Corin is a key regulator of endochondral ossification and bone development via modulation of vascular endothelial...

Corin has been studied extensively within the vascular system and is known to regulate blood pressure. We have shown that corin is one of the most highly upregulated genes during osteogenic differentiation of human adipose-derived stem cells (hASCs). This study tested the hypothesis that, through modulation of angiogenic signalling pathways, corin is a critical regulator of osteogenic differentiation and endochondral ossification. In vitro, corin expression in hASC was suppressed via siRNA knockdown and vascular endothelial growth factor A (VEGF-A) expression was quantified via reverse transcription polymerase chain reaction. In vivo, a murine corin knockout model (female, 10 weeks) was used to determine the effect of corin deficiency on long bone development. Wild-type and corin knockout long bones were compared via haematoxylin and eosin staining to assess tissue characteristics and cellular organization, three-point bending to assess mechanical characteristics, and immunohistochemistry to visualize VEGF-A expression patterns. Corin knockdown significantly (p < 0.05) increased VEGF-A mRNA expression during osteogenic differentiation. In vivo, corin knockout reduced tibial growth plate thickness (p < 0.01) and severely diminished the hypertrophic region. Corin knockout femurs had significantly increased stiffness (p < 0.01) and maximum loads (p < 0.01) but reduced postyield deflections (p < 0.01). In corin knockout mice, VEGF-A expression was increased near the growth plate but was reduced throughout the tibial shaft and distal head of the tibiae. This is the first study to show that corin is a key regulator of bone development by modulation of VEGF-A expression. Further elucidation of this mechanism will aid in the development of optimized bone tissue engineering and regenerative medicine therapies.