Adenoviral Delivery of LIM Mineralization Protein-1 Induces New-Bone Formation in Vitro and in Vivo

Viggeswarapu, Manjula; Boden, Scott D.; Liu, Yuying; Hair, Gregory A.; Louis-Ugbo, John; Murakami, Hideki; Kim, Hak-Sun; Mayr, Matthew T.; Hutton, William; Titus, Louisa

doi:10.2106/00004623-200103000-00008

Cited by 121 publications

(68 citation statements)

References 28 publications

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“…Although the mechanism of action of LMP-1 is unknown, it has been demonstrated to induce expression, either directly or indirectly, of certain genes involved in bone formation, including several BMPs such as BMP-2, -4, and -6. [1][2][3][4][5][6] Thus it has been proposed that gene transfer of LMP may be more effective than BMPs for the induction of new bone formation in vivo.…”

Section: Discussionmentioning

confidence: 99%

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Efficient bone formation by gene transfer of human LIM mineralization protein-3

et al. 2004

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LIM mineralization protein (LMP) is a novel positive regulator of the osteoblast differentiation program. In humans, three different LMP splice variants have been identified: LMP-1, LMP-2, and LMP-3. Gene transfer of human LMP-1 (hLMP-1) induces expression of genes involved in bone formation, including certain bone morphogenetic proteins (BMPs), promotes bone nodule formation in vitro, ectopic bone formation in vivo, and is therapeutic in animal models of posterior thoracic and lumbar spine fusion. To examine the osteoinductive properties of the LMP-3 in vitro and in vivo, we have generated plasmid and adenoviral vectors expressing codon-optimized hLMP-3. Here we demonstrate that gene transfer of hLMP-3 induces expression of the bonespecific genes osteocalcin, osteopontin, and bone sialoprotein and induced bone mineralization in preosteoblastic and fibroblastic cells. We also demonstrate that hLMP-3 is able to induce bone mineralization and the expression of the bonespecific genes, BMP-2, OSX, RunX2, and alkaline phosphatase in human mesenchymal stem cells in a dose-dependent manner. Finally, we demonstrate that direct gene transfer of hLMP-3 into murine skeletal muscle results in ectopic bone formation more efficiently than BMP-2. These results demonstrate that hLMP-3 gene transfer can be used to promote bone formation in cell culture and in vivo as or more efficiently than BMP-2, thus establishing feasibility and efficacy of direct gene delivery of hLMP-3 to produce bone in vivo. These results suggest that gene transfer of hLMP-3 could be developed as a bone-inductive therapeutic agent for clinical applications.

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Section: Discussionmentioning

confidence: 99%

“…[4][5][6][7] In the spine models, bone marrow-derived buffy coat cells were modified to express LMP-1 by adenoviral gene transfer followed by transplantation of the genetically altered cells. However, it is unclear if LMP-3 is able to induce bone formation in vivo as well as induce bone-specific gene expression in culture.…”

Section: Introductionmentioning

confidence: 99%

Efficient bone formation by gene transfer of human LIM mineralization protein-3

et al. 2004

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“…Four and half lim protein-2 (FHL2) and Lim mineralization proteins 1 and 3 (LMP 1 and LMP3) are recently investigated proteins that were shown to induce bone regeneration. (144,145) LMP-1 and LMP-3 can also act synergistically with BMPs. (146,147) NEL-like molecule-1 (Nell-1) is another molecule under investigation for its osteogenic properties in repair of large segmental defects.…”

Section: Perspectivementioning

confidence: 99%

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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“…This adenoviral-LMP-1 construct has proven to be osteoinductive in osteoblast cell cultures as well as in vivo in spine fusion experiments in rabbits. 69 …”

Section: Choice Of Delivery Vectormentioning

confidence: 99%

“…69 In this study, peripheral blood was successfully substituted for bone marrow as the source of buffy coat cells, making this strategy more practical for a clinical setting. All animals achieved a successful lumbar spine fusion without complications (Figures 4 and 5).…”

Section: Transduction Conditionsmentioning

confidence: 99%