Recombinant human growth/differentiation factor‐5 (rhGDF‐5) induced bone formation in murine calvariae

Yoshimoto, Takehiko; Yamamoto, Masahide; Kadomatsu, Hideshi; Sakoda, Kenji; Yonamine, Yutaka; Izumi, Yuichi

doi:10.1111/j.1600-0765.2005.00847.x

Cited by 47 publications

(52 citation statements)

References 44 publications

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“…Because angiogenesis plays an important role in establishing blood flow to the fracture site in the bone repair process [Glowacki, 1998;Ferguson et al, 1999], Ad-GDF5-transduced hMSCs may be superior to cells combined with BMP2. However, other researchers have reported that BMP2 can promote heterotopic bone formation more strongly than GDF5 [Spiro et al, 2000;Yoshimoto et al, 2006]. This phenomenon may be explained by the different affinities of GDF5 and BMP2 for the BMP receptor IA (BMPR-IA) and BMP receptor IB (BMPR-IB).…”

Section: Discussionmentioning

confidence: 67%

Overexpression of GDF5 through an Adenovirus Vector Stimulates Osteogenesis of Human Mesenchymal Stem Cells in vitro and in vivo

Cheng

Yang

Meng

et al. 2012

Cells Tissues Organs

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The use of stem cells combined with gene therapy could be an important way to facilitate bone regeneration. In this study, the aim was to investigate the potential of growth and differentiation factor-5 (GDF5) to genetically manipulate human mesenchymal stem cells (hMSCs) for bone regeneration. Recombinant adenovirus Ad-GDF5 and Ad-GFP were constructed and identified, and the titer of both were determined. Third-passage hMSCs were infected with adenovirus, and the expression of GDF5 was confirmed by detection of GFP-positive cells, GDF5 mRNA levels, Western blotting, and enzyme-linked immunosorbent assay (ELISA). hMSCs at passage 3 were divided into four groups: (1) an experimental group infected with Ad-GDF5, (2) a positive control group cultured with osteogenic differentiation medium, (3) a control group infected with Ad-GFP cultured with standard medium, and (4) a blank control group cultured with standard medium. Evaluation of cell morphology and proliferation, analysis of the expression of genes related to osteogenic differentiation, von Kossa staining, and immunofluorescent staining of collagen I were used to investigate the osteogenesis of cells among the groups. After culturing the cells for 2 days under each corresponding condition, the cells were detached and subcutaneously injected into the backs of nude mice to evaluate bone formation. Samples were collected for histological staining, protein Western blotting, and micro-computer tomography. When infected with Ad-GDF5, hMSCs could overexpress GDF5 for a prolonged period in vitro and reach a concentration of 160 ng/ml. Cells infected with Ad-GDF5 or cultured in osteogenic medium displayed osteogenic differentiation based on their histological and cellular properties and on their gene and protein expression patterns. Furthermore, Ad-GDF5 showed a better ability to upregulate the expression of collagen I, alkaline phosphatase, and osteocalcin mRNA than the osteogenic medium. Furthermore, Ad-GDF5 expression was associated with enhanced bone formation in vivo. Our findings suggest that hMSCs infected with Ad-GDF5 can differentiate in an osteogenic direction and may be a promising cell source for bone regeneration.

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Section: Discussionmentioning

confidence: 67%

Overexpression of GDF5 through an Adenovirus Vector Stimulates Osteogenesis of Human Mesenchymal Stem Cells in vitro and in vivo

Cheng

Yang

Meng

et al. 2012

Cells Tissues Organs

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“…In vitro and in vivo studies suggested that the administration of GDF-5 with suitable carriers induced the formation of tendon-/ligament-like and cartilage/bone-like tissues in some rodents, ruminants and primates [4][5][6]. For bone tissue engineering GDF-5 has been used in combination with scaffolds such as collagen [5,7,8] or mineralized collagen [9] which, however, do not provide any biomechanical stability. Therefore, in a weight bearing situation additional stabilization is required [10].…”

Section: Introductionmentioning

confidence: 97%

“…Therefore, comparative studies with the use of different growth factors are mandatory. Although the osteoinductivity of GDF-5 is well established, a reduced amount of ectopic bone is formed compared to other members of the TGF-b superfamily like BMP-2 [8,9]. We hypothesized that mutations of BMP-receptor-interacting residues of GDF-5 to amino acids present in BMP-2 may improve the bone formation capacity of the mutant GDF-5 to allow its extended use in bone regeneration.…”

Section: Introductionmentioning

confidence: 97%

The effect of two point mutations in GDF-5 on ectopic bone formation in a β-tricalciumphosphate scaffold

Kasten

Beyen

Bormann³

et al. 2010

Biomaterials

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“…In embryonic chondrogenesis, GDF-5 increases chondroprogenitor migration and condensation in vitro [8,9,15,21] and in vivo [15,46]. Exogenous GDF-5 induces de novo chondrogenesis [43], osteogenesis [11,26,29,39,40,50], tenogenesis [47], and angiogenesis [48]. Supplementation of GDF-5 to mesenchymal progenitor cells in culture increases chondrogenic pellet size [2], cellular proliferation [18,19], and stimulates the expression of chondrogenic and osteogenic markers [2,18,19,28,38,49,51,52].…”

Section: Introductionmentioning

confidence: 99%

“…Administration of GDF-5 induces de novo bone formation at ectopic sites [11,39,40] in applications such as spinal fusion [26,39,40], nonunion repair [39,40], and calvarial defects [29,50]. However, GDF-5 is less osteogenic than the more commonly used members of the TGF-b family, such as OP-1 [18,19].…”

Section: Introductionmentioning

confidence: 99%

Delayed Fracture Healing in Growth Differentiation Factor 5-deficient Mice: A Pilot Study

Coleman

Scheremeta

Boyce

et al. 2011

Clinical Orthopaedics &Amp; Related Research

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Background Growth differentiation factor-5 (GDF-5) is a key regulator of skeletogenesis and bone repair and induces bone formation in spinal fusions and nonunion applications by enhancing chondrocytic and osteocytic differentiation and stimulating angiogenesis. Elucidating the contribution of GDF-5 to fracture repair may support its clinical application in complex fractures. Questions/purpose We therefore asked whether the absence of GDF-5 during fracture repair impaired bone healing as assessed radiographically, histologically, and mechanically. Methods In this pilot study, we performed tibial osteotomies on 10-week-old male mice, stabilized by intramedullary and extramedullary nailing. Healing was assessed radiographically and histologically on Days 1 (n = 1 wild-type; n = 5 bp [brachopodism]), 5 (n = 3 wild-type; n = 3 bp), 10 (n = 6 wild-type; n = 3 bp), 14 (n = 6 wild-type; n = 6 bp), 21 (n = 6 wild-type; n = 6 bp), 28 (n = 7 wild-type; n = 6 bp), and 56 (n = 6 wild-type; n = 6 bp) after fracture. After 10 (n = 7 wildtype; n = 7 bp contralateral and n = 3 bp fractured tibiae), 14 (n = 6 wild-type; n = 6 bp), 21 (n = 6 wildtype; n = 6 bp), 28 (n = 6 wild-type; n = 3 bp), and 56 (n = 8 wild-type; n = 6 bp) days, the callus crosssectional area was calculated. We characterized the mechanical integrity of the healing fracture by yield stress and Young's modulus at 28 (n = 6 wild-type; n = 3 bp) and 56 (n = 8 wild-type; n = 6 bp) days postfracture. Results The absence of GDF-5 impaired cartilaginous matrix deposition in the callus and reduced callus crosssectional area. After 56 days, the repaired bp fracture was mechanically comparable to that of controls. Conclusions Although GDF-5 deficiency did not compromise long-term fracture healing, a delay in cartilage formation and remodeling supports roles for GDF-5 in the early phase of bone repair.One or more of the authors (RT) received funding from National Institutes of Health grant ZO1 AR41131. Each author certifies that his or her institution approved the animal protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research. This work was performed at

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Recombinant human growth/differentiation factor‐5 (rhGDF‐5) induced bone formation in murine calvariae

Abstract: Exposure to GDF-5 promotes proliferation and differentiation of calvarial cells, which give rise to ectopic bone formation.

Cited by 47 publications

References 44 publications

Overexpression of GDF5 through an Adenovirus Vector Stimulates Osteogenesis of Human Mesenchymal Stem Cells in vitro and in vivo

Overexpression of GDF5 through an Adenovirus Vector Stimulates Osteogenesis of Human Mesenchymal Stem Cells in vitro and in vivo

The effect of two point mutations in GDF-5 on ectopic bone formation in a β-tricalciumphosphate scaffold

Delayed Fracture Healing in Growth Differentiation Factor 5-deficient Mice: A Pilot Study

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