EXPRESSION OF THE PEBP2-ALPHA-A AML3/CBFA1 GENE IS REGULATED BY BMP4/7 HETERODIMER AND ITS OVEREXPRESSION SUPPRESSES TYPE-I COLLAGEN AND OSTEOCALCIN GENE-EXPRESSION IN OSTEOBLASTIC AND NONOSTEOBLASTIC MESENCHYMAL CELLS/

PEBP2 alpha A/AML3/CBFA1 is one of the transcription regulators that b elong to the PEBP2/AML family, The knockout mice, where the gene encod ing PEBP2 alpha A/AML3/CBFA1 was inactivated, showed no osteogenesis, indicating the critical role of this transcription factor in osteoblas tic differentiation (Komori, Y. et al, Cell 89:755-764; 1997), The aim of this study is to examine the regulation of PEBP2 alpha A/AML3/CBFA 1 expression in skeletal (MC3T3E1, ROS17/2.8) and nonskeletal (C3H10T1 /2, C2C12, NIH3T3) cell lines, The basal levels of PEBP2 alpha A/AML3/ CBFA1 were time dependent and were increased during culture in ROS17/2 .8 by day 2, remaining similar during cultures in other types of cells , Treatment with a 100-ng/mL BMP4/7 heterodimer enhanced the expressio n of PEBP2 alpha A/AML3/CBFA1 mRNA levels in MC3T3E1 and C2C12 cells, whereas BMP2 did not significantly alter PEBP2 alpha A/AML3/CBFA1 mRNA levels in both skeletal and nonskeletal cells, The PEBP2 alpha A/AML3 /CBFA1 mRNA level in ROS17/2.8 cells was relatively high on day 2, and was not further enhanced by treatment with BMP4/7, In contrast to the reported type I collagen gene upregulation by the overexpression of O sf2/CBFA1, which differs from PEBP2 alpha A/AML3/CBFA1 by containing a unique 87 amino acid sequence at its amino terminal end, overexpressi on of PEBP2 alpha A/AML3/ CBFA1 suppressed type I collagen mRNA levels in MC3T3E1, C2C12, and C3H10T1/2 cells and suppressed osteocalcin mRN A levels in ROS17/2.8 cells, The osteopontin mRNA level was enhanced b y overexpression of PEBP2 alpha A/AML3/CBFA1 in MC3T3E1, while the lev el was similar in ROS17/2.8 cells and was suppressed in C2C12 cells, T hese data indicate that PEBP2 alpha A/AML3/CBFA1 is one of the targets of BMP4/7 and participates in the regulation of the expression of gen es related to osteoblast phenotype, The overexpression study suggests that PEBP2 alpha A/AML3/CBFA1 and Osf2/CBFA1 may have a different func tion in the regulation of the expression of the genes related to the o steoblast phenotype. (C) 1998 by Elsevier Science Inc. All rights rese rved.