NDLI: Control of chondrocyte gene expression by actin dynamics: a novel role of cholesterol/Ror-α signalling in endochondral bone growth

Content Provider	PubMed Central
Author	Woods, Anita James, Claudine G. Wang, Guoyan Dupuis, Holly Beier, Frank
Copyright Year	2009
Abstract	Elucidating the signalling pathways that regulate chondrocyte differentiation, such as the actin cytoskeleton and Rho GTPases, during development is essential for understanding of pathological conditions of cartilage, such as chondrodysplasias and osteoarthritis. Manipulation of actin dynamics in tibia organ cultures isolated from E15.5 mice results in pronounced enhancement of endochondral bone growth and specific changes in growth plate architecture. Global changes in gene expression were examined of primary chondrocytes isolated from embryonic tibia, treated with the compounds cytochalasin D, jasplakinolide (actin modifiers) and the ROCK inhibitor Y27632. Cytochalasin D elicited the most pronounced response and induced many features of hypertrophic chondrocyte differentiation. Bioinformatics analyses of microarray data and expression validation by real-time PCR and immunohistochemistry resulted in the identification of the nuclear receptor retinoid related orphan receptor-α (Ror-α) as a novel putative regulator of chondrocyte hypertrophy. Expression of Ror-α target genes, (Lpl, fatty acid binding protein 4 [Fabp4], Cd36 and kruppel-like factor 5 [Klf15]) were induced during chondrocyte hypertrophy and by cytochalasin D and are cholesterol dependent. Stimulation of Ror-α by cholesterol results in increased bone growth and enlarged, rounded cells, a phenotype similar to chondrocyte hypertrophy and to the changes induced by cytochalasin D, while inhibition of cholesterol synthesis by lovastatin inhibits cytochalasin D induced bone growth. Additionally, we show that in a mouse model of cartilage specific (Col2-Cre) Rac1, inactivation results in increased Hif-1α (a regulator of Rora gene expression) and Ror-α+ cells within hypertrophic growth plates. We provide evidence that cholesterol signalling through increased Ror-α expression stimulates chondrocyte hypertrophy and partially mediates responses of cartilage to actin dynamics.
Related Links	http://dx.doi.org/10.1111/j.1582-4934.2009.00684.x
Ending Page	3516
Page Count	20
Starting Page	3497
File Format	PDF
ISSN	15824934
e-ISSN	15824934
Journal	Journal of Cellular and Molecular Medicine
Issue Number	9b
Volume Number	13
Language	English
Publisher	John Wiley & Sons, Ltd
Publisher Date	2009-09-01
Access Restriction	Open
Rights Holder	John Wiley & Sons, Ltd
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Molecular Medicine

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