Adenosine Receptor Stimulation Improves Glucocorticoid-Induced Osteoporosis in a Rat Model

Glucocorticoid-induced osteoporosis (GIO) is a secondary cause of bone loss. Bisphosphonates approved for GIO, might induce jaw osteonecrosis; thus additional therapeutics are required. Adenosine receptor agonists are positive regulators of bone remodeling, thus the efficacy of adenosine receptor stimulation for treating GIO was tested. In a preventive study GIO was induced in Sprague-Dawley rats by methylprednisolone (MP) for 60 days. Animals were randomly assigned to receive polydeoxyribonucleotide (PDRN), an adenosine A2 receptor agonist, or PDRN and DMPX (3,7-dimethyl-1-propargylxanthine, an A2 antagonist), or vehicle (0.9% NaCl). Another set of animals was used for a treatment study, following the 60 days of MP-induction rats were randomized to receive (for additional 60 days) PDRN, or PDRN and DMPX (an adenosine A2 receptor antagonist), or zoledronate (as control for gold standard treatment), or vehicle. Control animals were administered with vehicle for either 60 or 120 days. Femurs were analyzed after treatments for histology, imaging, and breaking strength analysis. MP treatment induced severe bone loss, the concomitant use of PDRN prevented the developing of osteoporosis. In rats treated for 120 days, PDRN restored bone architecture and bone strength; increased b-ALP, osteocalcin, osteoprotegerin and stimulated the Wnt canonical and non-canonical pathway. Zoledronate reduced bone resorption and ameliorated the histological features, without significant effects on bone formation. Our results suggest that adenosine receptor stimulation might be useful for preventing and treating GIO.

[1]  F. Diez,et al.  Turnover , 2019, Fundamentals of HR Analytics.

[2]  B. Cronstein,et al.  Direct or indirect stimulation of adenosine A2A receptors enhances bone regeneration as well as bone morphogenetic protein‐2 , 2015, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[3]  Jacques P. Brown,et al.  Diagnosis and Management of Osteonecrosis of the Jaw: A Systematic Review and International Consensus , 2015, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[4]  Timothy M. Errington,et al.  Replication Study: Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET , 2018, eLife.

[5]  Y. Minami,et al.  Noncanonical Wnt5a enhances Wnt/β-catenin signaling during osteoblastogenesis , 2014, Scientific Reports.

[6]  N. Guañabens,et al.  The Role of Wnt Signaling and Sclerostin in the Pathogenesis of Glucocorticoid-Induced Osteoporosis , 2014, Current Osteoporosis Reports.

[7]  D. Cucinotta,et al.  The effect of PDRN, an adenosine receptor A2A agonist, on the healing of chronic diabetic foot ulcers: results of a clinical trial. , 2014, The Journal of clinical endocrinology and metabolism.

[8]  S. Ruiz-Gaspà,et al.  Effect of glucocorticoid treatment on Wnt signalling antagonists (sclerostin and Dkk-1) and their relationship with bone turnover. , 2013, Bone.

[9]  B. Cronstein,et al.  Adenosine regulates bone metabolism via A1, A2A, and A2B receptors in bone marrow cells from normal humans and patients with multiple myeloma , 2013, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[10]  B. Cronstein,et al.  Activation of adenosine A2A receptor reduces osteoclast formation via PKA‐ and ERK1/2‐mediated suppression of NFκB nuclear translocation , 2013, British journal of pharmacology.

[11]  S. Adami,et al.  Involvement of WNT/β-catenin Signaling in the Treatment of Osteoporosis , 2013, Calcified Tissue International.

[12]  D. Ferrari,et al.  Extracellular purines promote the differentiation of human bone marrow-derived mesenchymal stem cells to the osteogenic and adipogenic lineages. , 2013, Stem cells and development.

[13]  W. Lems,et al.  Glucocorticoid-induced osteoporosis: an update on current pharmacotherapy and future directions , 2013, Expert opinion on pharmacotherapy.

[14]  S. Kato,et al.  Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis , 2012, Nature Medicine.

[15]  G. Karsenty,et al.  The contribution of bone to whole-organism physiology , 2012, Nature.

[16]  A. Bitto,et al.  Polydeoxyribonucleotide reduces cytokine production and the severity of collagen-induced arthritis by stimulation of adenosine A(₂A) receptor. , 2011, Arthritis and rheumatism.

[17]  J. Rutkowski.  Combined use of glucocorticoids and bisphosphonates may increase severity of bisphosphonate-related osteonecrosis of the jaw. , 2011, The Journal of oral implantology.

[18]  K. Lyons,et al.  Wnt10b Deficiency Results in Age-Dependent Loss of Bone Mass and Progressive Reduction of Mesenchymal Progenitor Cells , 2010, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[19]  B. Fredholm,et al.  Adenosine A(1) receptors regulate bone resorption in mice: adenosine A(1) receptor blockade or deletion increases bone density and prevents ovariectomy-induced bone loss in adenosine A(1) receptor-knockout mice. , 2010, Arthritis and rheumatism.

[20]  A. Bitto,et al.  Protective effect of genistein aglycone on the development of osteonecrosis of the femoral head and secondary osteoporosis induced by methylprednisolone in rats. , 2009, The Journal of endocrinology.

[21]  A. Bitto,et al.  Genistein aglycone reverses glucocorticoid‐induced osteoporosis and increases bone breaking strength in rats: a comparative study with alendronate , 2009, British journal of pharmacology.

[22]  H. Nagatsuka,et al.  Stromal cells promote bone invasion by suppressing bone formation in ameloblastoma , 2008, Histopathology.

[23]  P. Pietschmann,et al.  Age-dependent Wnt gene expression in bone and during the course of osteoblast differentiation , 2008, AGE.

[24]  L. Valdatta,et al.  Effects of heat deproteinate bone and polynucleotides on bone regeneration: an experimental study on rat. , 2007, Micron.

[25]  O. MacDougald,et al.  Regulation of bone mass by Wnt signaling. , 2006, The Journal of clinical investigation.

[26]  Michael C. Wendl,et al.  Argonaute—a database for gene regulation by mammalian microRNAs , 2005, BMC Bioinformatics.

[27]  Toshio Matsumoto,et al.  Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2. , 2005, Blood.

[28]  C. Cooper,et al.  Use of Oral Corticosteroids and Risk of Fractures , 2005, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[29]  Gary S Stein,et al.  The Wnt antagonist secreted frizzled-related protein-1 is a negative regulator of trabecular bone formation in adult mice. , 2004, Molecular endocrinology.

[30]  P. Govoni,et al.  Polydeoxyribonucleotide (PDRN) promotes human osteoblast proliferation: a new proposal for bone tissue repair. , 2003, Life sciences.

[31]  G. Evans,et al.  Long-Term Zoledronic Acid Treatment Increases Bone Structure and Mechanical Strength of Long Bones of Ovariectomized Adult Rats , 2003, Calcified Tissue International.

[32]  C. Cooper,et al.  The Epidemiology of Corticosteroid-Induced Osteoporosis: a Meta-analysis , 2002, Osteoporosis International.

[33]  C. Balduini,et al.  Effect of polydeoxyribonucleotides on human fibroblasts in primary culture , 1999, Cell biochemistry and function.

[34]  G. Schettini,et al.  Polydeoxyribonucleotides enhance the proliferation of human skin fibroblasts: involvement of A2 purinergic receptor subtypes. , 1999, Life sciences.

[35]  A. Bitto,et al.  Adenosine receptor stimulation by polynucleotides (PDRN) reduces inflammation in experimental periodontitis. , 2013, Journal of clinical periodontology.