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  • Letter to the Editor
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Proteasome inhibition therapies in childhood cancer

Leukemia volume 22, pages 883–884 (2008)Cite this article

We enjoyed the excellent and timely review by Terpos et al.1 in a recent issue of Leukemia on the effects of novel anti-myeloma agents on bone metabolism. In this review, the authors elaborate on the ubiquitin/proteasome system in bone, and the use of proteasome inhibitors (PIs) in myeloma bone disease. The authors emphasize that PIs, including bortezomib, act locally in the bone to stimulate osteoblast differentiation while inhibiting osteoclast formation and making them attractive agents for further investigation, as they may combine anti-myeloma activity with beneficial effects on bone. Indeed, recent in vitro and in vivo observations support the hypothesis that a direct stimulatory effect on the bone formation process could occur during bortezomib treatment.2 Terpos et al. propose prospective studies with specific clinical end points, such as bone mineral density, to be undertaken. However, when designing such studies, we believe that it is important to pay particular attention to the recent observation that systemic administration of PIs specifically impairs the ubiquitin/proteasome system in chondrocytes and growth plate cartilage.3

In these studies, our team used an array of model systems, including 5-week-old mice (three different mouse strains), rat metatarsal bones cultured ex vivo and chondrocytic cell lines (of rat and human origin). Our investigations showed that PIs (bortezomib and MG262) specifically target stem-like and proliferative chondrocytes in the growth plate causing growth retardation in young mice, an effect which was observed both during treatment as well as 45 days after the cessation of the treatment with PIs.3 We found that PIs trigger apoptosis mainly in stem-like and proliferative chondrocytes, and this was mediated at least in part through p53 and apoptosis-inducing factor. Interestingly, we observed that apoptosis-inducing factor serves as a direct target protein for ubiquitin in chondrocytes, thus explaining its prominent upregulation in this cell type upon proteasome inhibition. The stem-like chondrocytes are essential as this small population of cells gives rise to proliferative chondrocytes and provides the basis for normal longitudinal bone growth. Each stem-like chondrocyte in the growth plate is believed to be programmed to give rise to one chondrocyte column and to have the capacity to undergo a limited number of cell divisions.4 Consequently, loss of stem-like chondrocytes will decrease the number of chondrocyte columns and the total number of chondrocytes leading to irreversible growth retardation.

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References

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Authors and Affiliations

  1. Department of Woman and Child Health, Pediatric Endocrinology Unit, Astrid Lindgren Children's Hospital, Karolinska Institutet, Stockholm, Sweden

    F Zaman & L Sävendahl

  2. Division of Biochemical Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

    B Fadeel

Authors
  1. F Zaman
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  2. B Fadeel
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  3. L Sävendahl
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Correspondence to F Zaman.

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Zaman, F., Fadeel, B. & Sävendahl, L. Proteasome inhibition therapies in childhood cancer. Leukemia 22, 883–884 (2008). https://doi.org/10.1038/sj.leu.2404997

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