In:
Development, The Company of Biologists, ( 2015-01-01)
Abstract:
Extracellular phosphate plays a critical role in growth plate maturation by inducing Erk1/2 phosphorylation, leading to hypertrophic chondrocyte apoptosis. The Raf kinases induce Mek1/2 and Erk1/2 phosphorylation, however a role for Raf kinases in endochondral bone formation has not been identified. Ablation of both A- and B-Raf in chondrocytes does not alter growth plate maturation. Because C-Raf phosphorylation is increased by extracellular phosphate and C-Raf is the predominant isoform expressed in hypertrophic chondrocytes, chondrocyte-specific C-Raf knockout mice (C-Raf f/f;Col II-Cre+) were generated to define a role for C-Raf in growth plate maturation. In vivo studies demonstrated that loss of C-Raf in chondrocytes leads to expansion of the hypertrophic layer of the growth plate with decreased p-Erk1/2 immunoreactivity and impaired hypertrophic chondrocyte apoptosis. However, cultured hypertrophic chondrocytes from these mice did not exhibit impairment of phosphate-induced Erk1/2 phosphorylation. Studies performed to reconcile the discrepancy between the in vitro and in vivo hypertrophic chondrocyte phenotypes revealed normal chondrocyte differentiation in C-Raf f/f;Col II-Cre+ mice and lack of compensatory increase in expression of A-Raf and B-Raf. However, VEGF immunoreactivity in the hypertrophic chondrocytes of C-Raf f/f;Col II-Cre+ mice was significantly reduced, associated with increased ubiquitination of VEGF protein. Thus C-Raf plays an important role in growth plate maturation by regulating vascular invasion, which is critical for replacement of terminally differentiated hypertrophic chondrocytes by bone.
Type of Medium:
Online Resource
ISSN:
1477-9129
,
0950-1991
Language:
English
Publisher:
The Company of Biologists
Publication Date:
2015
detail.hit.zdb_id:
2007916-3
SSG:
12
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