title: Bortezomib modulates CHIT1 and YKL40 in monocyte-derived osteoclast and in myeloma cells.
abstract: Osteolytic bone disease is a common manifestation of multiple myeloma (MM) that leads to progressive skeleton destruction and is the most severe cause of morbidity in MM patients. It results from increased osteolytic activity and decrease osteoblastic function. Activation of mammalian chitinases chitotriosidase (CHIT1) and YKL40 is associated with osteoclast (OCs) differentiation and bone digestion. In the current study, we investigated the effect of two Bortezomib's concentration (2.5 and 5 nM) on osteoclastogenesis by analyzing regulation of chitinase expression. OCs exposition to bortezomib (BO) was able to inhibit the expression of different OCs markers such as RANK, CTSK, TRAP, and MMP9. In addition BO-treatment reduced CHIT1 enzymatic activity and both CHIT1 and YKL40 mRNA expression levels and cytoplasmatic and secreted protein. Moreover, immunofluorescence evaluation of mature OCs showed that BO was able to translocate YKL40 into the nucleus, while CHIT1 remained into the cytoplasm. Since MM cell lines such as U266, SKM-M1 and MM1 showed high levels of CHIT1 activity, we analyzed bone resorption ability of U266 using dentin disk assay resorption pits. Silencing chitinase proteins in U266 cell line with specific small interfering RNA, resulted in pits number reduction on dentine disks. In conclusion, we showed that BO decreases osteoclastogenesis and reduces bone resorption in OCs and U266 cell line by modulating the chitinases CHIT1 and YKL40. These results indicate that chitinases may be a therapeutic target for bone disease in MM patients.
authors.affiliation: Section of Hematology, Department of Surgery and Medical Specialties, University of Catania , Catania, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Tibullo
authors.affiliation: Department of Biomedical and Biotechnology Sciences, University of Catania , Catania, Italy.
authors.forename: Michelino
authors.initials: M
authors.lastname: Di Rosa
authors.affiliation: Section of Hematology, Department of Surgery and Medical Specialties, University of Catania , Catania, Italy.
authors.forename: Cesarina
authors.initials: C
authors.lastname: Giallongo
authors.affiliation: Section of Hematology, Department of Surgery and Medical Specialties, University of Catania , Catania, Italy.
authors.forename: Piera
authors.initials: P
authors.lastname: La Cava
authors.affiliation: Section of Hematology, Department of Surgery and Medical Specialties, University of Catania , Catania, Italy.
authors.forename: Nunziatina L
authors.initials: NL
authors.lastname: Parrinello
authors.affiliation: Section of Hematology, Department of Surgery and Medical Specialties, University of Catania , Catania, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Romano
authors.affiliation: Section of Hematology, Department of Surgery and Medical Specialties, University of Catania , Catania, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Conticello
authors.affiliation: Department of Biological, Geological and Environmental Sciences, University of Catania , Catania, Italy.
authors.forename: Maria V
authors.initials: MV
authors.lastname: Brundo
authors.affiliation: Department of Biological, Geological and Environmental Sciences, University of Catania , Catania, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Saccone
authors.affiliation: Department of Biomedical and Biotechnology Sciences, University of Catania , Catania, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Malaguarnera
authors.affiliation: Section of Hematology, Department of Surgery and Medical Specialties, University of Catania , Catania, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Raimondo
keywords: CHIT1; SKM-M1; U266; YKL40; bortezomib; chitinases; multiple myeloma; osteoclasts