The purine nucleoside adenosine regulates such physiologic functions as heart rate, vasodilation and inflammation and receptors for adenosine have been targeted for such diverse conditions as Parkinson's Disease and, indirectly, Rheumatoid Arthritis. Few studies have addressed the role of adenosine and its receptors in bone metabolism despite clear demonstrations of bony pathology in children with marked elevations in adenosine levels due to adenosine deaminase deficiency. We had previously observed that adenosine A1 receptors regulate the stimulated formation of multinucleated giant cells by cultured human peripheral blood monocytes and therefore determined whether adenosine A1 receptors also regulated formation of osteoclasts, a related form of multinucleated giant cell. We were surprised to find, in preliminary studies, that either blockade or knockout of adenosine receptors prevents osteoclast formation in vitro. Moreover, adenosine A1 receptor knockout mice have increased bone formation in vivo and adenosine receptor blockade blocks bone loss in ovariectomized mice. Preliminary studies further demonstrate that blockade of adenosine A1 receptors in vitro alters signaling events required for osteoclastogenesis. We propose four aims to confirm and expand on our preliminary findings. In the first aim we will examine the role of adenosine and adenosine A1 receptors in osteoclast function and bone remodeling and confirm and expand on our preliminary studies.
The second aim i s to determine the biochemical basis for adenosine generation during bone remodeling using animals deficient in the enzymes that convert extracellular adenine nucleotides to adenosine (NPP-1, TNAP, CD39 and CD73).
The third aim i s to dissect the mechanism by which adenosine A1 receptors modulate the formation and function of osteoclasts in vitro using a combination of molecular techniques and inhibitors of signaling enzymes. The demonstration that adenosine A1 receptors play a critical role in regulating the formation and function of osteoclasts suggests a novel therapeutic target for the treatment of disorders characterized by osteoclast-mediated bone resorption. One of the most pressing public health problems for the aging population is the increasing fragility and brittleness of bones, osteoporosis;brittle and de-mineralized bones are much more susceptible to fractures which are a major problem for the elderly. We have discovered that adenosine, a substance which is present in almost all bodily fluids, can bind to a receptor which is critical for formation and function of osteoclasts, the cells that break down bone. We propose to investigate the role of these adenosine receptors in regulating bone remodeling and the mechanism by which adenosine and its receptor modulate osteoclast function. The studies proposed here are directly relevant to human disease and may lead to the rapid development of new therapies for the treatment and prevention of osteoporosis and the resulting susceptibility to fractures that is so common in the elderly.?
|Ishack, Stephanie; Mediero, Aranzazu; Wilder, Tuere et al. (2017) Bone regeneration in critical bone defects using three-dimensionally printed ?-tricalcium phosphate/hydroxyapatite scaffolds is enhanced by coating scaffolds with either dipyridamole or BMP-2. J Biomed Mater Res B Appl Biomater 105:366-375|
|Feig, Jessica L; Mediero, Aranzazu; Corciulo, Carmen et al. (2017) The antiviral drug tenofovir, an inhibitor of Pannexin-1-mediated ATP release, prevents liver and skin fibrosis by downregulating adenosine levels in the liver and skin. PLoS One 12:e0188135|
|Mediero, Aránzazu; Wilder, Tuere; Ramkhelawon, Bhama et al. (2016) Netrin-1 and its receptor Unc5b are novel targets for the treatment of inflammatory arthritis. FASEB J 30:3835-3844|
|Mediero, Aránzazu; Ramkhelawon, Bhama; Wilder, Tuere et al. (2016) Netrin-1 is highly expressed and required in inflammatory infiltrates in wear particle-induced osteolysis. Ann Rheum Dis 75:1706-13|
|Mediero, Aránzazu; Wilder, Tuere; Reddy, Vishnu S R et al. (2016) Ticagrelor regulates osteoblast and osteoclast function and promotes bone formation in vivo via an adenosine-dependent mechanism. FASEB J 30:3887-3900|
|Mediero, Aránzazu; Ramkhelawon, Bhama; Perez-Aso, Miguel et al. (2015) Netrin-1 is a critical autocrine/paracrine factor for osteoclast differentiation. J Bone Miner Res 30:837-54|
|Goodman, Susan M; Cronstein, Bruce N; Bykerk, Vivian P (2015) Outcomes related to methotrexate dose and route of administration in patients with rheumatoid arthritis: a systematic literature review. Clin Exp Rheumatol 33:272-8|
|Mediero, Aránzazu; Perez-Aso, Miguel; Wilder, Tuere et al. (2015) Brief Report: Methotrexate Prevents Wear Particle-Induced Inflammatory Osteolysis in Mice Via Activation of Adenosine A2A Receptor. Arthritis Rheumatol 67:849-55|
|Montesinos, M Carmen; Desai-Merchant, Avani; Cronstein, Bruce N (2015) Promotion of Wound Healing by an Agonist of Adenosine A2A Receptor Is Dependent on Tissue Plasminogen Activator. Inflammation 38:2036-41|
|Perez-Aso, Miguel; Montesinos, M Carmen; Mediero, Aránzazu et al. (2015) Apremilast, a novel phosphodiesterase 4 (PDE4) inhibitor, regulates inflammation through multiple cAMP downstream effectors. Arthritis Res Ther 17:249|
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