Bone building with bortezomib
G. David Roodman
G. David Roodman
Published January 24, 2008
Citation Information: J Clin Invest. 2008;118(2):462-464. https://doi.org/10.1172/JCI34734.
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Commentary

Bone building with bortezomib

Abstract

In this issue of the JCI, Mukherjee et al. report that bortezomib, a clinically available proteasome inhibitor active against myeloma, induces the differentiation of mesenchymal stem/progenitor cells (MSCs) — rather than mature osteoprogenitor cells — into osteoblasts, resulting in new bone formation (see the related article beginning on page 491). These results were observed when MSCs were implanted subcutaneously in mice or were used to treat a mouse model of postmenopausal bone loss. Others have reported that immunomodulatory drugs (e.g., thalidomide and lenalidomide), which are active against myeloma, also block the activity of bone-resorbing osteoclasts. These results reflect the utility of targeting endogenous MSCs for the purpose of tissue repair and suggest that combining different classes of agents that are antineoplastic and also inhibit bone destruction and increase bone formation should be very beneficial for myeloma patients suffering from severe bone disease.

Authors

G. David Roodman

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Figure 1

Combination treatment of myeloma bone disease.

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Combination treatment of myeloma bone disease. Myeloma cells produce or ...
Myeloma cells produce or induce OAFs, which increase osteoclast formation as well as produce osteoblast-inhibiting factors, which block bone formation. In this issue of the JCI, Mukherjee et al. (1) show that the proteasome inhibitor Bzb can induce bone formation by increasing BMP-2 production by osteoblasts, which in turn increases Runx-2 levels, which induces MSCs to differentiate into osteoblasts and enhance bone regeneration in mice. In addition, other studies have shown that Bzb and lenalidomide can inhibit osteoclast (OCL) formation in addition to blocking the growth of myeloma cells (10, 16). These results suggest that combination therapy that includes Bzb with lenalidomide or thalidomide may both enhance the antineoplastic effects of either agent and increase bone formation by stimulating osteoblast activity and inhibiting osteoclastic bone destruction, respectively.