title: Bioactivity and circulation time of PEGylated NELL-1 in mice and the potential for osteoporosis therapy.
abstract: Osteoporosis is a progressive bone disease due to low osteoblast activity and/or high osteoclast activity. NELL-1 is a potential therapy for osteoporosis because it specifically increases osteoblast differentiation. However, similar to other protein drugs, the bioavailability of NELL-1 may be limited by its in vivo half-life and rapid clearance from body. The purpose of the present study is to prolong NELL-1 circulation time in vivo by PEGylation with three monomeric PEG sizes (5, 20, 40 kDa). While linear PEG 5k yielded the most efficient PEGylation and the most thermally stable conjugate, linear PEG 20k resulted in the conjugate with the highest Mw and longest in vivo circulation. Compared to non-modified NELL-1, all three PEGylated conjugates showed enhanced thermal stability and each prolonged the in vivo circulation time significantly. Furthermore, PEGylated NELL-1 retained its osteoblastic activity without any appreciable cytotoxicity. These findings motivate further studies to evaluate the efficacy of PEGylated NELL-1 on the prevention and treatment of osteoporosis.
authors.affiliation: Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Materials Science and Engineering, and Division of Advanced Prosthodontics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Weintraub Center for Reconstructive Biotechnology, and Dental and Craniofacial Research Institute, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Velasco
authors.affiliation: Weintraub Center for Reconstructive Biotechnology, and Dental and Craniofacial Research Institute, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Xinli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Weintraub Center for Reconstructive Biotechnology, and Dental and Craniofacial Research Institute, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Orthopaedic Surgery, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Kang
authors.initials: K
authors.lastname: Ting
authors.affiliation: Weintraub Center for Reconstructive Biotechnology, and Dental and Craniofacial Research Institute, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Orthopaedic Surgery, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Chia
authors.initials: C
authors.lastname: Soo
authors.affiliation: Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Materials Science and Engineering, and Division of Advanced Prosthodontics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Weintraub Center for Reconstructive Biotechnology, and Dental and Craniofacial Research Institute, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Orthopaedic Surgery, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: benwu@ucla.edu.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Wu
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D001808:Blood Vessels / Q000166:cytology; D002113:Calcification, Physiologic / Q000187:drug effects; D002135:Calcium-Binding Proteins / Q000097:blood* / Q000378:metabolism / Q000627:therapeutic use*; D016923:Cell Death; D002460:Cell Line; D006023:Glycoproteins / Q000097:blood* / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010024:Osteoporosis / Q000097:blood / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D055550:Protein Stability; D012886:Skull / Q000166:cytology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013696:Temperature; D013997:Time Factors
chemical_list: D002135:Calcium-Binding Proteins; D006023:Glycoproteins; C513122:Nell1 protein, mouse; D011092:Polyethylene Glycols; D000469:Alkaline Phosphatase
keywords: Bioactivity; Characterization; Circulation time; NELL-1; PEGylation