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.
Highlights
Multiple myeloma (MM) is a clonal B-cell malignancy characterized by accumulation of clonal plasma cells (PCs) in the bone marrow (BM) leading to bone destruction and BM failure
A recent study of our group demonstrated that CHIT1 and chitinase 3-like-1 (YKL40) have a crucial role in osteoclastogenesis and in osteolysis mediated by matrix metalloproteinase-9 (MMP9; Di Rosa et al, 2014)
BO Inhibits OCs Differentiation To detect whether BO was able to modulate the process of OC differentiation, we treated monocytes with RANKL (25 ng/ml), MCSF (20 ng/ml) and w/o BO for 21 days
Summary
Multiple myeloma (MM) is a clonal B-cell malignancy characterized by accumulation of clonal plasma cells (PCs) in the bone marrow (BM) leading to bone destruction and BM failure. Osteolytic bone disease is a common manifestation of MM that leads to a progressive destruction of the skeleton. This is the most severe cause of morbidity because of pathological fractures, spinal cord compression, chronic bone pain and extreme disability (Mundy, 1998; Terpos et al, 2013). MM cells promote osteoclastogenic effect both by exerting themselves bone destruction and through recruitment, differentiation and activation of OC progenitors within the BM (Calvani et al, 2005). In response to PC, tumor associated stromal cells, that physiologically differentiate into OBs produce numerous pro-osteoclastogenic factors increasing OC recruitment and OC-mediated bone loss at sites proximal to the PC tumor (Farrugia et al, 2003; Heider et al, 2005; Zannettino et al, 2005). The drug induces the stabilization of NF-κB antagonist I-κB and AP-1 transcription factors c-Fos and c-Jun resulting in reduction of OCs differentiation (von Metzler et al, 2007; Hongming and Jian, 2009)
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