| Perlecan modulates VEGF signaling and is essential for vascularization in endochondral bone formation. | |
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MedLine Citation:
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PMID: 22421594 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Perlecan (Hspg2) is a heparan sulfate proteoglycan expressed in basement membranes and cartilage. Perlecan deficiency (Hspg2(-/-)) in mice and humans causes lethal chondrodysplasia, which indicates that perlecan is essential for cartilage development. However, the function of perlecan in endochondral ossification is not clear. Here, we report the critical role of perlecan in VEGF signaling and angiogenesis in growth plate formation. The Hspg2(-/-) growth plate was significantly wider but shorter due to severely impaired endochondral bone formation. Hypertrophic chondrocytes were differentiated in Hspg2(-/-) growth plates; however, removal of the hypertrophic matrix and calcified cartilage was inhibited. Although the expression of MMP-13, CTGF, and VEGFA was significantly upregulated in Hspg2(-/-) growth plates, vascular invasion into the hypertrophic zone was impaired, which resulted in an almost complete lack of bone marrow and trabecular bone. We demonstrated that cartilage perlecan promoted activation of VEGF/VEGFR by binding to the VEGFR of endothelial cells. Expression of the perlecan transgene specific to the cartilage of Hspg2(-/-) mice rescued their perinatal lethality and growth plate abnormalities, and vascularization into the growth plate was restored, indicating that perlecan in the growth plate, not in endothelial cells, is critical in this process. These results suggest that perlecan in cartilage is required for activating VEGFR signaling of endothelial cells for vascular invasion and for osteoblast migration into the growth plate. Thus, perlecan in cartilage plays a critical role in endochondral bone formation by promoting angiogenesis essential for cartilage matrix remodeling and subsequent endochondral bone formation. |
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Authors:
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Muneaki Ishijima; Nobuharu Suzuki; Kentaro Hozumi; Tomoya Matsunobu; Keisuke Kosaki; Haruka Kaneko; John R Hassell; Eri Arikawa-Hirasawa; Yoshihiko Yamada |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't Date: 2012-03-07 |
Journal Detail:
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Title: Matrix biology : journal of the International Society for Matrix Biology Volume: 31 ISSN: 1569-1802 ISO Abbreviation: Matrix Biol. Publication Date: 2012 May |
Date Detail:
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Created Date: 2012-04-30 Completed Date: 2012-08-13 Revised Date: 2013-05-03 |
Medline Journal Info:
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Nlm Unique ID: 9432592 Medline TA: Matrix Biol Country: Netherlands |
Other Details:
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Languages: eng Pagination: 234-45 Citation Subset: IM |
Copyright Information:
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Published by Elsevier B.V. |
Affiliation:
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Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892-4370, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Basement Membrane / metabolism Bone Marrow / metabolism, pathology Cartilage / metabolism, pathology Cell Differentiation Cell Movement Chondrocytes / metabolism, pathology Embryo, Mammalian / embryology, metabolism Endothelial Cells / metabolism, pathology Growth Plate / metabolism, pathology Heparan Sulfate Proteoglycans / genetics, metabolism* Hypertrophy / metabolism Matrix Metalloproteinase 13 / genetics, metabolism Mice Mice, Knockout Mice, Transgenic / genetics, metabolism Neovascularization, Pathologic / metabolism* Osteoblasts / metabolism Osteogenesis* Signal Transduction* Transgenes Vascular Endothelial Growth Factor A / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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ZIA DE000483-21/DE/NIDCR NIH HHS; ZIA DE000483-22/DE/NIDCR NIH HHS; ZIA DE000483-23/DE/NIDCR NIH HHS; ZIA DE000720-03/DE/NIDCR NIH HHS; ZIA DE000720-04/DE/NIDCR NIH HHS; ZIA DE000720-05/DE/NIDCR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Heparan Sulfate Proteoglycans; 0/Vascular Endothelial Growth Factor A; 0/vascular endothelial growth factor A, mouse; 143972-95-6/perlecan; EC 3.4.24.-/Matrix Metalloproteinase 13; EC 3.4.24.-/Mmp13 protein, mouse |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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