Divergent upstream osteogenic events contribute to the differential modulation of MG63 cell osteoblast differentiation by MMP-1 (collagenase-1) and MMP-13 (collagenase-3)

Abstract

Previously we showed that MMP-1 (collagenase-1) and MMP-13 (collagenase-3) differentially regulate the expression of osteoblastic markers in a heterogenous population of primary human periodontal ligament cells. The mechanisms for these differential responses are not known, but may result from divergence in regulation of early osteogenic transcription factors. The purpose of this study was to elucidate where in the hierarchy of osteoblast-specific transcription factors and markers the differences in MMP-1- and -13-mediated regulation of osteoblastic differentiation arise. We found that the overexpression of MMP-1 resulted in significant decreases in BMP-2, Dlx5, AP, OP and BSP and increases in TGF-β1 and MSX2. In contrast, MMP-13 overexpression resulted in significant decreases in Runx2, OP and BSP, and increases in TGF-β1, MSX2 and OC. The knockdown of MMP-1 caused significant increases in all osteoblastic markers. MMP-13 knockdown produced significant increases only in TGF-β1, MSX2 and Osx, but decreases in Runx2 and OC. Suppression of both MMPs together resulted in significant increases of all osteoblastic markers except Runx2. MMP-1 had a more robust and generalized effect in regulating osteoblast transcription factors and markers than MMP-13. Finally, of the markers and transcription factors assayed, Runx2 is the most early stage transcription factor induced by suppression of MMP-1, while Osx and MSX2 are the most early stage transcription factors regulated by MMP-13. These data show that MMP-1’s and -13’s differential regulation of osteoblastic markers in MG63 cells likely results from their modulation of divergent signaling pathways involved in osteoblastic differentiation.

bFGF and JAGGED1 regulate alkaline phosphatase expression and mineralization in dental tissue-derived mesenchymal stem cells

“…In this regard, the osteogenic differentiation was associated with the MMP1 downregulation [Hayami et al, ]. In addition, the inhibition of MMP expression resulted in the enhancement of ostegenic marker gene expression [Hayami et al, ]. In the present study, we noted the attenuation effect of bFGF on MMP expression, implying another potential mechanism of bFGF on mineralization.…”

Controlled Release of Simvastatin from In situ Forming Hydrogel Triggers Bone Formation in MC3T3-E1 Cells

“…Here, we demonstrated that incubation of 1 and 3 mg/ml SIM-loaded GPT-hydrogel with cultured MC3T3-E1 cells produced no detectable cytotoxicity yet provided a complete osteogenic differentiation for 14 days. As known, MMP-13 was considered to be an important factor in bone matrix turnover during bone formation/remodeling and also a marker for mature osteoblasts (45). Therefore, the observed elevation in MMP-13 expression, fibronectin, and procollagen gene activation could foster an increased collagen synthesis and osteoblast recruitment associated with local SIM-induced bone growth (46,47).…”

Identification of Putative Target Genes of the Transcription Factor RUNX2

“…Both are previously known targets of RUNX2 [39,40], and encode proteins involved in bone development [41]. …”