The proteasome inhibitor bortezomib stimulates osteoblastic differentiation of human osteoblast precursors via upregulation of vitamin D receptor signalling

2013 ◽  
Vol 90 (4) ◽  
pp. 263-272 ◽  
Author(s):  
Martin F. Kaiser ◽  
Ulrike Heider ◽  
Maren Mieth ◽  
Chuanbing Zang ◽  
Ivana von Metzler ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Proteasome Inhibitor ◽  
Osteoblastic Differentiation ◽  
Human Osteoblast ◽  
Receptor Signalling ◽  
Osteoblast Precursors

The Proteasome Inhibitor Bortezomib Stimulates Osteoblastic Differentiation of Human Osteoblast Precursor Cells Via Upregulation of Vitamin D Receptor Signaling

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1899-1899
Author(s):  
Martin Kaiser ◽  
Maren Mieth ◽  
Orhan Sezer ◽  
Ulrike Heider
Keyword(s):  
Multiple Myeloma ◽  
Vitamin D ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Fold Increase ◽  
Osteoblastic Differentiation ◽  
Luciferase Reporter ◽  
Human Osteoblast ◽  
Myeloma Cells ◽  
Osteoblast Precursors

Abstract Abstract 1899 Introduction In multiple myeloma (MM), interactions of the malignant plasma cell clone with the bone marrow microenvironment lead to an enhanced osteoclast recruitment and impaired osteoblast activity. The proteasome inhibitor bortezomib has been shown to suppress osteoclast activity, and there is recent evidence that bortezomib enhances osteoblast differentiation. The aim of this study was to investigate the effects of bortezomib on human osteoblast precursors, focusing on vitamin D (VD) dependent osteoblastic differentiation. Since vitamin D receptor (VDR) is degraded by the proteasome, we hypothesized that bortezomib could influence its signaling and hence vitamin D induced osteoblastic differentiation. This might be of clinical importance, since an increased rate of vitamin D deficiency has recently been reported in patients with MM. Methods Primary human mesenchymal stem cells (hMSC) and primary human osteoblasts (hOB) were isolated from bone marrow aspirates or from bone fragments of healthy donors undergoing orthopedic surgery, respectively. Ascorbic acid and β-glycerolphosphate were used for osteoblastic stimulation (OS), either in combination with or without vitamin D. In order to analyze the effects of proteasome inhibition on osteoblastic differentiation and activity, hMSC and hOB were incubated with bortezomib at subapoptotic doses (1 - 5 nM). In addition, coculture experiments of hMSC, hOB and myeloma cells were performed. Expression of osteocalcin and osteopontin (OPN) were quantified by real-time PCR as markers of osteoblastic lineage differentiation. Expression of VDR was analyzed by western blot in subcellular fractions and VDR signaling was investigated using luciferase reporter assays. Results In coculture experiments, myeloma cells inhibited the vitamin D dependent differentiation and activity of osteoblast precursors, e.g. coculture of hMSC with the myeloma cell line LP-1 for 4 days decreased their osteocalcin expression by 58%. Treatment with bortezomib led to an increased osteoblastic differentiation of hMSC and hOB by OS, represented by an enhanced expression of osteoblast markers osteocalcin and OPN. Importantly, this effect could be further increased, when vitamin D was added. In hMSC stimulated with OS only, addition of 5 nM bortezomib led to an 18.3 fold increase in OPN mRNA expression. In comparison, hMSC stimulated with OS + vitamin D showed a 27.5 fold increase in OPN mRNA with the addition of bortezomib. Osteocalcin expression was increased 1.9 fold by bortezomib in the presence of OS and vitamin D, but not with OS alone. Similar results were obtained with osteoblasts: Incubation with bortezomib slightly increased osteocalcin and OPN mRNA expression in cells stimulated with OS only (1.3 fold and 2.4 fold, respectively). In comparison, in cells stimulated with OS and vitamin D, bortezomib elevated osteocalcin and OPN expression 2.9 fold and 5.5 fold, respectively. Bortezomib led to an increase in nuclear VDR levels in hMSC in western blot analyses. Primary hMSC transfected with a VDR luciferase reporter construct showed a 3.7 fold increase in VDR signaling with bortezomib. Conclusion Our data show that bortezomib stimulates osteoblastic differentiation of hMSCs and hOBs and acts, at least in part, through VDR signaling. Substitution of vitamin D in multiple myeloma patients treated with bortezomib may be beneficial for bone turnover and needs clinical evaluation. Disclosures: Kaiser: Johnson & Johnson: Research Funding. Mieth:Johnson & Johnson: Research Funding. Sezer:Johnson & Johnson: Research Funding. Heider:Johnson & Johnson: Research Funding.

scholarly journals Mycobacterial lipoprotein activates autophagy via TLR2/1/CD14 and a functional vitamin D receptor signalling

2010 ◽  
Vol 12 (11) ◽  
pp. 1648-1665 ◽  
Author(s):  
Dong-Min Shin ◽  
Jae-Min Yuk ◽  
Hye-Mi Lee ◽  
Sang-Hee Lee ◽  
Ji Woong Son ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Receptor Signalling

Association of vitamin D receptor genotypes with early onset rheumatoid arthritis

2001 ◽  
Vol 28 (1) ◽  
pp. 89-93 ◽  
Author(s):  
J. R. Garcia-Lozano ◽  
M. F. Gonzalez-Escribano ◽  
A. Valenzuela ◽  
A. Garcia ◽  
A. Nunez-Roldan
Keyword(s):  
Rheumatoid Arthritis ◽  
Vitamin D ◽  
Vitamin D Receptor ◽  
Early Onset

803: Interactions Between Ultraviolet Radiation and Polymorphisms in the Vitamin D Receptor Gene Mediate Prostate Cancer Susceptibility

2006 ◽  
Vol 175 (4S) ◽  
pp. 260-260
Author(s):  
Nicholas J. Rukin ◽  
Samuel J. Moon ◽  
Dhaval Bodiwala ◽  
Christopher J. Luscombe ◽  
Mark F. Saxby ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Vitamin D ◽  
Ultraviolet Radiation ◽  
Vitamin D Receptor ◽  
Cancer Susceptibility ◽  
Receptor Gene ◽  
Vitamin D Receptor Gene ◽  
Prostate Cancer Susceptibility
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