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The proteasome inhibitor bortezomib stimulates osteoblastic differentiation of human osteoblast precursors via upregulation of vitamin D receptor signalling
Author(s) -
Kaiser Martin F.,
Heider Ulrike,
Mieth Maren,
Zang Chuanbing,
Metzler Ivana,
Sezer Orhan
Publication year - 2013
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/ejh.12069
Subject(s) - downregulation and upregulation , bortezomib , osteoblast , proteasome inhibitor , chemistry , cancer research , proteasome , signalling , microbiology and biotechnology , pharmacology , endocrinology , medicine , biology , biochemistry , multiple myeloma , gene , in vitro
Interactions of myeloma cells with the bone marrow microenvironment lead to enhanced osteoclast recruitment and impaired osteoblast activity. Recent evidence revealed that the proteasome inhibitor bortezomib stimulates osteoblast differentiation, but the mechanisms are not fully elucidated. We hypothesised that bortezomib could influence osteoblastic differentiation via alteration of vitamin D signalling by blocking the proteasomal degradation of the vitamin D receptor ( VDR ). This is of clinical importance, as a high rate of vitamin D deficiency was reported in patients with myeloma. We performed cocultures of primary human mesenchymal stem cells ( hMSC s) and human osteoblasts ( hOB s) with myeloma cells, which resulted in an inhibition of the vitamin D ‐dependent differentiation of osteoblast precursors. Treatment with bortezomib led to a moderate increase in osteoblastic differentiation markers in hMSC s and hOB s. Importantly, this effect could be strikingly increased when vitamin D was added. Bortezomib led to enhanced nuclear VDR protein levels in hMSC s. Primary hMSC s transfected with a VDR luciferase reporter construct showed a strong increase in VDR signalling with bortezomib. In summary, stimulation of VDR signalling is a mechanism for the bortezomib‐induced stimulation of osteoblastic differentiation. The data suggest that supplementation of vitamin D in patients with myeloma treated with bortezomib is crucial for optimal bone formation.