Transcriptional regulation of bone formation by the osteoblast-specific transcription factor Osx

Zhang, Chi

doi:10.1186/1749-799x-5-37

Cited by 179 publications

(161 citation statements)

References 36 publications

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“…Thus, dosing, temporal, and spatial parameters of RNAi must be finely tuned. Temporally, Runx2 and Osx expression have been determined to peak within the first 72 hours after BMP stimulation [44]; furthermore, Runx2 expression is antecedent to Osx [69]. Thus, our RNAi treatments were engineered to deliver Runx2 siRNA 24 hours before and Osx siRNA simultaneously to rhBMP-2 administration.…”

Section: Discussionmentioning

confidence: 99%

Cationic Nanogel-mediated Runx2 and Osterix siRNA Delivery Decreases Mineralization in MC3T3 Cells

Shrivats

Hsu

Averick

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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Background Heterotopic ossification (HO) may occur after musculoskeletal trauma, traumatic brain injury, and total joint arthroplasty. As such, HO is a compelling clinical concern in both military and civilian medicine. A possible etiology of HO involves dysregulated signals in the bone morphogenetic protein osteogenic cascade. Contemporary treatment options for HO (ie, nonsteroidal antiinflammatory drugs and radiation therapy) have adverse effects associated with their use and are not biologically engineered to abrogate the molecular mechanisms that govern osteogenic differentiation. Questions/purposes We hypothesized that (1) nanogelmediated short interfering RNA (siRNA) delivery against Runt-related transcription factor 2 (Runx2) and osterix (Osx) genes will decrease messenger RNA expression; (2) inhibit activity of the osteogenic marker alkaline phosphatase (ALP); and (3) inhibit hydroxyapatite (HA) deposition in osteoblast cell cultures. Methods Nanogel nanostructured polymers delivered siRNA in 48-hour treatment cycles against master osteogenic regulators, Runx2 and Osx, in murine calvarial preosteoblasts (MC3T3-E1.4) stimulated for osteogenic differentiation by recombinant human bone morphogenetic protein (rhBMP-2). The efficacy of RNA interference (RNAi) therapeutics was determined by quantitation of messenger RNA knockdown (by quantitative reverse transcription-polymerase chain reaction), downstream protein knockdown (determined ALP enzymatic activity assay), and HA deposition (determined by OsteoImage TM assay). Results Gene expression assays demonstrated that nanogelbased RNAi treatments at 1:1 and 5:1 nanogel:short interfering RNA weight ratios reduced Runx2 expression by 48.59% ± 19.53% (p \ 0.001) and 43.22% ± 18.01% (both p \ 0.001). The same 1:1 and 5:1 treatments against both Runx2 and Osx reduced expression of Osx by 51.65% ± 10.85% and 47.65% ± 9.80% (both p \ 0.001). Moreover, repeated 48-hour RNAi treatment cycles against Runx2 and Osx rhBMP-2 administration reduced ALP activity after 4 and 7 days. ALP reductions after 4 days in culture by nanogel 5:1 and 10:1 RNAi treatments were 32.4% ± 12.0% and 33.6% ± 13.8% (both p \ 0.001). After 7 days in culture, nanogel 1:1 and 5:1 RNAi treatments produced 35.9% ± 14.0% and 47.7% ± 3.2% reductions in ALP activity. Osteoblast mineralization data after 21 days suggested that Two of the authors (ARS, EH) contributed equally.

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Section: Discussionmentioning

confidence: 99%

Cationic Nanogel-mediated Runx2 and Osterix siRNA Delivery Decreases Mineralization in MC3T3 Cells

Shrivats

Hsu

Averick

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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“…The expression of SOX9, SP7, RUNX2, TWIST1 and IHH was tested because these molecules serve as regulators of normal skeletal development and control lineagespecific tumor differentiation. [13][14][15][16][17] Unlike cDNA expression profiling, which reports the pooled molecular signature of all cells within a tumor, immunohistochemical profiling reveals the intratumoral distribution of protein expression, an advantage in polymorphic cellular populations.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms are complex and include combinatorial interactions of multiple molecules promoting osteoblast and chondrocyte differentiation. [13][14][15][16][17] Nevertheless, studies suggest that the signal transduction molecule Indian hedgehog (IHH), and the transcription factors SP7 (also known as osterix, OSX), sex-determining region Y-box 9 (SOX9), runt-related transcription factor 2 (RUNX2, also known as CBFA1) and TWIST1 regulate the differentiation of osteogenic and chondrogenic cells from mesenchymal precursors. 13,[18][19][20][21] Furthermore, the aberrant function of these same molecules has also been implicated in the pathogenesis of some bone tumors including osteosarcoma and giant cell tumor.…”

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confidence: 99%

Regulators of skeletal development: a cluster analysis of 206 bone tumors reveals diagnostically useful markers

et al. 2012

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The molecules Indian hedgehog (IHH), SP7 (also known as osterix), sex-determining region Y-box 9 (SOX9), runt-related transcription factor 2 (RUNX2) and TWIST1 regulate the normal differentiation of osteo-and chondrogenic cells from precursors during skeletal development and remodeling. The aberrant function of the same molecules has been implicated in the pathogenesis of bone tumors. Preliminary studies suggest that antibodies against these molecules have practical, diagnostic or prognostic utility in tumors. However, a comprehensive analysis of the expression of these molecules in a large, diverse set of bone tumors has yet to be reported. The goals of this study were to compare the immunohistochemical profiles of IHH, SP7, SOX9, RUNX2 and TWIST1 among bone tumors and to determine the optimum panel for diagnostic utility. Tissue microarrays prepared from 206 undecalcified tumors (71 osteosarcomas, 26 osteoblastomas/osteoid osteomas, 50 giant cell tumors, 5 chondromyxoid fibromas and 54 chondroblastomas) were stained with antibodies to IHH, SP7, SOX9, RUNX2 and TWIST1. The stains were scored for intensity (0À3 þ ) and distribution. The results were analyzed by cluster analysis. Optimum antibody panels for diagnostic sensitivity and specificity were calculated. Analysis revealed six main clusters that corresponded well to tumor types and suggested a close relationship between the stromal cells of giant cell tumor and the osteoblasts of osteosarcoma. The expression profile of chondromyxoid fibroma and chondroblastoma also suggested related differentiation. The distribution of osteoblastomas and osteoid osteomas was more heterogeneous. RUNX2, SOX9 and TWIST1 represented the most sensitive and specific immunohistochemical panel to distinguish among these diagnoses with the limitation that no result could discriminate between chondroblastoma and chondromyxoid fibroma. IHH and SP7 did not yield additional utility.

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“…6 Osterix (OSX) is essential for the differentiation of preosteoblasts into mature osteoblasts, and one study showed that it might be stimulated by estrogen. 7 OSX is also expressed in osteoblasts 8 and cementoblasts.…”

Section: Introductionmentioning

confidence: 99%

The role of Osterix protein in the pathogenesis of peripheral ossifying fibroma

et al. 2017

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Peripheral ossifying fibroma (POF) is a reactive lesion of oral tissues, associated with local factors such as trauma or presence of dental biofilm. POF treatment consists of curettage of the lesion combined with root scaling of adjacent teeth and/or removal of other sources of irritants. This study aimed to analyze the clinical and pathological features of POF and to investigate the immunoexpression of Osterix and STRO-1 proteins. Data such as age, gender, and size were obtained from 30 cases of POF. Microscopic features were assessed by conventional light microscopy using hematoxylin-eosin staining and immunohistochemical markers, and by polarized light microscopy using Picrosirius red staining. The age range was 11-70 years and 70% of the patients were female. Moreover, the size of POF varied from 0.2 to 5.0 cm; in 43.33% of the cases, the mineralized content consisted exclusively of bony trabeculae. The immunohistochemical analysis showed nuclear staining for Osterix in 63% and for STRO-1 in 20% of the cases. Mature collagen fibers were observed in mineralized tissue in 76.67% of the cases. The clinical and microscopic features observed were in agreement with those described in the literature. Osterix was overexpressed, while STRO-1 was poorly expressed. Osterix was expressed particularly in cells entrapped in and around mineralized tissue, indicating the presence of a stimulus that triggers the differentiation of these cells into osteoblasts or cementoblasts, i.e., cells that produce mineralized tissue. Based on our results, Osterix may play a role in the pathogenesis of POF.

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Transcriptional regulation of bone formation by the osteoblast-specific transcription factor Osx

Cited by 179 publications

References 36 publications

Cationic Nanogel-mediated Runx2 and Osterix siRNA Delivery Decreases Mineralization in MC3T3 Cells

Cationic Nanogel-mediated Runx2 and Osterix siRNA Delivery Decreases Mineralization in MC3T3 Cells

Regulators of skeletal development: a cluster analysis of 206 bone tumors reveals diagnostically useful markers

The role of Osterix protein in the pathogenesis of peripheral ossifying fibroma

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