Osteoblast-Specific Loss of IGF1R Signaling Results in Impaired Endochondral Bone Formation During Fracture Healing

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dc.contributor.author Wang, Tao en
dc.contributor.author Wang, Y en
dc.contributor.author Menendez, A en
dc.contributor.author Fong, C en
dc.contributor.author Babey, M en
dc.contributor.author Tahimic, CGT en
dc.contributor.author Cheng, Z en
dc.contributor.author Li, A en
dc.contributor.author Chang, W en
dc.contributor.author Bikle, DD en
dc.date.accessioned 2018-11-13T02:44:43Z en
dc.date.issued 2015-09 en
dc.identifier.issn 0884-0431 en
dc.identifier.uri http://hdl.handle.net/2292/44170 en
dc.description.abstract Insulin-like growth factors (IGFs) are important local regulators during fracture healing. Although IGF1 deficiency is known to increase the risk of delayed union or non-union fractures in the elderly population, the underlying mechanisms that contribute to this defect remains unclear. In this study, IGF1 signaling during fracture healing was investigated in an osteoblast-specific IGF1 receptor (IGF1R) conditional knockout (KO) mouse model. A closed tibial fracture was induced in IGF1R(flox/flox) /2.3-kb α1(1)-collagen-Cre (KO) and IGF1R(flox/flox) (control) mice aged 12 weeks. Fracture callus samples and nonfractured tibial diaphysis were collected and analyzed by μCT, histology, immunohistochemistry, histomorphometry, and gene expression analysis at 10, 15, 21, and 28 days after fracture. A smaller size callus, lower bone volume accompanied by a defect in mineralization, bone microarchitectural abnormalities, and a higher cartilage volume were observed in the callus of these KO mice. The levels of osteoblast differentiation markers (osteocalcin, alkaline phosphatase, collagen 1α1) were significantly reduced, but the early osteoblast transcription factor runx2, as well as chondrocyte differentiation markers (collagen 2α1 and collagen 10α1) were significantly increased in the KO callus. Moreover, increased numbers of osteoclasts and impaired angiogenesis were observed during the first 15 days of fracture repair, but decreased numbers of osteoclasts were found in the later stages of fracture repair in the KO mice. Although baseline nonfractured tibias of KO mice had decreased trabecular and cortical bone compared to control mice, subsequent studies with mice expressing the 2.3-kb α1(1)-collagen-Cre ERT2 construct and given tamoxifen at the time of fracture and so starting with comparable bone levels showed similar impairment in fracture repair at least initially. Our data indicate that not only is the IGF1R in osteoblasts involved in osteoblast differentiation during fracture repair, but it plays an important role in coordinating chondrocyte, osteoclast, and endothelial responses that all contribute to the endochondral bone formation required for normal fracture repair. en
dc.publisher American Society for Bone and Mineral Research en
dc.relation.ispartofseries Journal of Bone and Mineral Research en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm en
dc.title Osteoblast-Specific Loss of IGF1R Signaling Results in Impaired Endochondral Bone Formation During Fracture Healing en
dc.type Journal Article en
dc.identifier.doi 10.1002/jbmr.2510 en
pubs.issue 9 en
pubs.begin-page 1572 en
pubs.volume 30 en
dc.rights.holder Copyright: The author en
dc.identifier.pmid 25801198 en
pubs.end-page 1584 en
dc.rights.accessrights http://purl.org/eprint/accessRights/RestrictedAccess en
pubs.subtype Article en
pubs.elements-id 680593 en
dc.identifier.eissn 1523-4681 en
pubs.record-created-at-source-date 2018-09-13 en
pubs.dimensions-id 25801198 en

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