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Published 1 March 2004. doi:10.1083/jcb.200312045
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 164, Number 5, 747-758
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Article

Sox5 and Sox6 are needed to develop and maintain source, columnar, and hypertrophic chondrocytes in the cartilage growth plate



Patrick Smits, Peter Dy, Srijeet Mitra, and Véronique Lefebvre

Department of Biomedical Engineering and Orthopaedic Research Center, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195

Address correspondence to Véronique Lefebvre, Dept. of Biomedical Engineering, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Ave., ND-20, Cleveland, OH 44195. Tel.: (216) 445-0762. Fax: (216) 444-9198. email: lefebvrv{at}bme.ri.ccf.org

Sox5 and Sox6 encode Sry-related transcription factors that redundantly promote early chondroblast differentiation. Using mouse embryos with three or four null alleles of Sox5 and Sox6, we show that they are also essential and redundant in major steps of growth plate chondrocyte differentiation. Sox5 and Sox6 promote the development of a highly proliferating pool of chondroblasts between the epiphyses and metaphyses of future long bones. This pool is the likely cellular source of growth plates. Sox5 and Sox6 permit formation of growth plate columnar zones by keeping chondroblasts proliferating and by delaying chondrocyte prehypertrophy. They allow induction of chondrocyte hypertrophy and permit formation of prehypertrophic and hypertrophic zones by delaying chondrocyte terminal differentiation induced by ossification fronts. They act, at least in part, by down-regulating Ihh signaling, Fgfr3, and Runx2 and by up-regulating Bmp6. In conclusion, Sox5 and Sox6 are needed for the establishment of multilayered growth plates, and thereby for proper and timely development of endochondral bones.

Key Words: chondrogenesis; development; differentiation; mouse; transcription factor

Abbreviations used in this paper: BMP, bone morphogenetic protein; E, embryonic day; NA, null allele.


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