The osteoinductive properties of Nell-1 in a rat spinal fusion model

Lu, Steven S.; Zhang, Xinli; Soo, Chia; Hsu, Tiffany; Napoli, Antonia Passarelli di; Aghaloo, Tara; Wu, Benjamin M.; Tsou, Paul M.; Ting, Kang; Wang, Jeffrey C.

doi:10.1016/j.spinee.2006.04.020

Cited by 109 publications

(73 citation statements)

References 41 publications

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“…9 Recently, we demonstrated that osteoinductive effects of NELL-1 are partially mediated through binding to the intracellular molecule apoptosis related protein 3 and integrin-b 1 . 10 In translational models of bone repair, exogenous NELL-1 induces potent osseous healing of critical-sized rat calvarial defects, 11 repair of rat femoral segmental defects (FSDs), 12 as well as successful spinal fusion in rats 13,14 and sheep. 15 Based on these results demonstrating reproducible preclinical osteoinductivity in multiple small and large animal models, NELL-1 is being developed for therapeutic use in spinal fusion in humans.…”

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confidence: 99%

Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2

Shen

James

Zhang

et al. 2016

The American Journal of Pathology

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The differentiation factor NEL-like molecule-1 (NELL-1) has been reported as osteoinductive in multiple in vivo preclinical models. Bone morphogenetic protein (BMP)-2 is used clinically for skeletal repair, but in vivo administration can induce abnormal, adipose-filled, poorquality bone. We demonstrate that NELL-1 combined with BMP2 significantly optimizes osteogenesis in a rodent femoral segmental defect model by minimizing the formation of BMP2-induced adipose-filled cystlike bone. In vitro studies using the mouse bone marrow stromal cell line M2-10B4 and human primary bone marrow stromal cells have confirmed that NELL-1 enhances BMP2-induced osteogenesis and inhibits BMP2-induced adipogenesis. Importantly, the ability of NELL-1 to direct BMP2-treated cells toward osteogenesis and away from adipogenesis requires intact canonical Wnt signaling. Overall, these studies establish the feasibility of combining NELL-1 with BMP2 to improve clinical bone regeneration and provide mechanistic insight into canonical Wnt pathway activity during NELL-1 and BMP2 osteogenesis. The novel abilities of NELL-1 to stimulate Wnt signaling and to repress adipogenesis may highlight new treatment approaches for bone loss in osteoporosis. NEL-like molecule-1 (NELL-1) is an osteoinductive growth factor first identified through its overexpression in pathologically fusing suture specimens from patients with craniosynostosis. 1,2 Transgenic Nell1-overexpressing mice recapitulate craniosynostosis-like phenotypes, exhibiting gross calvarial bone overgrowth and increased osteoblast differentiation. 3 Conversely, Nell1 deficiency severely disrupts bone growth, as mice with nonsense mutations in Nell1 die perinatally with major skeletal anomalies in the craniofacial complex, spine, and long bones. 4e6 Highlighting the central role of NELL-1 in skeletal development, NELL-1 mediates key downstream effects of the master osteogenic regulator runt-related transcription factor 2 (RUNX2) 7 and can partially rescue RUNX2 loss of function. 8 NELL-1 can also transiently activate mitogen-activated protein kinase signaling to induce RUNX2 phosphorylation and osteogenic differentiation. 9 Recently, we

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confidence: 99%

Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2

Shen

James

Zhang

et al. 2016

The American Journal of Pathology

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“…Orthotopic AV Viral particles in demineralized bone matrix enhanced spinal fusion in immunocompetent rats (149) AV ¼ adenovirus; AAV ¼ adeno-associated virus; RV ¼ retrovirus; BMP ¼ bone morphogenetic protein; TGFb ¼ transforming growth factor-b; VEGF ¼ vascular endothelial growth factor; PDGF ¼ platelet-derived growth factor; LMP1 ¼ latent membrane protein 1; Cbfa1 ¼ core binding factor alpha1 subunit protein (Runx2); Nell1 ¼ NEL-like 1. edges after 8 weeks, whereas naked pDNA and scaffolds alone gave no bone formation. Limited bone formation may in part be owing to the toxicity of PEI25; although the amount of implanted polymer was not provided, this is likely to be in excess of 32 µg (polymer:pDNA ratios are typically >1.0).…”

Section: Nell1mentioning

confidence: 99%

“…(146,147) NEL-like molecule-1 (Nell-1) is another molecule under investigation for its osteogenic properties in repair of large segmental defects. (148)(149)(150) Nell-1 was shown to be as effective as BMP-2 in repair of critical-size defect (151) and also works synergistically with BMPs (129) that are endogenously expressed at the defect site. These proteins and, their combinations, are expected to provide further leads in aiding or even replacing BMPs in functional bone regeneration.…”

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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“…Lee et al [52] used fibrin gel as a scaffold for ex vivo gene therapy in a rabbit spinal fusion model and reported its effectiveness. Lu et al [58] tested a new osteoinductive factor, Nell-1(Nel-like molecule-1), for in vivo gene therapy in a rat spinal fusion model and concluded that it may be a potent osteoinductive molecule.…”

Section: Gene Therapymentioning

confidence: 99%

An update on bone substitutes for spinal fusion

et al. 2009

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With the current advances in spinal surgery, an understanding of the precise biological mechanism of each bone substitute is necessary for inducing successful spinal fusion. In this review, the categories of bone substitutes include allografts, ceramics, demineralized bone matrix, osteoinductive factors, autogenous platelet concentrate, mesenchymal stem cells, and gene therapy. Further, clinical studies have been evaluated by their levels of evidence in order to elucidate the precise effect of the bone substitute employed and to establish clinical guidance. This article will review both clinical studies based on evidence and basic research in current advances in order to avoid as far as possible any chances of failure in the future and to understand cellular biology in novel technologies.

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The osteoinductive properties of Nell-1 in a rat spinal fusion model

Cited by 109 publications

References 41 publications

Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2

Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2

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

An update on bone substitutes for spinal fusion

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