Collagenase 3 is a target of Cbfa1, a transcription factor of the runt gene family involved in bone formation

Collagenase 3 (MMP-13) is a recently identified member of the matrix metall oproteinase (MMP) gene family that is expressed at high levels in diverse h uman carcinomas and in articular cartilage from arthritic patients. In addi tion to its expression in pathological conditions, collagenase 3 has been d etected in osteoblasts and hypertrophic chondrocytes during fetal ossificat ion. In this work, we have evaluated the possibility that Cbfa1 (core bindi ng factor 1), a transcription factor playing a major role in the expression of osteoblastic specific genes, is involved in the expression of collagena se 3 during bone formation. We have functionally characterized a Cbfa motif present in the promoter region of collagenase 3 gene and demonstrated, by cotransfection experiments and gel mobility shift assays, that this element is involved in the inducibility of the collagenase 3 promoter by Cbfa1 in osteoblastic and chondrocytic cells. Furthermore, overexpression of Cbfa1 i n osteoblastic cells unable to produce collagenase 3 leads to the expressio n of this gene after stimulation with transforming growth factor beta, Fina lly, we show that mutant mice deficient in Cbfa1, lacking mature osteoblast s but containing hypertrophic chondrocytes which are also a major source of collagenase 3, do not express this protease during fetal development. Thes e results provide in vivo evidence that collagenase 3 is a target of the tr anscriptional activator Cbfa1 in these cells. On the basis of these transcr iptional regulation studies, together with the potent proteolytic activity of collagenase 3 on diverse collagenous and noncollagenous bone and cartila ge components, we proposed that this enzyme may play a key role in the proc ess of bone formation and remodeling.