinct morphological, molecular and functional properties. These vessels are found in specific locations, mediate growth of the bone vasculature, generate distinct metabolic and molecular microenvironments, maintain perivascular osteoprogenitors and couple angiogenesis to osteogenesis. The abundance of these vessels and associated osteoprogenitors was strongly reduced in bone from aged animals, and pharmacological reversal of this decline allowed the restoration of bone mass.
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            Endothelial Notch activity promotes angiogenesis and osteogenesis in bone.

            Saravana Ramasamy, Anjali P Kusumbe, Lin Wang … (2014)
            Blood vessel growth in the skeletal system and osteogenesis seem to be coupled, suggesting the existence of molecular crosstalk between endothelial and osteoblastic cells. Understanding the nature of the mechanisms linking angiogenesis and bone formation should be of great relevance for improved fracture healing or prevention of bone mass loss. Here we show that vascular growth in bone involves a specialized, tissue-specific form of angiogenesis. Notch signalling promotes endothelial cell proliferation and vessel growth in postnatal long bone, which is the opposite of the well-established function of Notch and its ligand Dll4 in the endothelium of other organs and tumours. Endothelial-cell-specific and inducible genetic disruption of Notch signalling in mice not only impaired bone vessel morphology and growth, but also led to reduced osteogenesis, shortening of long bones, chondrocyte defects, loss of trabeculae and decreased bone mass. On the basis of a series of genetic experiments, we conclude that skeletal defects in these mutants involved defective angiocrine release of Noggin from endothelial cells, which is positively regulated by Notch. Administration of recombinant Noggin, a secreted antagonist of bone morphogenetic proteins, restored bone growth and mineralization, chondrocyte maturation, the formation of trabeculae and osteoprogenitor numbers in endothelial-cell-specific Notch pathway mutants. These findings establish a molecular framework coupling angiogenesis, angiocrine signals and osteogenesis, which may prove significant for the development of future therapeutic applications.
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              Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide

              Eric Fischer, Kerstin Böhm, John R Lydeard … (2014)
              In the 1950s the drug thalidomide administered as a sedative to pregnant women led to the birth of thousands of children with multiple defects. Despite its teratogenicity, thalidomide and its derivatives lenalidomide and pomalidomide (together known as Immunomodulatory Drugs: IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-dysplasia. IMiDs target the CUL4-RBX1-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase and promote the ubiquitination of Ikaros/Aiolos transcription factors by CRL4CRBN. Here we present the crystal structure of the DDB1-CRBN complex bound to thalidomide, lenalidomide and pomalidomide. The structure establishes CRBN as a CRL4CRBN substrate receptor, which enantioselectively binds IMiDs. Through an unbiased screen we identify the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4CRBN. Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4CRBN when recruiting Ikaros/Aiolos for degradation. This dual activity implies that small molecules can principally modulate a ligase to up- or down-regulate the ubiquitination of proteins.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Birth Defects Res C Embryo Today
                Journal ID (iso-abbrev): Birth Defects Res. C Embryo Today
                Journal ID (doi): 10.1002/(ISSN)1542-9768
                Journal ID (publisher-id): BDRC
                Title: Birth Defects Research
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 1542-975X
                ISSN (Electronic): 1542-9768
                Publication date (Electronic): 04 June 2015
                Publication date (Print): June 2015
                Volume: 105
                Issue: 2 ( doiID: 10.1002/bdrc.v105.2 )
                Pages: 140-156
                Affiliations
                [ 1 ] School of Medical SciencesInstitute of Medical Sciences, University of Aberdeen Foresterhill AberdeenUnited Kingdom
                Author notes
                [*] [* ]Correspondence to: Neil Vargesson, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom. E‐mail: n.vargesson@ 123456abdn.ac.uk ; nvargesson@ 123456gmail.com
                Article
                Publisher ID: BDRC21096
                DOI: 10.1002/bdrc.21096
                PMC ID: 4737249
                PubMed ID: 26043938
                SO-VID: f17aae73-f245-41d5-9b38-0555167c9b2c
                Copyright © Copyright © 2015 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc.
                License:

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 30 March 2015
                Date accepted : 12 May 2015
                Page count
                Pages: 17
                Funding
                Funded by: The Wellcome Trust
                Categories
                Subject: Review
                Subject: Reviews
                Custom metadata
                source-schema-version-number 2.0
                component-id bdrc21096
                cover-date June 2015
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:4.7.5 mode:remove_FC converted:26.01.2016

                Keywords: angiogenesis,reactive oxygen species,cell death,cereblon,actin cytoskeleton,limb development,fgf8,shh,phocomelia,vascular transition
                Data availability:
                Keywords: angiogenesis, reactive oxygen species, cell death, cereblon, actin cytoskeleton, limb development, fgf8, shh, phocomelia, vascular transition

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