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Article: From skeleton to cytoskeleton: osteocalcin transforms vascular fibroblasts to myofibroblasts via angiotensin II and Toll-like receptor 4

TitleFrom skeleton to cytoskeleton: osteocalcin transforms vascular fibroblasts to myofibroblasts via angiotensin II and Toll-like receptor 4
Authors
Keywordsfibroblast transformation
osteocalcin
angiotensin II
protein kinase C
toll-like receptor 4
Issue Date2012
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://circres.ahajournals.org
Citation
Circulation Research, 2012, v. 111 n. 3, p. e55-e66 How to Cite?
AbstractRATIONALE: The expression of osteocalcin is augmented in human atherosclerotic lesions. How osteocalcin triggers vascular pathogenesis and remodeling is unclear. OBJECTIVE: To investigate whether osteocalcin promotes transformation of adventitial fibroblast to myofibroblasts and the molecular mechanism involved. METHODS AND RESULTS: Immunohistochemistry indicated that osteocalcin was expressed in the neointima of renal arteries from diabetic patients. Western blotting and wound-healing assay showed that osteocalcin induced fibroblast transformation and migration, which were attenuated by blockers of the renin-angiotensin system and protein kinase Cδ (PKCδ), toll-like receptor 4 (TLR4) neutralizing antibody, and antagonist and inhibitors of free radical production and cyclooxygenase-2. Small interfering RNA silencing of TLR4 and PKCδ abolished fibroblast transformation. Angiotensin II level in the conditioned medium from the osteocalcin-treated fibroblasts was found elevated using enzyme immunoassay. Culturing of fibroblasts in conditioned medium collected from differentiated osteoblasts promoted fibroblast transformation. The expression of fibronectin, TLR4, and cyclooxygenase-2 is augmented in human mesenteric arteries after 5-day in vitro exposure to osteocalcin. CONCLUSIONS: Osteocalcin transforms adventitial fibroblasts to myofibroblasts through stimulating angiotensin II release and subsequent activation of PKCδ/TLR4/reactive oxygen species/cyclooxygenase-2 signaling cascade. This study reveals that the skeletal hormone osteocalcin cross-talks with vascular system and contributes to vascular remodeling.
Persistent Identifierhttp://hdl.handle.net/10722/159704
ISSN
2019 Impact Factor: 14.467
2015 SCImago Journal Rankings: 5.755
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorYuen, CY-
dc.contributor.authorWong, SL-
dc.contributor.authorLau, CW-
dc.contributor.authorTsang, SY-
dc.contributor.authorXu, A-
dc.contributor.authorZhu, Z-
dc.contributor.authorNg, CF-
dc.contributor.authorYao, X-
dc.contributor.authorKong, SK-
dc.contributor.authorLee, HK-
dc.contributor.authorHuang, Y-
dc.date.accessioned2012-08-16T05:54:12Z-
dc.date.available2012-08-16T05:54:12Z-
dc.date.issued2012-
dc.identifier.citationCirculation Research, 2012, v. 111 n. 3, p. e55-e66-
dc.identifier.issn0009-7330-
dc.identifier.urihttp://hdl.handle.net/10722/159704-
dc.description.abstractRATIONALE: The expression of osteocalcin is augmented in human atherosclerotic lesions. How osteocalcin triggers vascular pathogenesis and remodeling is unclear. OBJECTIVE: To investigate whether osteocalcin promotes transformation of adventitial fibroblast to myofibroblasts and the molecular mechanism involved. METHODS AND RESULTS: Immunohistochemistry indicated that osteocalcin was expressed in the neointima of renal arteries from diabetic patients. Western blotting and wound-healing assay showed that osteocalcin induced fibroblast transformation and migration, which were attenuated by blockers of the renin-angiotensin system and protein kinase Cδ (PKCδ), toll-like receptor 4 (TLR4) neutralizing antibody, and antagonist and inhibitors of free radical production and cyclooxygenase-2. Small interfering RNA silencing of TLR4 and PKCδ abolished fibroblast transformation. Angiotensin II level in the conditioned medium from the osteocalcin-treated fibroblasts was found elevated using enzyme immunoassay. Culturing of fibroblasts in conditioned medium collected from differentiated osteoblasts promoted fibroblast transformation. The expression of fibronectin, TLR4, and cyclooxygenase-2 is augmented in human mesenteric arteries after 5-day in vitro exposure to osteocalcin. CONCLUSIONS: Osteocalcin transforms adventitial fibroblasts to myofibroblasts through stimulating angiotensin II release and subsequent activation of PKCδ/TLR4/reactive oxygen species/cyclooxygenase-2 signaling cascade. This study reveals that the skeletal hormone osteocalcin cross-talks with vascular system and contributes to vascular remodeling.-
dc.languageeng-
dc.publisherLippincott Williams & Wilkins. The Journal's web site is located at http://circres.ahajournals.org-
dc.relation.ispartofCirculation Research-
dc.rightsThis is a non-final version of an article published in final form in (provide complete journal citation)-
dc.subjectfibroblast transformation-
dc.subjectosteocalcin-
dc.subjectangiotensin II-
dc.subjectprotein kinase C-
dc.subjecttoll-like receptor 4-
dc.titleFrom skeleton to cytoskeleton: osteocalcin transforms vascular fibroblasts to myofibroblasts via angiotensin II and Toll-like receptor 4-
dc.typeArticle-
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1524-4571 (Electronic)0009-7330 (Linkin&volume=111&issue=3&spage=e55&epage=66&date=2012&atitle=From+Skeleton+to+Cytoskeleton:+Osteocalcin+Transforms+Vascular+Fibroblasts+to+Myofibroblasts+Via+Angiotensin+II+and+Toll-Like+Receptor+4en_US
dc.identifier.emailXu, A: amxu@hkucc.hku.hk-
dc.identifier.authorityXu, A=rp00485-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1161/CIRCRESAHA.112.271361-
dc.identifier.pmid22679141-
dc.identifier.scopuseid_2-s2.0-84864278755-
dc.identifier.hkuros205682-
dc.identifier.volume111-
dc.identifier.issue3-
dc.identifier.spagee55-
dc.identifier.epagee66-
dc.identifier.isiWOS:000306994700001-
dc.publisher.placeUnited States-

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