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Open Access Publications from the University of California

Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2015)

Systemically delivered NELL-1, a potent pro-osteogenic protein, promotes bone formation in healthy and osteoporotic mouse models. PEGylation of NELL­1 (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. Weekly intravenous (IV) NELL-PEG injection significantly enhances overall bone properties. This study consists of a two-fold 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 IV – 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 hours. 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 (BMD), bone volume fraction (BV/TV), and trabecular bone formation in the targeted bone sites compared to the PBS 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.

    Cover page: Efficacy of Intraperitoneal Administration of PEGylated NELL-1 for Bone Formation
    • Thesis
    • Peer Reviewed
    UCLA Electronic Theses and Dissertations (2019)

    Age-related osteoporosis is commonly associated with decreased bone mass, deterioration of bone microarchitecture, and increased bone marrow adipose tissue. Various risk factors and biological changes that occur with aging exponentially increase the prevalence of osteoporosis, which affects more than 200 million people worldwide. With the staggering biomedical burden, significant efforts have been made to explore new therapies that target the primary regulator of bone metabolism, the Wnt signaling pathway, and suppress PPARγ-mediated adipogenesis to enhance therapeutic efficacy. NELL-1 is a potent pro-osteogenic protein that has been well-characterized for its local and systemic bone-forming effects. Previously, we discovered that PEGylation of NELL-1 (NELL-PEG) significantly improved NELL-1’s bioactivities and potency for local and systemic use without inducing considerable biotoxicity. The current study seeks to explore the feasibility of NELL-PEG, with the combination of PPARγ suppression, as a more scientifically sophisticated osteoporosis therapy in which bone formation is promoted and lipid accumulation in the bone marrow is suppressed. We discovered that co-treatment with NELL-PEG and PPARγ suppression significantly enhanced the expression of the Wnt pathway, which led to increased bone formation and reduced bone resorption. In addition, the dual treatment strategy also suppressed the expression of PPARγ and CEBPa, which resulted in decreased bone marrow fat formation. Moreover, the dual treatment strategy was found to significantly enhance cell proliferation and reduce cell apoptosis. These findings prove the feasibility of NELL-1 for use in combination with other molecules in order to enhance the efficacy and safety profile of the co-treatment strategy. The feasibility and readiness of the NELL-1 protein to be modified and used in combination with other molecules, without inducing undesirable side effects, is one of NELL-1’s unique features, in addition to its pro-osteogenic, anti-osteoclastic, and anti-adipogenic properties. In conclusion, optimizing the novel combination of a NELL-1-based therapy with a PPARγ suppressor could be crucial for facilitating long-term drug formulations that have improved efficacy and safety profiles. This development could serve as a novel platform that can be applied to other Wnt-ligand targeting therapies for the purpose of improving the efficacy and safety profile of current standard of care for osteoporosis.

      Cover page: Characterizing Novel Mechanisms of NELL-1 that Regulate the Balance Between Osteogenesis and Adipogenesis
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2022)
      Recent investigations into mechanisms behind the development of osteoporosis suggest that suppressing PPARγ-mediated adipogenesis can improve bone formation and bone mineral density. In this study, we investigated a co-treatment strategy to enhance bone formation by combining NELL-1, an osteogenic molecule that has been extensively studied for its potential use as a therapeutic for osteoporosis, with two methods of PPARγ suppression. First, we suppressed PPARγ genetically using lentiviral PPARγ-shRNA in immunocompromised mice for a proof of concept. Second, we used a PPARγ antagonist to suppress PPARγ pharmacologically in immunocompetent senile osteopenic mice for clinical transability. We found that the co-treatment strategy significantly increased bone formation, increased the proliferation stage cell population, decreased late apoptosis of primary mouse BMSCs, and increased osteogenic marker mRNA levels in comparison to the single agent treatment groups. The addition of PPARγ suppression to NELL-1 therapy enhanced NELL-1s effects on bone formation by upregulating anabolic processes without altering NELL-1s inhibitory effects on osteoclastic and adipogenic activities. Our findings suggest that combining PPARγ suppression with therapeutic NELL-1 may be a viable method that can be further developed as a novel strategy to reverse bone loss and decrease marrow adiposity in age-related osteoporosis.
        Cover page: Genetic and pharmacologic suppression of PPARγ enhances NELL-1-stimulated bone regeneration.
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2015)
        Osteoporosis is a skeletal disorder attributable to an imbalance in osteoblast and osteoclast activity. NELL-1, a secretory protein that promotes osteogenesis while suppressing osteoclastic activity, holds potential as an osteoporosis therapy. Recently, we demonstrated that PEGylation of NELL-1 significantly improves its thermostability while preserving its bioactivity in vitro. However, the effect of PEGylation on the pharmacokinetics and osteogenic potential of NELL-1 in vivo have yet to be investigated. The present study demonstrated that PEGylation of NELL-1 significantly increases the elimination half-life time of the protein from 5.5 h to 15.5 h while distributing more than 2-3 times the amount of protein to bone tissues (femur, tibia, vertebrae, calvaria) in vivo when compared to naked NELL-1. In addition, microCT and DXA analyses demonstrated that systemic NELL-PEG therapy administered every 4 or 7 days significantly increases not only femoral and lumbar BMD and percent bone volume, but also new bone formation throughout the overall skeleton after four weeks of treatment. Furthermore, immunohistochemistry revealed increased osteocalcin expression, while TRAP staining showed reduced osteoclast numbers in NELL-PEG groups. Our findings suggest that the PEGylation technique presents a viable and promising approach to further develop NELL-1 into an effective systemic therapeutic for the treatment of osteoporosis.
          Cover page: Pharmacokinetics and osteogenic potential of PEGylated NELL-1 in vivo after systemic administration.
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