Objectives: Fractures have serious health consequences including lengthy rehabilitation and the most serious, hip fractures, may cause prolonged or permanent disability and almost always require hospitalization and major surgery. We have engineered a bio-active silica based nanoparticle capable of promoting osteoblast differentiation and mineralization while inhibiting osteoclastogenesis. Furthermore, we have identified a potential key intracellular regulator of the effect in autophagy as well as key signaling pathway in NF-?B. These nanoparticles have the potential to promote new bone formation while simultaneously reducing bone breakdown. Research Plan: Our preliminary studies have identified the cellular process of autophagy as a potential key mechanism by which our nanoparticles differentially alter cell function in osteoblasts and osteoclasts. Autophagy is a highly regulated cellular process that can be induced by various stimuli, such as stress, cytokines, pathogens, aggregated proteins, damaged or surplus organelles that are ultimately degraded. Although only partially understood, autophagy has been linked to controlling cell signaling by targeting the proteasome and restricting inflammation through limiting the IKK/NF-?B pathway. Based on these studies we hypothesize that our engineered nanoparticle represents an agent capable of preventing and/or reversing age- related bone loss by stimulating autophagy in osteoblasts and osteoclasts. Methods: To test our hypothesis we will utilize we will utilize in vitro models of osteoblast and osteoclast differentiation and function to investigate the mechanism(s) by which our nanoparticles alter function. We will investigate the effects of nanoparticle induced autophagy on NF-?B signaling. We will utilize a model of aged induced osteoporosis to determine the effect of our particles in both promoting bone volume and blunting bone loss. Endpoints include a quantitative and qualitative analysis of bone and serum factors while ex vivo studies will address the effects of our nanoparticles individually on osteoblasts and osteoclast in vivo. Clinical Relevance: Fractures have serious health consequences including lengthy rehabilitation, prolonged or permanent disability, and hip fractures almost always require hospitalization with associated major surgery leading to increased morbidity. Prevention of fractures will greatly reduce both the personal and financial burden to veterans relative to post-fracture treatment. The development of """"""""anabolic"""""""" agents that can promote the rebuilding of lost bone mass would represent a significant impact on the field and on the treatment of bone disease. No current FDA approved agent is able to achieve this and the benefits of a novel therapeutic agent to supplement, or even replace, current therapies for patients suffering from either naturally occurring or disease associated bone wasting.

Public Health Relevance

Fractures have serious health consequences including lengthy rehabilitation, prolonged or permanent disability, and almost always require hospitalization with associated major surgery. We have engineered 50nm silica based nanoparticles that enhance the ability of bone forming osteoblasts while inhibiting bone resorbing osteoclasts. As such these nanoparticles represent a novel dual pro-anabolic-anti-catabolic compound. We will study both the mechanism of action of these particles in cell culture models and test the bone building effects in vivo in a model of aging-associated bone loss.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Endocrinology B (ENDB)
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Veterans Health Administration
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Ha, Shin-Woo; Viggeswarapu, Manjula; Habib, Mark M et al. (2018) Bioactive effects of silica nanoparticles on bone cells are size, surface, and composition dependent. Acta Biomater 82:184-196
Ha, Shin-Woo; Lee, Jin-Kyu; Beck Jr, George R (2017) Synthesis of pH stable, blue light-emitting diode-excited, fluorescent silica nanoparticles and effects on cell behavior. Int J Nanomedicine 12:8699-8710
Ha, Shin-Woo; Park, Jonathan; Habib, Mark M et al. (2017) Nano-Hydroxyapatite Stimulation of Gene Expression Requires Fgf Receptor, Phosphate Transporter, and Erk1/2 Signaling. ACS Appl Mater Interfaces 9:39185-39196
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
GutiƩrrez, Orlando M; Luzuriaga-McPherson, Alexandra; Lin, Yiming et al. (2015) Impact of Phosphorus-Based Food Additives on Bone and Mineral Metabolism. J Clin Endocrinol Metab 100:4264-71
Ha, Shin-Woo; Jang, Hae Lin; Nam, Ki Tae et al. (2015) Nano-hydroxyapatite modulates osteoblast lineage commitment by stimulation of DNA methylation and regulation of gene expression. Biomaterials 65:32-42
Lin, Yiming; McKinnon, Kelly E; Ha, Shin Woo et al. (2015) Inorganic phosphate induces cancer cell mediated angiogenesis dependent on forkhead box protein C2 (FOXC2) regulated osteopontin expression. Mol Carcinog 54:926-34
Weitzmann, M Neale; Ha, Shin-Woo; Vikulina, Tatyana et al. (2015) Bioactive silica nanoparticles reverse age-associated bone loss in mice. Nanomedicine 11:959-967
Ha, Shin-Woo; Sikorski, James A; Weitzmann, M Neale et al. (2014) Bio-active engineered 50 nm silica nanoparticles with bone anabolic activity: therapeutic index, effective concentration, and cytotoxicity profile in vitro. Toxicol In Vitro 28:354-64
Ha, Shin-Woo; Weitzmann, M Neale; Beck Jr, George R (2014) Bioactive silica nanoparticles promote osteoblast differentiation through stimulation of autophagy and direct association with LC3 and p62. ACS Nano 8:5898-910

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