Over 2 million long bone fractures are treated in the United States every year. Although most bone fractures heal spontaneously there is no gold standard for promoting bone regeneration in those settings in which either fractures do not heal or there is a critical sized segmental bone defect due to trauma or infection, devastating medical problems leading to significant disability. The recent development of custom printed biomaterial scaffolds that can fit and fill large bone defects may provide a novel solution and coating these scaffolds with agents designed to promote more rapid and complete bone healing may increase the efficacy of prosthetic scaffolds in healing segmental bone defects. Although currently used to promote bone generation, growth factors such as rh-BMP2 (BMP2) are of questionable efficacy and present significant safety issues. We have recently reported that adenosine A2A receptor (A2AR) stimulation increases osteoblast number and regulates osteoblast function in a murine model of inflammatory osteolysis and that A2AR stimulation diminishes osteoclast differentiation by inhibiting NFB activation and nuclear translocation. Moreover, A2ARs stimulate angiogenesis and vasculogenesis in vitro and in vivo. Thus, we propose to test the hypothesis that 3- dimensional printed scaffolds coated with an agent, dipyridamole, that increases local adenosine levels and indirectly stimulates A2ARs can further promote bone regeneration at critical sized segmental bone defects and to determine the cellular and molecular mechanisms for this phenomenon. We therefore propose the following aims: I. Development of coated bioactive ceramic scaffolds to treat critical segmental bone defects. We will determine whether implanting 3-dimensionally printed calcium triphosphate/hydroxyapatite scaffolds coated with dipyridamole, an agent which blocks cellular adenosine uptake and increases adenosine concentration in extracellular fluids, promotes bone regeneration in a rabbit radius model of segmental bone defect. We will further maximize scaffold design and dipyridamole dosing in vitro and in a murine calvaria model of bone regeneration. II. Determination of the cellular mechanism by which A2AR stimulation promotes bone regeneration. Using global and cell-selective knockouts of A2AR we will determine the cellular basis for A2AR-mediated bone regeneration in the murine calvaria model. III. Examination of the molecular mechanisms by which A2AR stimulation promotes bone regeneration in osteoblasts. We will test the hypothesis that A2AR signaling interacts with critical intracellular signaling cascades to promote bone regeneration using pharmacologic inhibitors of signaling pathways and by targeted knockdown of critical signaling molecules in primary cells and cell lines. The goals of this highly translational project are to establish the molecular and cellular basis for targeting A2ARs to stimulate bone regeneration and to rapidly translate these findings to the clinic.
Defects in long bones may develop following trauma, infection or as a result of tumor invasion and and there is a clear need for better ways to promote bone regeneration. We have developed a novel approach to stimulating bone regeneration using a combination of 3D-printed, resorbable scaffolds coated with an agent that indirectly stimulates adenosine A2A receptors, dipyridamole. We propose here to maximize this approach to promoting bone regeneration and to rapidly bring these scaffolds to patients and to better understand the mechanism by which dipyridamole improves bone regeneration.
| Friedman, Benjamin; Cronstein, Bruce (2018) Methotrexate mechanism in treatment of rheumatoid arthritis. Joint Bone Spine : |
| Mediero, Aránzazu; Wilder, Tuere; Shah, Lopa et al. (2018) Adenosine A2A receptor (A2AR) stimulation modulates expression of semaphorins 4D and 3A, regulators of bone homeostasis. FASEB J 32:3487-3501 |
| Haskó, György; Antonioli, Luca; Cronstein, Bruce N (2018) Adenosine metabolism, immunity and joint health. Biochem Pharmacol 151:307-313 |
| Yang, Lu; Fanok, Melania H; Mediero-Munoz, Aranzazu et al. (2018) Augmented Th17 Differentiation Leads to Cutaneous and Synovio-Entheseal Inflammation in a Novel Model of Psoriatic Arthritis. Arthritis Rheumatol 70:855-867 |
| Lopez, Christopher D; Witek, Lukasz; Torroni, Andrea et al. (2018) The role of 3D printing in treating craniomaxillofacial congenital anomalies. Birth Defects Res 110:1055-1064 |
| Bekisz, Jonathan M; Flores, Roberto L; Witek, Lukasz et al. (2018) Dipyridamole enhances osteogenesis of three-dimensionally printed bioactive ceramic scaffolds in calvarial defects. J Craniomaxillofac Surg 46:237-244 |
| Lopez, Christopher D; Diaz-Siso, J Rodrigo; Witek, Lukasz et al. (2018) Three dimensionally printed bioactive ceramic scaffold osseoconduction across critical-sized mandibular defects. J Surg Res 223:115-122 |
| Corciulo, Carmen; Lendhey, Matin; Wilder, Tuere et al. (2017) Endogenous adenosine maintains cartilage homeostasis and exogenous adenosine inhibits osteoarthritis progression. Nat Commun 8:15019 |
| Lopez, Christopher D; Alifarag, Adham M; Torroni, Andrea et al. (2017) Osseodensification for enhancement of spinal surgical hardware fixation. J Mech Behav Biomed Mater 69:275-281 |
| Bonfante, Estevam A; Suzuki, Marcelo; Hirata, Ronaldo et al. (2017) Resin composite repair for implant-supported crowns. J Biomed Mater Res B Appl Biomater 105:1481-1489 |
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