The current """"""""gold standard"""""""" for bone graft material is autologous bone graft, but autologous grafts are limited by availability and donor site morbidity. Various osteoinductive growth factor-based therapies have been developed in an attempt to find an effective and safer method of bone regeneration. Among the various osteoinductive factors available, bone morphogenetic proteins (BMPs) are believed to be the most potent osteoinductive factors and have been extensively studied for the treatment of many bone fractures and bone defects. However, BMPs are highly pleiotropic molecules and their supra-physiological dose requirement leads to adverse side effects such as cyst formation, and inefficient bone formation. Thus, there is a need to develop alternative osteoinductive growth factor strategies that can effectively complement BMP activity to maximize biological efficiency while minimizing the BMP dose. One alternative approach is to deliver no BMP at all, while enhancing the ability of the progenitor cells that participate in regeneration to respond to endogenous BMPs. This can be accomplished by delivering inhibitors of BMP antagonists such as Noggin, thereby enhancing endogenous BMP activities. Noggin is a direct target of BMP pathways in osteoprogenitors, and it is thus highly likely that supraphysiological BMP doses are required clinically in large part due to Noggin induction. Thus, we propose an approach for enhancing BMP signaling through down-regulation of Noggin. The potency of endogenous BMPs can be enhanced by delivering osteoinductive signals that are more specific and less pleiotropic than BMPs, such as Nell-1 [Nel-like molecule-1;Nel (a protein strongly expressed in neural tissue encoding epidermal growth factor like domain)]. In previous studies, Nell-1 has been shown to accelerate osteogenic differentiation in vitro and calvarial bone formation in vivo. Moreover, Nell-1 is a secreted protein that can be delivered extracellularly, and most importantly Nell-1 promotes synergistic effects with BMP2 on bone regeneration. By suppressing Noggin locally, we seek to enhance endogenous BMP signaling which in turn, should synergistically stimulate osteoblast differentiation induced by Nell-1, thereby leading to maximum bone formation without the concerns surrounding BMP mediated adverse effects. The specific hypothesis of this proposal is that controlled delivery of Nell-1 combined with the employment of Noggin suppression can enhance repair of segmental femoral defects.
Two specific aims are proposed to investigate this hypothesis.
Aim 1 : To enhance bone regeneration via Noggin suppression + Nell-1. In this specific aim, we will evaluate synergistic effects of Nell-1 combined with Noggin-suppressed MSC on osteogenic capacity and bone regeneration.
Aim 2 : To enhance bone regeneration via controlled delivery of Noggin-siRNA + Nell-1. In this aim, we will develop non-viral gene delivery/scaffolding systems that release Nell-1 and Noggin-siRNA and will test whether they can effectively regenerate bone in a segmental femoral defect model.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR060213-03
Application #
8501385
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Wang, Fei
Project Start
2011-07-25
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$329,175
Indirect Cost
$115,425
Name
University of California Los Angeles
Department
Dentistry
Type
Schools of Dentistry
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Fan, Jiabing; Guo, Mian; Im, Choong Sung et al. (2017) Enhanced Mandibular Bone Repair by Combined Treatment of Bone Morphogenetic Protein 2 and Small-Molecule Phenamil. Tissue Eng Part A 23:195-207
Cui, Zhong-Kai; Kim, Soyon; Baljon, Jessalyn J et al. (2017) Design and Characterization of a Therapeutic Non-phospholipid Liposomal Nanocarrier with Osteoinductive Characteristics To Promote Bone Formation. ACS Nano 11:8055-8063
Cui, Zhong-Kai; Sun, Justin A; Baljon, Jessalyn J et al. (2017) Simultaneous delivery of hydrophobic small molecules and siRNA using Sterosomes to direct mesenchymal stem cell differentiation for bone repair. Acta Biomater 58:214-224
Kim, Soyon; Cui, Zhong-Kai; Fan, Jiabing et al. (2016) Photocrosslinkable chitosan hydrogels functionalized with the RGD peptide and phosphoserine to enhance osteogenesis. J Mater Chem B 4:5289-5298
Fan, Jiabing; Im, Choong Sung; Guo, Mian et al. (2016) Enhanced Osteogenesis of Adipose-Derived Stem Cells by Regulating Bone Morphogenetic Protein Signaling Antagonists and Agonists. Stem Cells Transl Med 5:539-51
Choi, Bogyu; Cui, Zhong-Kai; Kim, Soyon et al. (2015) Glutamine-chitosan modified calcium phosphate nanoparticles for efficient siRNA delivery and osteogenic differentiation. J Mater Chem B 3:6448-6455
Cui, Zhong-Kai; Fan, Jiabing; Kim, Soyon et al. (2015) Delivery of siRNA via cationic Sterosomes to enhance osteogenic differentiation of mesenchymal stem cells. J Control Release 217:42-52
Fan, Jiabing; Im, Choong Sung; Cui, Zhong-Kai et al. (2015) Delivery of Phenamil Enhances BMP-2-Induced Osteogenic Differentiation of Adipose-Derived Stem Cells and Bone Formation in Calvarial Defects. Tissue Eng Part A 21:2053-65
Zhang, Yulong; Velasco, Omar; Zhang, Xinli et al. (2014) Bioactivity and circulation time of PEGylated NELL-1 in mice and the potential for osteoporosis therapy. Biomaterials 35:6614-21
Fan, Jiabing; Park, Hyejin; Lee, Matthew K et al. (2014) Adipose-derived stem cells and BMP-2 delivery in chitosan-based 3D constructs to enhance bone regeneration in a rat mandibular defect model. Tissue Eng Part A 20:2169-79

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