Transplantation of skin fibroblasts expressing BMP-2 promotes bone repair more effectively than those expressing Runx2

Hirata, K.; Tsukazaki, Tomoo; Kadowaki, Atsushi; Furukawa, Koichi; Shibata, Yasuaki; Moriishi, Takeshi; Okubo, Yasunori; Bessho, Kazuhisa; Komori, Toshihisa; Mizuno, Akio; Yamaguchi, Akira

doi:10.1016/s8756-3282(03)00054-1

Cited by 87 publications

(62 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Osteoblastlike differentiation of PRP-treated NIH3T3-G cells manifested in an increased expression of osteogenic makers, such as BMP2 and osteopontin, at both messenger RNA and protein levels, increased cytoplasmic ALP expression, and increased formation of bone nodules in vitro. Our PRP/NIH3T3-G system, in which no genetic manipulation was required to achieve fibroblast-osteoblast transformation, poses an inherent advantage over fibroblasts transduced with osteoinductive genes such as RUNX2 (10,26), BMPs (27)(28)(29), and LMP-3 (11). In addition, the copy number of viralmediated transfused osteoinductive genes could not be controlled in these genetically engineered fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

Transplantation of Embryonic Fibroblasts Treated with Platelet-Rich Plasma Induces Osteogenesis in SAMP8 Mice Monitored by Molecular Imaging

Chiou²,

Gelovani

et al. 2009

J Nucl Med

View full text Add to dashboard Cite

The aim of this study was to develop a cell-based boneregeneration approach evaluated by molecular imaging and immunohistochemistry. Methods: Genetically modified NIH3T3 embryonic fibroblasts carrying enhanced green fluorescent protein (NIH3T3-G) were predifferentiated into osteoblastlike cells using platelet-rich plasma (PRP) medium, followed by intraosseous transplantation into ovariectomized senescenceaccelerated mouse prone substrain 8 (OVX-SAMP8 mice). Results: PRP-conditioned NIH3T3-G (PRP/NIH3T3-G) engraftment prevented the development of osteoporosis. Molecular imaging and immunohistochemistry demonstrated the migration of NIH3T3-G cells from the implantation site throughout the skeleton. In situ analyses revealed coexpression of osteopontin and green fluorescent protein in the newly formed bone tissue, demonstrating that the transplant restored the bone trabecular architecture and mineral density in treated OVX-SAMP8 mice. Interestingly, the life span of OVX-SAMP8 mice receiving PRP/ NIH3T3-G transplantation was significantly prolonged and similar to that of the congenic senescence-resistant strain of mice. Conclusion: This unique and yet simple approach could potentially be applied to the treatment of senile postmenopausal osteoporosis and perhaps inborn genetic syndromes associated with accelerated aging, such as Hutchinson-Gilford progeria syndrome, and for the prolongation of life expectancy in general.

show abstract

Section: Discussionmentioning

confidence: 99%

Transplantation of Embryonic Fibroblasts Treated with Platelet-Rich Plasma Induces Osteogenesis in SAMP8 Mice Monitored by Molecular Imaging

Chiou²,

Gelovani

et al. 2009

J Nucl Med

View full text Add to dashboard Cite

show abstract

“…Recent studies have investigated the ability of cells committed to a fibroblastic lineage to undergo osteogenic differentiation. Specifically, human gingival and dermal fibroblasts were able to express osteoblast differentiation markers after transduction with vectors overexpressing BMPs [38,50,76]. Human dermal fibroblasts cultured on ultraporous b-tricalcium phosphate ceramics demonstrated increased osteogenic differentiation [36].…”

Section: Design Considerations For Functional Tissue Engineering Of Pmentioning

confidence: 99%

A Perspective: Engineering Periosteum for Structural Bone Graft Healing

Zhang

Awad

O’Keefe

et al. 2008

Clin Orthop Relat Res

206

169

View full text Add to dashboard Cite

Autograft is superior to both allograft and synthetic bone graft in repair of large structural bone defect largely due to the presence of multipotent mesenchymal stem cells in periosteum. Recent studies have provided further evidence that activation, expansion and differentiation of the donor periosteal progenitor cells are essential for the initiation of osteogenesis and angiogenesis of donor bone graft healing. The formation of donor cell-derived periosteal callus enables efficient host-dependent graft repair and remodeling at the later stage of healing. Removal of periosteum from bone autograft markedly impairs healing whereas engraftment of multipotent mesenchymal stem cells on bone allograft improves healing and graft incorporation. These studies provide rationale for fabrication of a biomimetic periosteum substitute that could fit bone of any size and shape for enhanced allograft healing and repair. The success of such an approach will depend on further understanding of the molecular signals that control inflammation, cellular recruitment as well as mesenchymal stem cell differentiation and expansion during the early phase of the repair process. It will also depend on multidisciplinary collaborations between biologists, material scientists and bioengineers to address issues of material selection and modification, biological and biomechanical parameters for functional evaluation of bone allograft healing.

show abstract

“…Runx2 directs osteogenic differentiation by binding to an osteoblast-specific cis-acting element, termed OSE2, in the promoter region of skeletal target genes and regulating their expression (Ducy et al, 1997). We and others have demonstrated that forced expression of Runx2 upregulates osteoblast-specific gene expression and induces mineralization in a cell-type-dependent manner (Byers et al, 2002;Ducy et al, 1997;Hirata et al, 2003;Yang et al, 2003). Intriguingly, both postnatal disruption of Runx2 by dominantnegative expression and overexpression of Runx2 from the pro-␣ (I) collagen promoter induce bone fragility and osteopenia in transgenic mice (Ducy et al, 1999;Liu et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoid-induced osteogenesis is negatively regulated by Runx2/Cbfa1 serine phosphorylation

Phillips

Gersbach

Wojtowicz

et al. 2006

Journal of Cell Science

119

View full text Add to dashboard Cite

Glucocorticoid hormones have complex stimulatory and inhibitory effects on skeletal metabolism. Endogenous glucocorticoid signaling is required for normal bone formation in vivo, and synthetic glucocorticoids, such as dexamethasone, promote osteoblastic differentiation in several in vitro model systems. The mechanism by which these hormones induce osteogenesis remains poorly understood. We demonstrate here that the coordinate action of dexamethasone and the osteogenic transcription factor Runx2/Cbfa1 synergistically induces osteocalcin and bone sialoprotein gene expression, alkaline phosphatase activity, and biological mineral deposition in primary dermal fibroblasts. Dexamethasone decreased Runx2 phosphoserine levels, particularly on Ser125, in parallel with the upregulation of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) through a glucocorticoid-receptor-mediated mechanism. Inhibition of MKP-1 abrogated the dexamethasone-induced decrease in Runx2 serine phosphorylation, suggesting that glucocorticoids modulate Runx2 phosphorylation via MKP-1. Mutation of Ser125 to glutamic acid, mimicking constitutive phosphorylation, inhibited Runx2-mediated osteoblastic differentiation, which was not rescued by dexamethasone treatment. Conversely, mutation of Ser125 to glycine, mimicking constitutive dephosphorylation, markedly increased osteoblastic differentiation, which was enhanced by, but did not require, additional dexamethasone supplementation. Collectively, these results demonstrate that dexamethasone induces osteogenesis, at least in part, by modulating the phosphorylation state of a negative-regulatory serine residue (Ser125) on Runx2. This work identifies a novel mechanism for glucocorticoid-induced osteogenic differentiation and provides insights into the role of Runx2 phosphorylation during skeletal development.

show abstract

Transplantation of skin fibroblasts expressing BMP-2 promotes bone repair more effectively than those expressing Runx2

Cited by 87 publications

References 36 publications

Transplantation of Embryonic Fibroblasts Treated with Platelet-Rich Plasma Induces Osteogenesis in SAMP8 Mice Monitored by Molecular Imaging

Transplantation of Embryonic Fibroblasts Treated with Platelet-Rich Plasma Induces Osteogenesis in SAMP8 Mice Monitored by Molecular Imaging

A Perspective: Engineering Periosteum for Structural Bone Graft Healing

Glucocorticoid-induced osteogenesis is negatively regulated by Runx2/Cbfa1 serine phosphorylation

Contact Info

Product

Resources

About