Transcriptional Induction of Matrix Metalloproteinase-13 (Collagenase-3) by 1α,25-Dihydroxyvitamin D3 in Mouse Osteoblastic MC3T3-E1 Cells

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Abstract
The removal of unmineralized matrix from the bone surface is essential for the initiation of osteoclastic bone resorption because osteoclasts cannot attach to the unmineralized osteoid. Matrix metalloproteinases (MMPs) are known to digest bone matrix. We recently reported that among the MMPs expressed in mouse osteoblastic cells, MMP-13 (collagenase-3) was the one most predominantly up-regulated by bone resorbing factors including 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3]. In this study, we examined the mechanism of regulation of MMP-13 expression by 1alpha,25(OH)2D3 in mouse osteoblastic MC3T3-E1 cells. 1Alpha,25(OH)2D3 increased steady-state messenger RNA (mRNA) and protein levels of MMP-13. De novo protein synthesis was essential for the induction because cycloheximide (CHX) decreased the effect of 1alpha,25(OH)2D3 on the MMP-13 mRNA level. 1Alpha,25(OH)2D3 did not alter the decay of MMP-13 mRNA in transcriptionally arrested MC3T3-E1 cells; however, it increased the MMP-13 heterogeneous nuclear RNA (hnRNA) level and MMP-13 transcriptional rate. The binding activity of nuclear extracts to the AP-1 binding site, but not to the Cbfa1 binding site, in the MMP-13 promoter region was up-regulated by 1alpha,25(OH)2D3, suggesting the mediation of AP-1 in this transcriptional induction. To determine the contribution of MMPs to bone resorption by 1alpha,25(OH)2D3, the inhibitory effect of BB94, an MMP inhibitor, on resorbed pit formation by mouse crude osteoclastic cells was examined on either an uncoated or collagen-coated dentine slice. BB94 did not prevent resorbed pit formation on uncoated dentine whereas it did on collagen-coated dentine. We therefore propose that the transcriptional induction of MMP-13 in osteoblastic cells may contribute to the degradation of unmineralized matrix on the bone surface as an early step of bone resorption by 1alpha,25(OH)2D3.

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