Logo image
Back
P450 oxidoreductase expressed in rat chondrocytes modulates chondrogenesis via cholesterol- and Indian Hedgehog-dependent mechanisms
Journal article   Open access   Peer reviewed

P450 oxidoreductase expressed in rat chondrocytes modulates chondrogenesis via cholesterol- and Indian Hedgehog-dependent mechanisms

Alexandra Aguilar, Shufang Wu, Francesco De Luca and Francesco DeLuca
Endocrinology (Philadelphia), v 150(6), pp 2732-2739
Jun 2009
DOI: https://doi.org/10.1210/en.2009-0043
PMID: 19264869
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1210/en.2009-0043View
Published, Version of Record (VoR)Maybe Open Access (Publisher Bronze),  Open

Abstract

Animals Apoptosis - drug effects Apoptosis - physiology Cell Differentiation - drug effects Cell Differentiation - physiology Cell Proliferation - drug effects Cells, Cultured Cholesterol - metabolism Chondrocytes - cytology Chondrocytes - drug effects Chondrocytes - metabolism Chondrogenesis - physiology Hedgehog Proteins - metabolism Hedgehog Proteins - pharmacology Humans Mice NADPH-Ferrihemoprotein Reductase - genetics NADPH-Ferrihemoprotein Reductase - metabolism Rats Rats, Sprague-Dawley Recombinant Proteins - pharmacology RNA, Messenger - metabolism RNA, Small Interfering - genetics RNA, Small Interfering - metabolism Signal Transduction - physiology Transfection
Cytochrome P450 oxidoreductase (POR) is the electron donor for microsomal cytochrome P450 enzymes and other non-P450 enzymes. Targeted deletion of POR expression in mice leads to a variety of embryonic defects, including bone abnormalities. In addition, POR mutations in humans are associated with impaired steroidogenesis and skeletal malformations. Yet, little is known on the mechanisms underlying the skeletal abnormalities secondary to impaired POR activity. In our study, rat chondrocytes transfected with POR-specific short interfering RNAs exhibited decreased cell proliferation and differentiation and induced apoptosis. In addition, the reduced expression of POR in chondrocytes caused decreased intracellular cholesterol content. The addition of cholesterol in the culture medium prevented the POR small interfering RNA (siRNA)-mediated effects on chondrocyte proliferation, differentiation, and apoptosis. Because cholesterol is required for normal activity of the hedgehog proteins, we evaluated the effects of POR siRNAs on the expression of Indian hedgehog (Ihh), an important regulator of chondrogenesis. POR siRNA-transfected chondrocytes exhibited reduced Ihh expression, with such effect being neutralized by cholesterol. Lastly, recombinant human/mouse Ihh prevented the POR siRNA-mediated effects on chondrocyte proliferation, differentiation, and apoptosis. Our findings suggest that the bone malformations associated with defective POR activity are due to reduced cholesterol synthesis and, in turn, reduced Ihh expression in chondrocytes.

Metrics

8 Record Views
16 citations in Web of Science
20 citations in Scopus

Details

UN Sustainable Development Goals (SDGs)

This publication has contributed to the advancement of the following goals:

#3 Good Health and Well-Being

InCites Highlights

Data related to this publication, from InCites Benchmarking & Analytics tool:

Collaboration types
Domestic collaboration
International collaboration
Web of Science research areas
Endocrinology & Metabolism
Logo image