Cationic Nanogel-mediated Runx2 and Osterix siRNA Delivery Decreases Mineralization in MC3T3 Cells
Identifieur interne : 003A47 ( Main/Exploration ); précédent : 003A46; suivant : 003A48Cationic Nanogel-mediated Runx2 and Osterix siRNA Delivery Decreases Mineralization in MC3T3 Cells
Auteurs : Arun R. Shrivats [États-Unis] ; Eric Hsu [États-Unis] ; Saadyah Averick [États-Unis] ; Molly Klimak [États-Unis] ; April C. S. Watt [États-Unis] ; Marlene Demaio [États-Unis] ; Krzysztof Matyjaszewski [États-Unis] ; Jeffrey O. Hollinger [États-Unis]Source :
- Clinical Orthopaedics and Related Research [ 0009-921X ] ; 2014.
Descripteurs français
- KwdFr :
- Animaux, Calcification physiologique (), Cations, Cellules 3T3, Durapatite (métabolisme), Facteurs de transcription (génétique), Facteurs de transcription (métabolisme), Facteurs temps, Gels, Interférence par ARN, Marqueurs biologiques (métabolisme), Nanostructures, Ostéoblastes (), Ostéoblastes (métabolisme), Petit ARN interférent (génétique), Petit ARN interférent (métabolisme), Phosphatase alcaline (métabolisme), Poly(acides méthacryliques) (), Protéine morphogénétique osseuse de type 2 (pharmacologie), Régulation négative, Souris, Sous-unité alpha 1 du facteur CBF (génétique), Sous-unité alpha 1 du facteur CBF (métabolisme), Transfection ().
- MESH :
- génétique : Facteurs de transcription, Petit ARN interférent, Sous-unité alpha 1 du facteur CBF.
- métabolisme : Durapatite, Facteurs de transcription, Marqueurs biologiques, Ostéoblastes, Petit ARN interférent, Phosphatase alcaline, Sous-unité alpha 1 du facteur CBF.
- pharmacologie : Protéine morphogénétique osseuse de type 2.
- Animaux, Calcification physiologique, Cations, Cellules 3T3, Facteurs temps, Gels, Interférence par ARN, Nanostructures, Ostéoblastes, Poly(acides méthacryliques), Régulation négative, Souris, Transfection.
English descriptors
- KwdEn :
- 3T3 Cells, Alkaline Phosphatase (metabolism), Animals, Biomarkers (metabolism), Bone Morphogenetic Protein 2 (pharmacology), Calcification, Physiologic (drug effects), Cations, Core Binding Factor Alpha 1 Subunit (genetics), Core Binding Factor Alpha 1 Subunit (metabolism), Down-Regulation, Durapatite (metabolism), Gels, Mice, Nanostructures, Osteoblasts (drug effects), Osteoblasts (metabolism), Polymethacrylic Acids (chemistry), RNA Interference, RNA, Small Interfering (genetics), RNA, Small Interfering (metabolism), Time Factors, Transcription Factors (genetics), Transcription Factors (metabolism), Transfection (methods).
- MESH :
- chemical , chemistry : Polymethacrylic Acids.
- chemical , genetics : Core Binding Factor Alpha 1 Subunit, RNA, Small Interfering, Transcription Factors.
- chemical , metabolism : Alkaline Phosphatase, Biomarkers, Core Binding Factor Alpha 1 Subunit, Durapatite, RNA, Small Interfering, Transcription Factors.
- chemical , pharmacology : Bone Morphogenetic Protein 2.
- drug effects : Calcification, Physiologic, Osteoblasts.
- metabolism : Osteoblasts.
- methods : Transfection.
- 3T3 Cells, Animals, Cations, Down-Regulation, Gels, Mice, Nanostructures, RNA Interference, Time Factors.
Abstract
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.
We hypothesized that (1) nanogel-mediated short interfering RNA (siRNA) delivery against Runt-related transcription factor 2 (
Nanogel nanostructured polymers delivered siRNA in 48-hour treatment cycles against master osteogenic regulators,
Gene expression assays demonstrated that nanogel-based RNAi treatments at 1:1 and 5:1 nanogel:short interfering RNA weight ratios reduced
Although mRNA and protein knockdown were confirmed as a result of RNAi treatments against
Successful HO prophylaxis should target and silence osteogenic markers critical for heterotopic bone formation processes. The identification of such markers, beyond RUNX2 and OSX, may enhance the effectiveness of RNAi prophylaxes for HO.
Url:
DOI: 10.1007/s11999-014-4073-0
PubMed: 25448327
PubMed Central: 4418993
Affiliations:
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Le document en format XML
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>3T3 Cells</term>
<term>Alkaline Phosphatase (metabolism)</term>
<term>Animals</term>
<term>Biomarkers (metabolism)</term>
<term>Bone Morphogenetic Protein 2 (pharmacology)</term>
<term>Calcification, Physiologic (drug effects)</term>
<term>Cations</term>
<term>Core Binding Factor Alpha 1 Subunit (genetics)</term>
<term>Core Binding Factor Alpha 1 Subunit (metabolism)</term>
<term>Down-Regulation</term>
<term>Durapatite (metabolism)</term>
<term>Gels</term>
<term>Mice</term>
<term>Nanostructures</term>
<term>Osteoblasts (drug effects)</term>
<term>Osteoblasts (metabolism)</term>
<term>Polymethacrylic Acids (chemistry)</term>
<term>RNA Interference</term>
<term>RNA, Small Interfering (genetics)</term>
<term>RNA, Small Interfering (metabolism)</term>
<term>Time Factors</term>
<term>Transcription Factors (genetics)</term>
<term>Transcription Factors (metabolism)</term>
<term>Transfection (methods)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term>
<term>Calcification physiologique ()</term>
<term>Cations</term>
<term>Cellules 3T3</term>
<term>Durapatite (métabolisme)</term>
<term>Facteurs de transcription (génétique)</term>
<term>Facteurs de transcription (métabolisme)</term>
<term>Facteurs temps</term>
<term>Gels</term>
<term>Interférence par ARN</term>
<term>Marqueurs biologiques (métabolisme)</term>
<term>Nanostructures</term>
<term>Ostéoblastes ()</term>
<term>Ostéoblastes (métabolisme)</term>
<term>Petit ARN interférent (génétique)</term>
<term>Petit ARN interférent (métabolisme)</term>
<term>Phosphatase alcaline (métabolisme)</term>
<term>Poly(acides méthacryliques) ()</term>
<term>Protéine morphogénétique osseuse de type 2 (pharmacologie)</term>
<term>Régulation négative</term>
<term>Souris</term>
<term>Sous-unité alpha 1 du facteur CBF (génétique)</term>
<term>Sous-unité alpha 1 du facteur CBF (métabolisme)</term>
<term>Transfection ()</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Polymethacrylic Acids</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Core Binding Factor Alpha 1 Subunit</term>
<term>RNA, Small Interfering</term>
<term>Transcription Factors</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Alkaline Phosphatase</term>
<term>Biomarkers</term>
<term>Core Binding Factor Alpha 1 Subunit</term>
<term>Durapatite</term>
<term>RNA, Small Interfering</term>
<term>Transcription Factors</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Bone Morphogenetic Protein 2</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Calcification, Physiologic</term>
<term>Osteoblasts</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Facteurs de transcription</term>
<term>Petit ARN interférent</term>
<term>Sous-unité alpha 1 du facteur CBF</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Osteoblasts</term>
</keywords>
<keywords scheme="MESH" qualifier="methods" xml:lang="en"><term>Transfection</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Durapatite</term>
<term>Facteurs de transcription</term>
<term>Marqueurs biologiques</term>
<term>Ostéoblastes</term>
<term>Petit ARN interférent</term>
<term>Phosphatase alcaline</term>
<term>Sous-unité alpha 1 du facteur CBF</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Protéine morphogénétique osseuse de type 2</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>3T3 Cells</term>
<term>Animals</term>
<term>Cations</term>
<term>Down-Regulation</term>
<term>Gels</term>
<term>Mice</term>
<term>Nanostructures</term>
<term>RNA Interference</term>
<term>Time Factors</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Calcification physiologique</term>
<term>Cations</term>
<term>Cellules 3T3</term>
<term>Facteurs temps</term>
<term>Gels</term>
<term>Interférence par ARN</term>
<term>Nanostructures</term>
<term>Ostéoblastes</term>
<term>Poly(acides méthacryliques)</term>
<term>Régulation négative</term>
<term>Souris</term>
<term>Transfection</term>
</keywords>
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<front><div type="abstract" xml:lang="en"><sec><title>Background</title>
<p>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.</p>
</sec>
<sec><title>Questions/purposes</title>
<p>We hypothesized that (1) nanogel-mediated short interfering RNA (siRNA) delivery against Runt-related transcription factor 2 (<italic>Runx2</italic>
) and osterix (<italic>Osx</italic>
) 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.</p>
</sec>
<sec><title>Methods</title>
<p>Nanogel nanostructured polymers delivered siRNA in 48-hour treatment cycles against master osteogenic regulators, <italic>Runx2</italic>
and <italic>Osx</italic>
, 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™ assay).</p>
</sec>
<sec><title>Results</title>
<p>Gene expression assays demonstrated that nanogel-based RNAi treatments at 1:1 and 5:1 nanogel:short interfering RNA weight ratios reduced <italic>Runx2</italic>
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 <italic>Runx2</italic>
and <italic>Osx</italic>
reduced expression of <italic>Osx</italic>
by 51.65% ± 10.85% and 47.65% ± 9.80% (both p < 0.001). Moreover, repeated 48-hour RNAi treatment cycles against <italic>Runx2</italic>
and <italic>Osx</italic>
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 nanogel 1:1, 5:1, and 10:1 RNAi treatments decreased mineralization (ie, HA deposition) from cultures treated only with rhBMP-2 (p < 0.001). However, despite RNAi attack on <italic>Runx2</italic>
and <italic>Osx</italic>
, HA deposition levels remained greater than non-rhBMP-2-treated cell cultures.</p>
</sec>
<sec><title>Conclusions</title>
<p>Although mRNA and protein knockdown were confirmed as a result of RNAi treatments against <italic>Runx2</italic>
and <italic>Osx</italic>
, complete elimination of mineralization processes was not achieved. RNAi targeting mid- and late-stage osteoblast differentiation markers such as ALP, osteocalcin, osteopontin, and bone sialoprotein) may produce the desired RNAi-nanogel nanostructured polymer HO prophylaxis.</p>
</sec>
<sec><title>Clinical Relevance</title>
<p>Successful HO prophylaxis should target and silence osteogenic markers critical for heterotopic bone formation processes. The identification of such markers, beyond RUNX2 and OSX, may enhance the effectiveness of RNAi prophylaxes for HO.</p>
</sec>
</div>
</front>
</TEI>
<affiliations><list><country><li>États-Unis</li>
</country>
<region><li>Pennsylvanie</li>
<li>Virginie</li>
</region>
</list>
<tree><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Shrivats, Arun R" sort="Shrivats, Arun R" uniqKey="Shrivats A" first="Arun R." last="Shrivats">Arun R. Shrivats</name>
</region>
<name sortKey="Averick, Saadyah" sort="Averick, Saadyah" uniqKey="Averick S" first="Saadyah" last="Averick">Saadyah Averick</name>
<name sortKey="Demaio, Marlene" sort="Demaio, Marlene" uniqKey="Demaio M" first="Marlene" last="Demaio">Marlene Demaio</name>
<name sortKey="Hollinger, Jeffrey O" sort="Hollinger, Jeffrey O" uniqKey="Hollinger J" first="Jeffrey O." last="Hollinger">Jeffrey O. Hollinger</name>
<name sortKey="Hsu, Eric" sort="Hsu, Eric" uniqKey="Hsu E" first="Eric" last="Hsu">Eric Hsu</name>
<name sortKey="Klimak, Molly" sort="Klimak, Molly" uniqKey="Klimak M" first="Molly" last="Klimak">Molly Klimak</name>
<name sortKey="Matyjaszewski, Krzysztof" sort="Matyjaszewski, Krzysztof" uniqKey="Matyjaszewski K" first="Krzysztof" last="Matyjaszewski">Krzysztof Matyjaszewski</name>
<name sortKey="Watt, April C S" sort="Watt, April C S" uniqKey="Watt A" first="April C. S." last="Watt">April C. S. Watt</name>
</country>
</tree>
</affiliations>
</record>
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