Abstract
Systemically delivered NEL-like molecule-1 (NELL-1), a potent pro-osteogenic protein, promotes bone formation in healthy and osteoporotic mouse models. PEGylation of NELL-1 (NELL-PEG) increases the half-life of the protein in a mouse model without compromising its osteogenic potential, thereby improving its pharmacokinetics upon systemic delivery. This study consists of a twofold approach: a biodistribution test and an in vivo osteogenic potential test. The biodistribution test compared two commonly used administration methods for drug delivery other than intravenous—intraperitoneal (IP) and subcutaneous (SC)—to examine NELL-PEG biodistribution in mice. Compared to a single-dose SC injection (1.25 mg/kg), a single-dose IP administration yielded a higher protein uptake in the targeted bone sites. When the IP injection dose was doubled to 2.5 mg/kg, the protein remained in the femurs, tibias, and vertebrae for up to 72 h. Next, based on the results of the biodistribution study, IP administration was selected to further investigate the in vivo osteogenic effects of weekly NELL-PEG injection (q7d). In vivo, the IP administered NELL-PEG group showed significantly greater bone mineral density, bone volume fraction, and trabecular bone formation in the targeted bone sites compared to the phosphate-buffered saline control. In summary, weekly NELL-PEG injection via IP administration successfully enhanced the overall bone quality. These findings demonstrate that systemic delivery of NELL-PEG via IP administration may serve as an effective osteogenic therapy for preventing and treating osteoporosis.
Highlights
IntroductionHuman NEL-like molecule-1 (NELL-1), a potent growth factor that is highly specific to the osteochondral lineage, was first identified by its overexpression in the context of human unilateral craniosynostosis (UCS), a congenital cranial defect characterized by premature fusion of one of the sutures in the developing cranium.[1,2] Over the past two decades, NELL-1 was closely studied for its local bone formation effects[3,4,5,6,7,8,9]; more recently, NELL-1 has demonstrated its osteogenic potential as a systemic therapy.[10,11,12] Mechanistically, NELL-1 affects multiple signaling pathways and has the potential to differentiate the multipotent bone mesenchymal stem cells (BMSCs) into osteoblasts a Justine Tanjaya et al 2016; Published by Mary Ann Liebert, Inc
Biodistribution study The biodistribution study was performed to compare the distribution of protein across various administration routes of NELL-polyethylene glycol (PEG) labeled with VivoTag 680XL
The results demonstrated that weekly injection of NELL-PEG increased the net uptake of 18F-NaF ions at the final time point (Fig. 3)
Summary
Human NEL-like molecule-1 (NELL-1), a potent growth factor that is highly specific to the osteochondral lineage, was first identified by its overexpression in the context of human unilateral craniosynostosis (UCS), a congenital cranial defect characterized by premature fusion of one of the sutures in the developing cranium.[1,2] Over the past two decades, NELL-1 was closely studied for its local bone formation effects[3,4,5,6,7,8,9]; more recently, NELL-1 has demonstrated its osteogenic potential as a systemic therapy.[10,11,12] Mechanistically, NELL-1 affects multiple signaling pathways and has the potential to differentiate the multipotent bone mesenchymal stem cells (BMSCs) into osteoblasts a Justine Tanjaya et al 2016; Published by Mary Ann Liebert, Inc.
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