Dual effects of heparin on BMP-2-induced osteogenic activity in MC3T3-E1 cells

Shin Kanzaki, Wataru Ariyoshi, Tetsu Takahashi, Toshinori Okinaga, Takeshi Kaneuji, Sho Mitsugi, Keisuke Nakashima, Toshiyuki Tsujisawa, Tatsuji Nishihara

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Heparin displays several types of biological activities by binding to various extracellular molecules, including pivotal roles in bone metabolism. We have previously reported that heparin competitively inhibits the binding activity of bone morphogenic protein-2 (BMP-2) to BMP and the BMP receptor (BMPR) and suppresses BMP-2 osteogenic activity. In the present study, we examined whether heparin affects osteoblast differentiation induced by BMP-2 at various time points in vitro. We found that 72 h of treatment with heparin inhibited alkaline phosphatase (ALP) activity. However, 144 h of treatment enhanced the ALP activity in BMP-2-stimulated MC3T3-E1 cells. Although heparin decreased the phosphorylation of Smad1/5/8 after 0.5 h of culture, prolonged periods of culture with heparin enhanced the Smad phosphorylation. In addition, 72 h of treatment with heparin enhanced the mRNA expression of runx2 and osterix in BMP-2-stimulated MC3T3-E1 cells. Furthermore, them RNA expression of BMP antagonists and inhibitory Smads induced by BMP-2 was preferentially blocked by heparin at the 24 and 48 h time points. These findings indicate biphasic effects of heparin on BMP-2 activity and suggest that heparin has complex effects on the BMP-2 osteogenic bioactivities. Prolonged culture with heparin stimulated BMP-2-induced osteogenic activity via down-regulation of BMP-2 antagonists and inhibitory Smads.

Original languageEnglish
Pages (from-to)1222-1230
Number of pages9
JournalPharmacological Reports
Volume63
Issue number5
DOIs
Publication statusPublished - 2011 Jan 1
Externally publishedYes

Keywords

  • BMP-2
  • Heparin
  • Osteoblast
  • Osterix
  • Runx2
  • Smad

ASJC Scopus subject areas

  • Pharmacology

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  • Cite this

    Kanzaki, S., Ariyoshi, W., Takahashi, T., Okinaga, T., Kaneuji, T., Mitsugi, S., Nakashima, K., Tsujisawa, T., & Nishihara, T. (2011). Dual effects of heparin on BMP-2-induced osteogenic activity in MC3T3-E1 cells. Pharmacological Reports, 63(5), 1222-1230. https://doi.org/10.1016/S1734-1140(11)70642-9