Original Article

The orphan nuclear receptor SHP is a positive regulator of osteoblastic bone formation

Byung-Chul Jeong 1, Yong-Soo Lee 2, In-Ho Bae 1, Chul-Ho Lee 3, Hong-In Shin 4, Hyun Jung Ha 5, Renny T Franceschi 6, Hueng-Sik Choi 2 *, Jeong-Tae Koh 1 *

1Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea 2Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea 3Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea 4Department of Oral Pathology and IHBR, School of Dentistry, Kyungpook National University, Daegu, Republic of Korea 5Department of Biochemistry, Biotechnology Research Institute, School of Life Sciences, Chungbuk National University, Cheongju, Republic of Korea 6Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA

email: Hueng-Sik Choi (hsc@chonnam.ac.kr) Jeong-Tae Koh (jtkoh@chonnam.ac.kr)

^*Correspondence to Hueng-Sik Choi, Hormone Research Center, Chonnam National University, Gwangju, 500-757, Republic of Korea.

^*Correspondence to Jeong-Tae Koh, Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, 500-757, Republic of Korea.

Keywords

Orphan nuclear receptor • small heterodimer partner (SHP) • osteoblast differentiation • bone morphogenetic protein (BMP) • Runx2

Abstract

The orphan nuclear receptor small heterodimer partner (SHP; NR0B2) interacts with a diverse array of transcription factors and regulates a variety of cellular events such as cell proliferation, differentiation, and metabolism. However, the role of SHP in bone formation has not yet been elucidated. SHP expression is significantly increased during osteoblast differentiation, and its expression is partially regulated by bone morphogenetic protein 2 (BMP-2), which plays an important role in bone formation. In our study, inhibition of SHP expression significantly repressed BMP-2-induced osteoblast differentiation and ectopic bone formation. In accordance with these in vitro and in vivo results, osteoblast differentiation in SHP-/- mice primary osteoblasts was significantly repressed, and the mice showed decreased bone mass resulting from decreased numbers of osteoblasts. Finally, SHP physically interacts and forms a complex with runt-related transcription factor 2 (Runx2) on the osteocalcin gene promoter, and overexpression of SHP increased Runx2 transactivity via competition with histone deacetylase 4 (HDAC4), an enzyme that inhibits DNA binding of Runx2 to its target genes. Taken together, these results indicate that SHP acts as a novel positive regulator of bone formation by augmenting osteoblast differentiation through regulation of the transcriptional activity of Runx2. © 2010 American Society for Bone and Mineral Research

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Received: 8 December 2008; Revised: 27 May 2009; Accepted: 6 July 2009

Digital Object Identifier (DOI)

10.1359/jbmr.090718  About DOI