Osteopenla in transgenic mice with osteoblast-targeted expression of the inducible camp early repressor

Yu-Feng Huang

Chung Shan Medical University, College of Oral Medicine, Department of Dentistry

ICER is a member of the CREM family of basic leucine zipper transcription factors that acts as a dominant negative regulator of gene transcription. Four different isoforms of ICER(I, Iγ, II and IIγ) are transcribed from the P2 promoter of the Crem gene. We previously found that each of the ICER isoforms is induced by parathyroid hormone in osteoblasts. That goal of the present study was to assess the function of ICER in bone by overexpressing ICER in osteoblasts of transgenic mine. ICER�TcDNA, containing an N-terminal FLAG epitope tag, was cloned downstream of a fragment containing 3.6 kb of the rat Col1a1 promoter and most of the rat Col1a1 first intron to produce pOBCol3.6-ICER I transgene, respectively. Multiple lines of ICER�Ttransgenic mice had lower body weights and decreased bone mineral density of femurs and vertebrae. Further studies were done with ICER �T transgenic mice, which had greatly reduced trabecular bone volume and a markedly decreased bone formation rate in femurs. Osteoblast differentiation and osteocalcin expression were reduced ex vivo bone marrow cultures from ICER�Ttransgenic mice. ICER�Tantagonized the activity of ATF4 at its consensus DNA binding site in the osteocalcin promoter in vitro. Thus, transgenic mice with osteoblast targeted overexpression of ICER exhibited osteopenia caused primarily by reduced bone formation. We speculate that ICER regulates the activity and/or expression of ATF/CREB factors required for normal bone formation.