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Molecular and Cellular Biology, February 2005, p. 1191-1199, Vol. 25, No. 3
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.3.1191-1199.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

TIEG1 Null Mouse-Derived Osteoblasts Are Defective in Mineralization and in Support of Osteoclast Differentiation In Vitro

Malayannan Subramaniam,^1* Genevieve Gorny,¹ Steven A. Johnsen,² David G. Monroe,¹ Glenda L. Evans,³ Daniel G. Fraser,⁴ David J. Rickard,⁵ Kay Rasmussen,¹ Jan M. A. van Deursen,⁶ Russell T. Turner,³ Merry Jo Oursler,⁴ and Thomas C. Spelsberg¹

Department of Biochemistry and Molecular Biology,¹ Orthopedic Research,³ Department of Pediatric and Adolescent Medicine,⁴ Division of Endocrinology, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota,⁶ Zentrum für Molekulare Neurobiologie, Universität Hamburg, Hamburg, Germany,² Musculoskeletal Diseases Biology, GlaxoSmithKline, Collegeville, Pennsylvania⁵

Received 25 May 2004/ Returned for modification 4 August 2004/ Accepted 4 November 2004

Transforming growth factor ß-inducible early gene 1 (TIEG1) is a member of the Krüppel-like transcription factor family. To understand the physiological role of TIEG1, we generated TIEG^–/– (null) mice and found that the TIEG^–/– mice had increased osteoblast numbers with no increased bone formation parameters. However, when calvarial osteoblasts (OBs) were isolated from neonatal TIEG^–/– and TIEG^+/+ mice and cultured in vitro, the TIEG^–/– cells displayed reduced expression of important OB differentiation markers. When the OBs were differentiated in vitro by treatment with bone morphogenic protein 2, the OBs from TIEG^+/+ calvaria displayed several mineralized nodules in culture, whereas those from TIEG^–/– mice showed no nodules. To characterize the OBs' ability to support osteoclast differentiation, the OBs from TIEG^+/+ and TIEG^–/– mice were cultured with marrow and spleen cells from TIEG^+/+ mice. Significantly fewer osteoclasts developed when TIEG^–/– OBs were used to support osteoclast differentiation than when TIEG^+/+ OBs were used. Examination of gene expression in the TIEG^–/– OBs revealed decreased RANKL and increased OPG expression compared to TIEG^+/+ OBs. The addition of RANKL to these cocultures only partially restored the ability of TIEG^–/– OBs to support osteoclast differentiation, whereas M-CSF alone or combined with RANKL had no additional effect on osteoclast differentiation. We conclude from these data that TIEG1 expression in OBs is critical for both osteoblast-mediated mineralization and osteoblast support of osteoclast differentiation.

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* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, 1601B Guggenheim Bldg., Mayo Clinic College of Medicine, 200 First St., S.W., Rochester, MN 55905. Phone: (507) 284-4909. Fax: (507) 284-2053. E-mail: subramaniam.malayannan{at}mayo.edu.

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Molecular and Cellular Biology, February 2005, p. 1191-1199, Vol. 25, No. 3
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.3.1191-1199.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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