Delivery of Transforming Growth Factor-β2-Perturbing Antibody in a Collagen Vehicle Inhibits Cranial Suture Fusion in Calvarial Organ Culture

Moursi, Amr M.; Winnard, Phillip L.; Fryer, Doug; Mooney, Mark P.

doi:10.1597/1545-1569(2003)040<0225:dotgfa>2.0.co;2

Cited by 21 publications

(20 citation statements)

References 27 publications

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“…Although most CG have reportedly been able to enhance osteogenesis, [36][37][38] it is important to note that this particular gel exhibited an inherent inhibitory effect on cell proliferation, matrix production, and bone mineralization 39 and thus was proposed to prevent bone formation along cranial suture sites. 40 Contrary to these reports, however, we observed robust mineralization with the largest amount of ectopic bone in mice treated with these gels after being loaded with MDSC-B4.…”

Section: Usas Et Almentioning

confidence: 99%

Bone Regeneration Mediated by BMP4-Expressing Muscle-Derived Stem Cells Is Affected by Delivery System

Ūsas

Cooper

et al. 2009

Tissue Engineering Part A

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This study investigated the delivery of bone morphogenetic protein (BMP)4-secreting muscle-derived stem cells (MDSC-B4) capable of inducing bone formation in mice using collagen gel (CG), fibrin sealant (FS), and gelatin sponge carriers. After implanting these various cell-loaded scaffolds intramuscularly or into critical-size skull defects, we measured the extent of heterotopic ossification and calvarial defect healing over a 6-week period via radiographic, radiomorphometric, histological, and micro-computed tomography analyses. As expected, in the absence of MDSC-B4, there was no ectopic ossification and only minimal calvarial regeneration using each type of scaffold. Although CG and gelatin sponges loaded with BMP4-secreting cells produced the most ectopic bone, FS constructs produced bone with comparably less mineralization. In the mouse calvaria, we observed MDSC-B4-loaded scaffolds able to promote bone defect healing to a variable degree, but there were differences between these implants in the volume, shape, and morphology of regenerated bone. MDSC-B4 delivery in a gelatin sponge produced hypertrophic bone, whereas delivery in a CG and FS healed the defect with bone that closely resembled the quantity and configuration of native calvarium. In summary, hydrogels are suitable carriers for osteocompetent MDSCs in promoting bone regeneration, especially at craniofacial injury sites.

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Section: Usas Et Almentioning

confidence: 99%

Bone Regeneration Mediated by BMP4-Expressing Muscle-Derived Stem Cells Is Affected by Delivery System

Ūsas

Cooper

et al. 2009

Tissue Engineering Part A

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“…Erk1/2 activity is a critical regulator of Fgf2 signaling during suture closure, as blocking Erk1/2-P abrogated the effect of Fgf2 on suture closure (Kim et al, 2003). Tgf-␤2 also induced premature suture closure both in vitro and in vivo (Opperman et al, 2000;Moursi et al, 2003); Mooney et al, manuscript submitted for publication). The present study showed that Erk1/2-P was also required for Tgf-␤2 regulation of suture patency, suggesting that signaling by means of Erk1/2 is required for the induction of suture closure.…”

Section: Discussionmentioning

confidence: 99%

“…Fgf2 treatment has been shown to induce premature suture closure (Kim et al, 1998(Kim et al, , 2003Ignelzi et al, 2003), and the map kinase Erk1/2 signaling pathway was required for Fgf-stimulated suture closure (Kim et al, 2003). In both in vitro and in vivo experiments, Tgf-␤3 rescued sutures from obliteration, whereas Tgf-␤2 induced suture obliteration (Opperman et al, 2000(Opperman et al, , 2002Chong et al, 2003;Moursi et al, 2003). Tgf-␤2 and Tgf-␤3 use the serine/threonine kinase Smad2/ Smad3 signaling pathway (Centrella et al, 1996;Massague and Wotton, 2000).…”

Section: Introductionmentioning

confidence: 99%

Erk1/2 signaling is required for Tgf‐β2–induced suture closure

Opperman

Fernandez

et al. 2005

Developmental Dynamics

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Transforming growth factors ␤ (Tgf-␤s) act by means of Smad signaling pathways and may also interact with the mitogen-activated protein kinase pathway. The hypothesis was tested that Erk1/2 signaling is required for Tgf-␤2-induced suture closure, by culturing embryonic mouse calvariae in the presence of Tgf-␤2 with or without Erk1/2 inhibitor PD98059 (PD). Suture widths were measured daily, and microdissected sutures and bones were homogenized and protein analyzed by Western blots. Tgf-␤2 induced narrowing of the sutures after 72 hr, an effect inhibited by treatment with PD. Erk1/2 and Egf but not Smad2/3 protein expression was up-regulated by Tgf-␤2 calvarial tissues at 72 hr. PD inhibited endogenous and Tgf-␤2-stimulated Erk1/2 protein as well as Tgf-␤2-stimulated Egf, but increased Smad2/3 protein expression. In tissues harvested 0, 15, and 30 min after exposure to Tgf-␤2, Erk1/2 phosphorylation was up-regulated after 15 min, an effect abrogated by the simultaneous addition of PD. In summary, Tgf-␤2 stimulated Erk1/2 phosphorylation and induced Egf and Erk1/2 expression, associated with suture closure after 72 hr. Blocking Erk1/2 activity with PD inhibited these effects but increased Smad2/3 expression. We postulate that Tgf-␤2 regulates suture closure directly by means of phosphorylation of Erk1/2 and indirectly by up-regulating Erk1/2, a substrate for Fgf receptor signaling required for Fgf induction of premature suture obliteration.

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“…The synostosed rabbits from this colony share important morphological features with human infants exhibiting congenital bicoronal craniosynostosis. Phenotypically, these rabbits show bony bridging at the coronal sutures as early as 21 days gestation, obliterated coronal sutures at birth, coronal ridging, and 1 We have adopted the convention used by Moursi et al (2003) in abbreviating both the gene product and antibody against it with only the first letter capitalized: Tgf-β2. et al, 1994a, 1994b, 1998b, 2002).…”

Section: Samplementioning

confidence: 99%

“…Although the pathogenesis of simple, nonsyndromic craniosynostosis is not well understood, Loeys et al (2005) show that mutations in TGF-β receptor 1 and 2 are associated with some cases of craniosynostosis in humans, and experimental manipulations of Tgf-β isoforms in various studies (Mehrara et al, 2002;Chong et al, 2003) corroborate their importance in maintenance of cranial suture patency and fusion. Specifically, inhibition of Tgf-β2 using neutralizing antibodies in rat calvariae has successfully rescued normally fusing sutures from obliteration in vitro (Opperman et al, 1999;Moursi et al, 2003).Building upon this previous work, we explored how treatment to inhibit Tgf-β2 at the suturectomy site affects growth of the neurocranium in a rabbit model in vivo. Using the same rabbit colony, Mooney et al (2007a) demonstrated that anti-Tgf-β2 treatment delays postoperative resynostosis of the coronal suture.…”

mentioning

confidence: 99%

Comparison of Craniofacial Phenotype in Craniosynostotic Rabbits Treated with Anti–Tgf-β2 at Suturectomy Site

Frazier

Mooney

Losken

et al. 2008

The Cleft Palate Craniofacial Journal

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Objective-Overexpression of transforming growth factor-beta 2 has been associated with craniosynostosis and resynostosis following surgery. We examined the effects of localized transforming growth factor-beta 2 inhibition on craniofacial phenotype in rabbits with craniosynostosis.Design-Twenty-five New Zealand white rabbits with bilateral coronal craniosynostosis were divided into three treatment groups: (1) suturectomy control (n = 8); (2) suturectomy with nonspecific, control immunoglobulin G antibody (n = 6); and (3) suturectomy with anti-transforming growth factor-beta 2 antibody (n = 11). At 10 days of age, a coronal suturectomy was performed on all rabbits. The sites in groups 2 and 3 were immediately filled with a slow-resorbing collagen gel mixed with either immunoglobulin G or anti-transforming growth factor-beta 2 antibody. Computed tomography scans of each rabbit were acquired at ages 10, 25, and 84 days. Craniofacial landmarks were collected from three-dimensional computed tomography reconstructions, and growth and form were compared among the three groups.Results-Rabbits treated with anti-transforming growth factor-beta 2 antibody differed in form at 84 days of age compared with suturectomy control rabbits, specifically in the snout and posterior neurocranium. Growth in some areas of the skull was greater in rabbits from the anti-transforming NIH Public Access Author ManuscriptCleft Palate Craniofac J. Author manuscript; available in PMC 2010 March 11. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript growth factor-beta 2 group than in suturectomy control rabbits, but not significantly greater than in IgG control rabbits.Conclusions-We find support for the hypothesis that transforming growth factor-beta 2 inhibition alters adult form, but these changes do not appear to be localized to the suturectomy region. Slight differences in form and growth between the two control groups suggest that the presence of the collagen vehicle itself may affect skull growth.Keywords coronal suturectomy; craniosynostosis; craniofacial; rabbits; Tgf-β2Craniosynostosis (i.e., premature fusion of one or more cranial sutures) impedes normal growth and development of the neurocranium and may result in associated abnormalities of the craniofacial complex (Babler, 1989; Cohen, 2000c;Richtsmeier, 2002). In humans, 95% of brain growth is completed by 6 years of age (Enlow, 1990), by which time the metopic suture has fused in about 90% of individuals. The remaining cranial sutures will not fuse fully until well into adulthood (Cohen, 2000b). The full impact of craniosynostosis on neurological development is not well understood. The early closure of even a single suture is widely thought to increase intracranial pressure (ICP) (Renier, 1989;Gault et al., 1992;Campbell et al., 1995;Thompson et al., 1995;Pollack et al., 1996;Hudgins et al., 1998;Mooney et al., 1998aMooney et al., , 1999 Jane and Persing, 2000;Fellows-Mayle et al., 2004), although this finding has been questioned because normative I...

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Delivery of Transforming Growth Factor-β2-Perturbing Antibody in a Collagen Vehicle Inhibits Cranial Suture Fusion in Calvarial Organ Culture

Cited by 21 publications

References 27 publications

Bone Regeneration Mediated by BMP4-Expressing Muscle-Derived Stem Cells Is Affected by Delivery System

Bone Regeneration Mediated by BMP4-Expressing Muscle-Derived Stem Cells Is Affected by Delivery System

Erk1/2 signaling is required for Tgf‐β2–induced suture closure

Comparison of Craniofacial Phenotype in Craniosynostotic Rabbits Treated with Anti–Tgf-β2 at Suturectomy Site

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