title: The Role of Mifamurtide in Chemotherapy-induced Osteoporosis of Children with Osteosarcoma.
abstract: BACKGROUND
  Osteosarcoma is the most frequent malignant bone tumor in childhood and young adulthood. Long-term survivors of osteosarcoma patients show high prevalence of osteoporosis and fractures. The immunomodulatory mifamurtide, which modulates macrophages activity, improves disease outcome.
  
  
  OBJECTIVE
  To evaluate the role of mifamurtide on macrophage component of bone, the osteoclasts, during chemotherapy in children with osteosarcoma.
  
  
  METHODS
  Osteoclasts, obtained from peripheral blood cells of healthy donors were harvested in the presence or not of mifamurtide. Moreover, osteoclast cultures were obtained from osteosarcoma patients, at onset and during chemotherapy, alone or with mifamurtide. Pro-osteoporotic tartrateresistant acid phosphatase (TRAP), phosphokinase-β-2 (PKCβ2), vanilloid receptor type 1 (TRPV1), and anti-osteoporotic cannabinoid receptor type 2 (CB2) biomarkers were analyzed by bio-molecular (qPCR), biochemical (Western Blotting), and morphological (TRAP assay) approaches.
  
  
  RESULTS
  Osteoclasts from osteosarcoma patients show significant increase of TRAP and decrease of CB2 with respect to osteoclasts from healthy donors. This osteoclast hyperactivity is more evident in osteoclasts from osteosarcoma patients during chemotherapy. Mifamurtide reduces pro-osteoporotic TRAP, PKCβ2, TRPV1 levels and increases CB2 in osteoclasts from healthy donors. Moreover, chemotherapy-induced effects on bone resorption markers are fully reverted in osteoclasts derived from osteosarcoma patients in chemotherapy plus mifamurtide.
  
  
  CONCLUSIONS
  Our data suggest a new therapeutic role for mifamurtide as possible anti-resorption agent in chemotherapy-induced osteoporosis in children with osteosarcoma.
authors.affiliation: Department of Experimental Medicine, Division of Pharmacology "Leonardo Donatelli", University of Campania "Luigi Vanvitelli", 80138 Naples. Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Bellini
authors.affiliation: Department of Women, Child and General and Specialist Surgery, University of Campania "Luigi Vanvitelli", 80138 Naples. Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Di Pinto
authors.affiliation: Department of Experimental Medicine, Division of Pharmacology "Leonardo Donatelli", University of Campania "Luigi Vanvitelli", 80138 Naples. Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Tortora
authors.affiliation: Department of Women, Child and General and Specialist Surgery, University of Campania "Luigi Vanvitelli", 80138 Naples. Italy.
authors.forename: Iolanda
authors.initials: I
authors.lastname: Manzo
authors.affiliation: Department of Experimental Medicine, Division of Pharmacology "Leonardo Donatelli", University of Campania "Luigi Vanvitelli", 80138 Naples. Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Punzo
authors.affiliation: Department of Women, Child and General and Specialist Surgery, University of Campania "Luigi Vanvitelli", 80138 Naples. Italy.
authors.forename: Fiorina
authors.initials: F
authors.lastname: Casale
authors.affiliation: Department of Women, Child and General and Specialist Surgery, The Second University of Naples, via Luigi De Crecchio, 4 - 80138 Naples. Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Rossi
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000293:Adolescent; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002478:Cells, Cultured; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D010024:Osteoporosis / Q000139:chemically induced* / Q000517:prevention & control; D012516:Osteosarcoma / Q000188:drug therapy*; D010714:Phosphatidylethanolamines / Q000494:pharmacology*; D020011:Protective Agents / Q000494:pharmacology; D064546:Protein Kinase C beta / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C588309:CNR2 protein, human; D010714:Phosphatidylethanolamines; D020011:Protective Agents; D043885:Receptor, Cannabinoid, CB2; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C037144:mifamurtide; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D064546:Protein Kinase C beta; C000605510:ACP5 protein, human; D000071681:Tartrate-Resistant Acid Phosphatase
keywords: Osteosarcoma-associated bone loss; cancer associated disease; osteoclast activation; osteosarcoma follow-up; resorption; tumor outcome