The orphan nuclear receptor SHP is a positive regulator of osteoblastic bone formation.
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.
Jeong
Byung-Chul
BC
Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea.
Lee
Yong-Soo
YS
Bae
In-Ho
IH
Lee
Chul-Ho
CH
Shin
Hong-In
HI
Ha
Hyun Jung
HJ
Franceschi
Renny T
RT
Choi
Hueng-Sik
HS
Koh
Jeong-Tae
JT
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology*; D010012:Osteogenesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*
C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D050659:Core Binding Factor Alpha 1 Subunit; D018160:Receptors, Cytoplasmic and Nuclear; C493716:Runx2 protein, mouse; C099713:nuclear receptor subfamily 0, group B, member 2; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases