Disease relevance of Runx2

• These interactions between Runx2 and C/EBPdelta, and their activation by prostaglandin E(2), provide new evidence for their importance during skeletal remodeling, inflammatory bone disease, or fracture repair [1].
• Altered Cbfa1 expression and biomineralization in an osteosarcoma cell line [2].

High impact information on Runx2

• Here, we have combined transient-overexpression, coimmunoprecipitation, in situ colocalization, chromatin immunoprecipitation, and glutathione S-transferase pull-down analyses to demonstrate that in osteoblastic cells expressing OC, VDR interacts directly with Runx2 bound to site B, which is located immediately adjacent to the VDRE [3].
• This mechanism involves the intersection of two major pathways: Runx2, a "master" transcriptional regulator of osteoblast differentiation, and 1alpha,25-dihydroxyvitamin D3, a hormone that promotes expression of genes associated with these terminally differentiated bone cells [3].
• Bone-specific transcription factor Runx2 interacts with the 1alpha,25-dihydroxyvitamin D3 receptor to up-regulate rat osteocalcin gene expression in osteoblastic cells [3].
• Together, our results indicate that Runx2 plays a key role in the 1alpha,25-dihydroxyvitamin D3-dependent stimulation of the OC promoter in osteoblastic cells by further stabilizing the interaction of the VDR with the VDRE [3].
• This stimulatory effect requires intact Runx2/Cbfa1 binding sites and the vitamin D-responsive element [4].

Biological context of Runx2

• Stronger Runx2 mRNA signals in subchondral bone corresponded with the increase in the recruitment of osteoblasts and chondroclasts, which preceded the increase of new bone formation in the condyle [5].
• Exposure to prostaglandin E(2) increased Runx-dependent gene transactivation independently of Runx2 binding to DNA [1].
• Overexpression of AJ18 suppressed Runx2-mediated transactivation of an osteocalcin promoter construct in transient transfection assays and reduced alkaline phosphatase activity in bone morphogenetic protein-induced C3H10T1/2 cells [6].
• These studies, therefore, have identified a novel zinc finger transcription factor in bone that can modulate Runx2 activity and osteogenic differentiation [6].
• This region of the C/EBPdelta promoter directed high reporter gene expression in osteoblasts, and specifically bound Runx2 in osteoblast-derived nuclear extract [1].

Anatomical context of Runx2

• TNAP-positive cells in the dental follicle localized nearer to alveolar bone than Runx2-positive cells [7].
• We tested the hypothesis that Runx2 is responsible for signaling chondrocyte maturation and endochondral ossification in the condyle during mandibular advancement [5].
• Thus, Runx2 mediates chondrocyte terminal maturation and endochondral ossification in the mandibular condyle in response to mandibular advancement [5].
• To address these limitations, retroviral gene delivery was used to examine the effects of sustained and elevated expression of the Runx2 osteoblastic transcription factor on osteoblastic gene and protein expression and mineralization in primary rat bone marrow stromal cells [8].
• Here we investigated whether and to what extent the MAPK (JNK/ERK)-AP-1/Runx2 signaling pathways are engaged in this phenomenon, and assessed their involvement in the functional biology of articular cartilage [9].

Associations of Runx2 with chemical compounds

• Runx2 integrates estrogen activity in osteoblasts [10].
• Unlike the stimulatory effect of estrogen and the inhibitory effect of glucocorticoid, androgen fails to increase Runx2 activity, whereas Runx2 potently suppresses gene expression induced by all three steroids [10].
• Osteoblast differentiation markers (Runx2, collagen alpha1 type I [COLI], alkaline phosphatase [ALP], osteocalcin [OCN]) were analyzed using quantitative RT-PCR [11].
• Additionally, the transcriptional co-activator p300 is recruited to the OC promoter by Runx2 where it up-regulates both basal and 1alpha,25-dihydroxy Vitamin D3-enhanced OC expression [12].
• These additive effects suggest complementary interactions between Runx2 and dexamethasone-responsive regulatory factors [8].

Physical interactions of Runx2

• Consistent with this interaction, the stimulatory effect of estrogen on Runx2 activity is lost when the DNA binding domain of the estrogen receptor is eliminated [10].
• C/EBPdelta gene promoter activity was reduced by mutating the Runx binding sequence or by co-transfecting with Runx2 antisense expression plasmid, and was enhanced by overexpression of Runx-2 [1].

Regulatory relationships of Runx2

• The isoform Runx2 (previously termed CBFa1) is highly expressed by osteoblasts and regulates expression of the TGF-beta receptor I in these cells [13].
• In conclusion, this study demonstrates that BMP-2 and TGFbeta1 suppress collagenase-3 promoter activity in osteoblasts and establishes a link between BMP-2 action and collagenase-3 expression via Runx2, a major regulator of osteoblast formation and function [14].

Other interactions of Runx2

• We further identified ligand-independent physical interaction between Smad2 and Runx2 [15].
• Cotransfection of Smad2 and Runx2 constructs had a cooperative effect on TGF-beta 1-stimulated collagenase-3 promoter activity in these cells [15].
• We have shown for the first time that Runx2 (a bone transcription factor and a potential substrate for the MAPK pathway) is phosphorylated in response to TGF-beta 1 treatment in osteoblastic cells [15].
• This interaction contributes significantly to 1alpha,25-dihydroxyvitamin D3-dependent enhancement of the OC promoter and requires a region located C terminal to the runt homology DNA binding domain of Runx2 and the N-terminal region of VDR [3].
• Estrogen receptor and Runx2 can be collected by co-immunoprecipitation [10].

Analytical, diagnostic and therapeutic context of Runx2

• Mandibular advancement elicited Runx2 expression in condylar cartilage, and subsequently led to an expansion of type X collagen domain in the hypertrophic layer [5].
• Skeletal unloading rapidly (4-7 days) decreased osteoblast transcription factor Runx2, osteocalcin (OC), and type I collagen messenger RNA (mRNA) levels and reduced bone formation in the long bone metaphysis [16].
• Synergy between genetic and tissue engineering: Runx2 overexpression and in vitro construct development enhance in vivo mineralization [17].
• Finally, Runx2 overexpression and in vitro construct development synergistically enhanced in vivo mineralization compared with in vitro construct development or genetic engineering alone [17].
• To ascertain whether implanted Cbfa1 overexpressing cells could differentiate into osteogenic cells to create bone or whether it stimulated the surrounding recipient tissue to regenerate bone, implanted male donor cells were visualized by fluorescent in situ hybridization analysis [18].

References