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
Highlights
The atypical orphan nuclear receptor (NR) small heterodimer partner (SHP) is a versatile protein with broad cellular functions
Activation of androgen receptors stimulates bone sialoprotein (BSP) gene transcription via cAMP response element (CRE) and AP1/glucocorticoid response elements (GRE).(23) Estrogen prevents bone loss via ERa,(24) and estrogen receptor–related receptor a (ERRa) regulates osteopontin expression through a noncanonical ERRa response element.[25]. In this study we investigated the effects of the orphan nuclear receptor, SHP in osteoblast differentiation, and our results show that SHP promotes osteoblast differentiation and bone formation via regulation of Runx2 transactivity
SHP is expressed in various tissues and involved in a complex regulatory network comprised of a variety of NRs and transcription factors.[2,3] To assess whether SHP might play a functional role in bone metabolism, the endogenous expression of SHP was examined in various progenitor cells
Summary
The atypical orphan nuclear receptor (NR) SHP is a versatile protein with broad cellular functions. SHP has a putative ligand-binding domain (LBD) that lacks a classic DNAbinding domain (DBD) and harbors two functional LXXLL-like motifs, which are typical of NR-binding proteins.[1] SHP interacts with various nuclear receptors and transcription factors, such as the estrogen receptor (ER), peroxisome proliferator–activated receptor (PPAR), retinoic acid receptor (RAR), liver X receptor (LXR), Nur, c-Jun, Smad, histone deacetylase 1 (HDAC1), and the Swi/Snf/mSin3a corepressor complex. Osteoblast differentiation is controlled by various hormones and cytokines, such as bone morphogenetic proteins (BMPs), and multiple transcription factors such as Runx, Osx, Dlx, Msx, Twist, AP1 (Fos/Jun), Krox-20, Sp3, and ATF4.(10,11) Among these, BMPs are the primary regulators of osteoblast differentiation.[12] As a member of the transforming growth
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