Osteolytic bone disease is a common manifestation of multiple myeloma (MM) that leadsto progressive skeleton destruction and is the most severe cause of morbidity in MMpatients. It results from increased osteolytic activity and decrease osteoblastic function.Activation of mammalian chitinases chitotriosidase (CHIT1) and YKL40 is associated withosteoclast (OCs) differentiation and bone digestion. In the current study, we investigatedthe effect of two Bortezomib’s concentration (2.5 and 5 nM) on osteoclastogenesisby 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 bothCHIT1 and YKL40 mRNA expression levels and cytoplasmatic and secreted protein.Moreover, immunofluorescence evaluation of mature OCs showed that BO was able totranslocate YKL40 into the nucleus, while CHIT1 remained into the cytoplasm. SinceMM 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, resultedin pits number reduction on dentine disks. In conclusion, we showed that BO decreasesosteoclastogenesis and reduces bone resorption in OCs and U266 cell line by modulatingthe chitinases CHIT1 and YKL40. These results indicate that chitinases may be atherapeutic target for bone disease in MM patients.

Bortezomib modulates CHIT1 and YKL40 in monocyte-derived osteoclast and in myeloma cells.

Tibullo D;DI ROSA, MICHELINO DANIELE ANTONIO
;
Giallongo C;Romano A;BRUNDO, MARIA VIOLETTA;SACCONE, Salvatore;MALAGUARNERA, Lucia;DI RAIMONDO, FRANCESCO
2015-01-01

Abstract

Osteolytic bone disease is a common manifestation of multiple myeloma (MM) that leadsto progressive skeleton destruction and is the most severe cause of morbidity in MMpatients. It results from increased osteolytic activity and decrease osteoblastic function.Activation of mammalian chitinases chitotriosidase (CHIT1) and YKL40 is associated withosteoclast (OCs) differentiation and bone digestion. In the current study, we investigatedthe effect of two Bortezomib’s concentration (2.5 and 5 nM) on osteoclastogenesisby 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 bothCHIT1 and YKL40 mRNA expression levels and cytoplasmatic and secreted protein.Moreover, immunofluorescence evaluation of mature OCs showed that BO was able totranslocate YKL40 into the nucleus, while CHIT1 remained into the cytoplasm. SinceMM 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, resultedin pits number reduction on dentine disks. In conclusion, we showed that BO decreasesosteoclastogenesis and reduces bone resorption in OCs and U266 cell line by modulatingthe chitinases CHIT1 and YKL40. These results indicate that chitinases may be atherapeutic target for bone disease in MM patients.
2015
osteoclasts; chitinases; multiple myeloma; U266; SKM-M1; CHIT1; YKL40; bortezomib
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11769/42910
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