The Effects of Systemic Therapy of PEGylated NEL-Like Protein 1 (NELL-1) on Fracture Healing in Mice

Tanjaya, Justine; Lord, Elizabeth L.; Wang, Chenchao; Zhang, Yulong; Kim, Jong Kil; Nguyen, Alan; Baik, Llyod; Pan, Hsin Chuan; Chen, Eric; Kwak, Jin Hee; Zhang, Xinli; Wu, Benjamin M.; Ting, Kang

doi:10.1016/j.ajpath.2017.11.018

Cited by 11 publications

(7 citation statements)

References 65 publications

(94 reference statements)

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“…The study revealed an influx of antigen-1 positive mesenchymal progeny cells and complete bone fusion across all samples (100% spinal fusion rate) [117]. Recently, it was tested by systemic administration of PEGylated NELL-1 using a mouse fracture healing model with positive results [118]. All of these pre-clinical data indicate that NELL-1-based therapy for local or systemic bone formation can be further pursued for clinical translation.…”

Section: Bone Graft Substitutes Combined With Active Biomoleculesmentioning

confidence: 99%

Bone regeneration strategies: Engineered scaffolds, bioactive molecules and stem cells current stage and future perspectives

et al. 2018

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Bone fractures are the most common traumatic injuries in humans. The repair of bone fractures is a regenerative process that recapitulates many of the biological events of embryonic skeletal development. Most of the time it leads to successful healing and the recovery of the damaged bone. Unfortunately, about 5-10% of fractures will lead to delayed healing or non-union, more so in the case of co-morbidities such as diabetes. In this article, we review the different strategies to heal bone defects using synthetic bone graft substitutes, biologically active substances and stem cells. The majority of currently available reviews focus on strategies that are still at the early stages of development and use mostly in vitro experiments with cell lines or stem cells. Here, we focus on what is already implemented in the clinics, what is currently in clinical trials, and what has been tested in animal models. Treatment approaches can be classified in three major categories: i) synthetic bone graft substitutes (BGS) whose architecture and surface can be optimized; ii) BGS combined with bioactive molecules such as growth factors, peptides or small molecules targeting bone precursor cells, bone formation and metabolism; iii) cell-based strategies with progenitor cells combined or not with active molecules that can be injected or seeded on BGS for improved delivery. We review the major types of adult stromal cells (bone marrow, adipose and periosteum derived) that have been used and compare their properties. Finally, we discuss the remaining challenges that need to be addressed to significantly improve the healing of bone defects.

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Section: Bone Graft Substitutes Combined With Active Biomoleculesmentioning

confidence: 99%

Bone regeneration strategies: Engineered scaffolds, bioactive molecules and stem cells current stage and future perspectives

et al. 2018

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“…James et al showed that recombinant NELL-1 (rhNELL-1) induces WNT/ß-catenin activation via the ß1 integrin in osteoblast precursors and osteoclasts in vitro and can prevent ovariectomy-induced bone loss in mice 193 . Follow-up work by this group showed that increasing the half-life and bone retention of rhNELL-1 by PEGylation and inactive bisphosphonate-linkage can improve bone fracture healing in ground control mice and mitigate bone loss in mice undergoing spaceflight 194 , 195 . Clinical evaluation, including long-term follow-up, of rhNELL-1 in osteoporotic patients on Earth, is needed before this treatment can be examined in astronauts.…”

Section: Microgravity Countermeasure Developmentmentioning

confidence: 99%

Update on the effects of microgravity on the musculoskeletal system

et al. 2021

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With the reignited push for manned spaceflight and the development of companies focused on commercializing spaceflight, increased human ventures into space are inevitable. However, this venture would not be without risk. The lower gravitational force, known as microgravity, that would be experienced during spaceflight significantly disrupts many physiological systems. One of the most notably affected systems is the musculoskeletal system, where exposure to microgravity causes both bone and skeletal muscle loss, both of which have significant clinical implications. In this review, we focus on recent advancements in our understanding of how exposure to microgravity affects the musculoskeletal system. We will focus on the catabolic effects microgravity exposure has on both bone and skeletal muscle cells, as well as their respective progenitor stem cells. Additionally, we report on the mechanisms that underlie bone and muscle tissue loss resulting from exposure to microgravity and then discuss current countermeasures being evaluated. We reveal the gaps in the current knowledge and expound upon how current research is filling these gaps while also identifying new avenues of study as we continue to pursue manned spaceflight.

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“…Combining NELL-1 with a smoothened agonist enhanced bone healing, with a significant increase in both bone volume and bone mineral density [42]. Modification of NELL-1 by polyethylene glycol can result in enhanced pharmacokinetics for systemic therapy [43]. Long-term expression of NELL-1 can be achieved by viral mediation, which can eliminate or minimize multiple administrations or dose escalation [12].…”

Section: Discussionmentioning

confidence: 99%

NELL-1 Increased the Osteogenic Differentiation and mRNA Expression of Spheroids Composed of Stem Cells

et al. 2021

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Background and objectives: NELL-1 is a competent growth factor and it reported to target cells committed to the osteochondral lineage. The secreted, osteoinductive glycoproteins are reported to rheostatically control skeletal ossification. This study was performed to determine the effects of NELL-1 on spheroid morphology and cell viability and the promotion of osteogenic differentiation of stem cell spheroids. Materials and Methods: Cultures of stem cell spheroids of gingiva-derived stem cells were grown in the presence of NELL-1 at concentrations of 1, 10, 100, and 500 ng/mL. Evaluations of cell morphology were performed using a microscope, and cell viability was assessed using a two-color assay and Cell Counting Kit-8. Evaluation of the activity of alkaline phosphatase and calcium deposition assays involved anthraquinone dye assay to determine the level of osteogenic differentiation of cell spheroids treated with NELL-1. Real-time quantitative polymerase chain reaction (qPCR) was used to evaluate the expressions of RUNX2, BSP, OCN, COL1A1, and β-actin mRNAs. Results: The applied stem cells produced well-formed spheroids, and the addition of NELL-1 at tested concentrations did not show any apparent changes in spheroid shape. There were no significant changes in diameter with addition of NELL-1 at 0, 1, 10, 100, and 500 ng/mL concentrations. The quantitative cell viability results derived on Days 1, 3, and 7 did not show significant disparities among groups (p > 0.05). There was statistically higher alkaline phosphatase activity in the 10 ng/mL group compared with the unloaded control on Day 7 (p < 0.05). A significant increase in anthraquinone dye staining was observed with the addition of NELL-1, and the highest value was noted at 10 ng/mL (p < 0.05). qPCR results demonstrated that the mRNA expression levels of RUNX2 and BSP were significantly increased when NELL-1 was added to the culture. Conclusions: Based on these findings, we conclude that NELL-1 can be applied for increased osteogenic differentiation of stem cell spheroids.

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The Effects of Systemic Therapy of PEGylated NEL-Like Protein 1 (NELL-1) on Fracture Healing in Mice

Cited by 11 publications

References 65 publications

Bone regeneration strategies: Engineered scaffolds, bioactive molecules and stem cells current stage and future perspectives

Bone regeneration strategies: Engineered scaffolds, bioactive molecules and stem cells current stage and future perspectives

Update on the effects of microgravity on the musculoskeletal system

NELL-1 Increased the Osteogenic Differentiation and mRNA Expression of Spheroids Composed of Stem Cells

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