Non-healing skeletal defects are addressed in over 2.2 million surgical cases each year. Bone morphogenetic protein 2 (BMP2), the main growth factor for bone regeneration, has significant adverse effects at the FDA approved dose for human use. These effects include life-threatening cervical swelling and promotion of adipogenesis or """"""""cyst-like bone voids"""""""" from dose-dependent peroxisome proliferator-activated receptor ? (PPAR ?) upregulation. Thus, a critical barrier to progress in improving the safety and efficacy of BMP2 is development of molecular signaling strategies that effectively target osteogenesis induction and adipogenesis suppression to optimize bone formation. The current New Investigator resubmission addresses this barrier using NELL-1 (Nel-like molecule, type I). NELL-1 is a secreted factor that induces significant in vivo bone formation in multiple small and large animal models. NELL-1 represses BMP2-induced adipogenesis and augments BMP2-induced osteogenesis. Moreover, our new data indicate that NELL-1 activates Wnt/?-catenin signaling and suppresses PPAR ? signaling. This has led to our central hypothesis that NELL-1 improves the efficacy of BMP2-induced bone formation through: [1] activation of Wnt/ ? -catenin signaling, and [2] suppression of PPAR ? signaling, tested in four specific aims.
In AIM 1, we will determine the involvement of Wnt/ ? -catenin and PPAR ? signaling in NELL-1+BMP2 mediated bone repair. Using our published rodent femoral segmental defect (FSD) model, we will precisely evaluate Wnt and PPAR ? signaling in TOPgal Wnt reporter mice. Next in AIM 2, we will evaluate the necessity of Wnt/ ? -catenin signaling in NELL-1+BMP2 regulated bone healing. Here, we will induce Wnt/ ? -catenin 'loss of function'by biochemical (Wnt inhibitor) or RNAi (? -catenin shRNA) methods in our FSD model.
In AIM 3, we will determine if increased Wnt/ ? -catenin signaling is sufficient to reproduce NELL-1's effects on promoting BMP2-induced osteogenesis and inhibiting BMP2-induced adipogenesis. Here, we will induce Wnt/ ? -catenin """"""""gain of function"""""""" by genetic means using Axin2-/- (null mice) and examine its effects in our FSD model. Finally in AIM 4, we will determine if decreased PPAR ? signaling can reproduce NELL-1's effects on promoting BMP2-induced osteogenesis and inhibiting BMP2-induced adipogenesis. PPAR ? """"""""loss of function"""""""" will be induced using PPAR ? +/- mice and RNAi (PPAR ? shRNA) methods in our FSD model. Successful completion of the AIMS will improve efficacy and reduce adverse effects for BMP2 based skeletal regeneration based on the combination therapeutic NELL-1+BMP2. Moreover, increased induction of osteogenesis and suppression of adipogenesis among mesenchymal stem cells will lead to marked improvements in clinical bone repair.

Public Health Relevance

Non-healing bone defects are addressed in over 2.2 million surgical cases worldwide each year. Bone Morphogenetic Protein2 (BMP2), the most commonly used bone growth factor, has significant adverse effects including formation of poor quality, fatty bone. Our innovative solution uses NELL-1, a novel bone forming molecule to inhibit fatty bone formation and to improve the efficacy of BMP2-based bone regeneration therapies.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Musculoskeletal Tissue Engineering Study Section (MTE)
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Wang, Fei
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University of California Los Angeles
Schools of Medicine
Los Angeles
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Shi, Jiayu; Lee, Soonchul; Uyeda, Michael et al. (2016) Guidelines for Dual Energy X-Ray Absorptiometry Analysis of Trabecular Bone-Rich Regions in Mice: Improved Precision, Accuracy, and Sensitivity for Assessing Longitudinal Bone Changes. Tissue Eng Part C Methods 22:451-63
James, Aaron W; LaChaud, Gregory; Shen, Jia et al. (2016) A Review of the Clinical Side Effects of Bone Morphogenetic Protein-2. Tissue Eng Part B Rev 22:284-97
Guo, Mian; James, Aaron W; Kwak, Jin Hee et al. (2016) Cyclophilin A (CypA) Plays Dual Roles in Regulation of Bone Anabolism and Resorption. Sci Rep 6:22378
Shen, Jia; James, Aaron W; Zhang, Xinli et al. (2016) Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2. Am J Pathol 186:419-34
James, Aaron W; Shen, Jia; Zhang, Xinli et al. (2015) NELL-1 in the treatment of osteoporotic bone loss. Nat Commun 6:7362
Lee, Soonchul; Zhang, Xinli; Shen, Jia et al. (2015) Brief Report: Human Perivascular Stem Cells and Nel-Like Protein-1 Synergistically Enhance Spinal Fusion in Osteoporotic Rats. Stem Cells 33:3158-63
Kwak, Jin Hee; Zhang, Yulong; Park, Juyoung et al. (2015) Pharmacokinetics and osteogenic potential of PEGylated NELL-1 in vivo after systemic administration. Biomaterials 57:73-83
Guo, Mian; Shen, Jia; Kwak, Jin Hee et al. (2015) Novel role for cyclophilin A in regulation of chondrogenic commitment and endochondral ossification. Mol Cell Biol 35:2119-30
Pang, Shen; Shen, Jia; Liu, Yi et al. (2015) Proliferation and osteogenic differentiation of mesenchymal stem cells induced by a short isoform of NELL-1. Stem Cells 33:904-15
Chung, Choon G; James, Aaron W; Asatrian, Greg et al. (2014) Human perivascular stem cell-based bone graft substitute induces rat spinal fusion. Stem Cells Transl Med 3:1231-41

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