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¹ Department of Physiology, The University of Western Ontario, London, Ontario, Canada N6A 5C1
² Retinoid Research, Department of Chemistry and Department of Biology, Allergan Inc., Irvine, CA 92623
³ Department of Pharmacology and Department of Oncology, Faculty of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 5C1
⁴ School of Dentistry, Faculty of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 5C1

Address correspondence to T. Michael Underhill, CIHR Group in Skeletal Development and Remodeling, School of Dentistry, Faculty of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada, N6A 5C1. Tel.: (519) 661-2111, ex. 86111. Fax: (519) 850-2316. E-mail: tunderhi{at}uwo.ca

Chondrogenesis is a multistep process culminating in the establishment of a precisely patterned template for bone formation. Previously, we identified a loss in retinoid receptor–mediated signaling as being necessary and sufficient for expression of the chondroblast phenotype (Weston et al., 2000. J. Cell Biol. 148:679–690). Here we demonstrate a close association between retinoic acid receptor (RAR) activity and the transcriptional activity of Sox9, a transcription factor required for cartilage formation. Specifically, inhibition of RAR-mediated signaling in primary cultures of mouse limb mesenchyme results in increased Sox9 expression and activity. This induction is attenuated by the histone deacetylase inhibitor, trichostatin A, and by coexpression of a dominant negative nuclear receptor corepressor-1, indicating an unexpected requirement for RAR-mediated repression in skeletal progenitor differentiation.

Inhibition of RAR activity results in activation of the p38 mitogen-activated protein kinase (MAPK) and protein kinase A (PKA) pathways, indicating their potential role in the regulation of chondrogenesis by RAR repression. Accordingly, activation of RAR signaling, which attenuates differentiation, can be rescued by activation of p38 MAPK or PKA. In summary, these findings demonstrate a novel role for active RAR-mediated gene repression in chondrogenesis and establish a hierarchical network whereby RAR-mediated signaling functions upstream of the p38 MAPK and PKA signaling pathways to regulate emergence of the chondroblast phenotype.

Key Words: chondrogenesis; Sox9; p38 MAPK; protein kinase A; nuclear corepressors

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