The influence of the stable expression of BMP2 in fibrin clots on the remodelling and repair of osteochondral defects

Vogt, Stephan; Wexel, Gabriele; Tischer, Thomas; Schillinger, Ulrike; Ueblacker, Peter; Wagner, Bettina; Hensler, Daniel; Wilisch, Jonas; Geis, Christopher; Wübbenhorst, Daniela; Aigner, J.; Gerg, Michael; Krüger, Achim; Salzmann, Gian M.; Martinek, V.; Anton, Martina; Plank, Christian; Imhoff, Andreas B.; Gänsbacher, Bernd

doi:10.1016/j.biomaterials.2009.01.016

Cited by 43 publications

(40 citation statements)

References 30 publications

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“…This goal is different from the synthesis of a therapeutic product from the synovium that mostly remains diffuse in the synovial fluid. Several groups (Che et al, 2010;Cucchiarini and Madry, 2005;Gelse et al, 2008;Gysin et al, 2002;Ivkovic et al, 2010;Kaul et al, 2006;Madry et al, 2005 Turgeman et al, 2001;Vogt et al, 2009) are developing targeted approaches to deliver genetically modified cells or gene vectors directly into cartilage lesions, by means of an arthrotomy or via arthroscopy as demonstrated by Goodrich et al (2007). This concept is dependent on the feasibility of adequately containing modified cells or vectors in the defect.…”

Section: The Challenge Of Treating Focal Articular Cartilage Defectsmentioning

confidence: 99%

“…In this regard, reparative and regenerative properties have been attributed to growth and transcription factors (TGF-β, BMPs, IGF-I, FGF-2, GDF-5, PTHrP; SOX, RUNX2, Cart-1 and Ets families), signalling and regulatory molecules (Wnt, hedgehog families, CD-RAP) and to components of the extracellular matrix or enzymes that produce them (type-II collagen, COMP, tenascin), several of which having been successfully reported to improve the healing of cartilage defects in various experimental models (Cucchiarini and Madry, 2005). Much work has been already performed in various small (Che et al, 2010;Cucchiarini and Madry, 2005;Gelse et al, 2008;Gysin et al, 2002;Kaul et al, 2006;Madry et al, 2005;Madry et al, 2010a;Park et al, 2006;Turgeman et al, 2001;Vogt et al, 2009) and large animals (Goodrich et al, 2007;Heiligenstein et al, 2011;Hidaka et al, 2003). For instance, it has been shown that tissue-engineered cartilage displays better in vitro properties following genebased modification with IGF-I in vitro (Madry et al, 2002).…”

Section: Therapeutic Candidatesmentioning

confidence: 99%

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Tissue engineering for articular cartilage repair – the state of the art

Johnstone

Alini

Cucchiarini

et al. 2013

eCM

313

250

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Adult articular cartilage exhibits little capacity for intrinsic repair, and thus even minor injuries or lesions may lead to progressive damage and osteoarthritic joint degeneration, resulting in significant pain and disability. While there have been numerous attempts to develop tissue-engineered grafts or patches to repair focal chondral and osteochondral defects, there remain significant challenges in the clinical application of cell-based therapies for cartilage repair. This paper reviews the current state of cartilage tissue engineering with respect to different cell sources and their potential genetic modification, biomaterial scaffolds and growth factors, as well as preclinical testing in various animal models. This is not intended as a systematic review, rather an opinion of where the field is moving in light of current literature. While significant advances have been made in recent years, the complexity of this problem suggests that a multidisciplinary approach -combining a clinical perspective with expertise in cell biology, biomechanics, biomaterials science and high-throughput analysis will likely be necessary to address the challenge of developing functional cartilage replacements. With this approach we are more likely to realise the clinical goal of treating both focal defects and even large-scale osteoarthritic degenerative changes in the joint.

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Section: The Challenge Of Treating Focal Articular Cartilage Defectsmentioning

confidence: 99%

Section: Therapeutic Candidatesmentioning

confidence: 99%

Tissue engineering for articular cartilage repair – the state of the art

Johnstone

Alini

Cucchiarini

et al. 2013

eCM

313

250

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“…The Wnt/β-catenin signaling pathway plays a key role during the early stages of cartilage formation (14,15). The Wnt/β-catenin pathway regulates the DNA-binding proteins of the TCF/LEF family, mainly in regard to the stability of β-catenin in the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

BMP2 promotes chondrocyte proliferation via the Wnt/β-catenin signaling pathway

Peng

et al. 2011

Mol Med Report

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Abstract. Bone morphogenetic protein 2 (BMP2), a member of the transforming growth factor-β (TGF-β) superfamily, plays a key role in the induction of the differentiation of mesenchymal cells into chondrocytes to form cartilage tissue. However, it is not clear whether BMP2 regulates the proliferation of chondrocytes. In the present study, the effect of BMP2 on the proliferation of chondrocytes and its underlying mechanism was investigated. Chondrocytes isolated from the knee of SD rats were cultured and identified using toluidine blue staining. The second generation chondrocytes were collected and stimulated with or without BMP2 for 48 h. Cell viability was analyzed using the MTT assay. mRNA and protein expression levels of β-catenin, GSK-3β, Dvl1 and Cyclin D1 were detected using real-time RT-PCR and Western blotting, respectively. The cell cycle distribution of the chondrocytes was analyzed by flow cytometry. BMP2 stimulation was found to significantly increase cell viability. In addition, following BMP2 treatment, β-catenin, Cyclin D1 and Dvl1 expression was significantly increased, whereas GSK-3β expression was significantly decreased. Moreover, the percentage proportion of chondrocytes in the G0/G1 phase was significantly decreased, whereas that in the S phase was significantly increased. The results indicate that BMP2 promotes chondrocyte proliferation via the Wnt/β-catenin signaling pathway.

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“…Similarly, 0.25 ng BMP-2/clot/day was produced by chondrocyte clots transduced ex vivo with a retrovirus for repair of an osteochondral defect. (106) Higher secretion rates (1 to 5 ng/day for BMP-2 (107) and BMP-7 (108) ) were reported with another AV system used for transfecting human bone marrow stromal cells for intraosseous implantation. It appears that BMP production rates range from 0.1 to 5 ng/day with current delivery systems, but the absolute level of protein secretions ($ng/day) are significantly lower than amounts used in equivalent preclinical studies (>1 mg/implant).…”

Section: Duration Of Transgene Expressionmentioning

confidence: 95%

Realizing the potential of gene-based molecular therapies in bone repair

Rose

Uludağ

2013

Journal of Bone and Mineral Research

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A better understanding of osteogenesis at genetic and biochemical levels is yielding new molecular entities that can modulate bone regeneration and potentially act as novel therapies in a clinical setting. These new entities are motivating alternative approaches for bone repair by utilizing DNA-derived expression systems, as well as RNA-based regulatory molecules controlling the fate of cells involved in osteogenesis. These sophisticated mediators of osteogenesis, however, pose unique delivery challenges that are not obvious in deployment of conventional therapeutic agents. Viral and nonviral delivery systems are actively pursued in preclinical animal models to realize the potential of the gene-based medicines. This article will summarize promising bone-inducing molecular agents on the horizon as well as provide a critical review of delivery systems employed for their administration. Special attention was paid to synthetic (nonviral) delivery systems because they are more likely to be adopted for clinical testing because of safety considerations. We present a comparative analysis of dose-response relationships, as well as pharmacokinetic and pharmacodynamic features of various approaches, with the purpose of clearly defining the current frontier in the field. We conclude with the authors' perspective on the future of genebased therapy of bone defects, articulating promising research avenues to advance the field of clinical bone repair. © 2013 American Society for Bone and Mineral Research. KEY WORDS: OSTEOGENESIS; BIOENGINEERING; MOLECULAR PATHWAYS; GENE-BASED THERAPYClinical Need for New Bone-Regeneration Strategies N early 2.2 million bone grafts are performed worldwide annually (1) and up to 20% of fractures are hampered by impaired healing. (2) The economic impact of nonunions is enormous, with the cost of spinal fusions alone reaching $20 billion annually. (3) The gold standard for repair of large segmental defects remains autologous grafts, where bone harvested from a non-weight-bearing site, usually the iliac crest, is used to repair defects. Bone grafts, however, are limited in several aspects, including potency of the grafts and the physiological detriment resulting from harvest surgery. Allografts are alternatively employed, where donor tissue is used to repair the defect, but the risk of disease transmission is always a concern. Allografts are extensively processed to reduce this risk, but osteopotency of the graft could be decreased in this way. (4) Demineralized bone matrix derived from decalcified bone can similarly act as a substitute; its potency, however, is variable and depends on the processing conditions. Synthetic scaffolds have been used to provide a hospitable environment for new bone formation. Scaffolds have been constructed from the organic (collagen) and inorganic (hydroxyapatite [HA]) components of bone, but such scaffolds are incapable of inducing osteogenesis on their own and they are more suitable for smaller defects.Osteogenic proteins are frequently employed to render ost...

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The influence of the stable expression of BMP2 in fibrin clots on the remodelling and repair of osteochondral defects

Cited by 43 publications

References 30 publications

Tissue engineering for articular cartilage repair – the state of the art

Tissue engineering for articular cartilage repair – the state of the art

BMP2 promotes chondrocyte proliferation via the Wnt/β-catenin signaling pathway

Realizing the potential of gene-based molecular therapies in bone repair

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