Skeletal growth is enhanced by a shared role for SOX8 and SOX9 in promoting reserve chondrocyte commitment to columnar proliferation.

Abstract

SOX8 was linked in a genome-wide association study to human height heritability, but roles in chondrocytes for this close relative of the master chondrogenic transcription factor SOX9 remain unknown. We undertook here to fill this knowledge gap. High-throughput assays demonstrate expression of human <i>SOX8</i> and mouse <i>Sox8</i> in growth plate cartilage. In situ assays show that <i>Sox8</i> is expressed at a similar level as <i>Sox9</i> in reserve and early columnar chondrocytes and turned off when <i>Sox9</i> expression peaks in late columnar and prehypertrophic chondrocytes. <i>Sox8^-/-</i> mice and <i>Sox8^fl/flPrx1Cre</i> and <i>Sox9^fl/+Prx1Cre</i> mice (inactivation in limb skeletal cells) have a normal or near normal skeletal size. In contrast, juvenile and adult <i>Sox8^fl/flSox9^fl/+Prx1Cre</i> compound mutants exhibit a 15 to 20% shortening of long bones. Their growth plate reserve chondrocytes progress slowly toward the columnar stage, as witnessed by a delay in down-regulating <i>Pthlh</i> expression, in packing in columns and in elevating their proliferation rate. <i>SOX8</i> or <i>SOX9</i> overexpression in chondrocytes reveals not only that SOX8 can promote growth plate cell proliferation and differentiation, even upon inactivation of endogenous <i>Sox9</i>, but also that it is more efficient than SOX9, possibly due to greater protein stability. Altogether, these findings uncover a major role for SOX8 and SOX9 in promoting skeletal growth by stimulating commitment of growth plate reserve chondrocytes to actively proliferating columnar cells. Further, by showing that SOX8 is more chondrogenic than SOX9, they suggest that SOX8 could be preferred over SOX9 in therapies to promote cartilage formation or regeneration in developmental and degenerative cartilage diseases.