To the editor:
Apo2L/TRAIL is a promising new cancer therapeutic with demonstrated efficacy against a variety of malignancies.1 A number of recent studies have demonstrated the ability of different versions of recombinant Apo2L/TRAIL to inhibit both human and mouse osteoclastogenesis, and influence the survival of mature osteoclasts.2-4 Recent work by Zauli and colleagues also demonstrated that injection of mice with recombinant TRAIL induced a significant increase in tibial trabecular thickness and total bone mass, suggesting that Apo2L/TRAIL may regulate normal bone metabolism via inhibition of host osteoclast differentiation and bone resorption.4 In contrast, other studies have suggested that different versions of recombinant Apo2/TRAIL might promote osteoclastogenesis5 and different molecular mechanisms to explain these observations have been proposed, with the interplay between TRAIL and the RANKL/RANK/OPG system being central to the cause.5 We have shown that the version of Apo2L/TRAIL that is currently being used in phase 1b clinical trials, inhibited breast cancer growth within bone and protected against cancer-induced osteolysis in a murine model.6 These results could be explained by the potential of Apo2L/TRAIL to either (1) directly induce apoptosis of breast cancer cells within the bone microenvironment, or, based on the above evidence, (2) block osteoclastogenesis or osteoclast activity via direct inhibitory effects. We have examined in detail the effect of the clinical grade recombinant Apo2L/TRAIL on bone histology in mice, and also its effect on osteoclast differentiation and bone resorption in 3 independent in vitro models of osteoclastogenesis. Firstly, we found that Apo2L/TRAIL did not block RANKL+ macrophage–colony stimulating factor (M-CSF)–mediated osteoclast differentiation or bone resorption from human peripheral blood mononuclear cells (PBMC; Figure 1A) or from the murine monocytic cell line, RAW264.7 (Figure 1B). Furthermore, Apo2L/TRAIL had no effect on bone resorption by mature osteoclasts isolated from human giant cell tumors of bone (GCT; Figure 1C). In addition, Apo2L/TRAIL could not reverse the antiosteoclastogenic effect of recombinant Fc-OPG or native OPG, a finding that has now been substantiated by Zauli and colleagues7 (Figure 1D). Secondly, extensive histomorphometric analysis of bones from Apo2L/TRAIL–treated animals showed no changes in any bone histomorphometric parameter, compared with the untreated animals (data not shown). It is now well accepted that various preparations of recombinant Apo2L/TRAIL may have different biologic activities, perhaps explaining the findings in osteoclasts,2-4 in addition to the toxicity reported previously in human hepatocytes.8 The specificity and purity of the soluble Apo2L/TRAIL protein used in our study has been verified both in vitro,1 in animal models in vivo,9 and in human clinical trials.10 In conclusion, our results argue against a direct effect of Apo2L/TRAIL on osteoclast differentiation and activity and suggest that the protective effects of this agent on cancer-induced osteolysis are due to direct actions on cancer cells themselves within the bone microenvironment, resulting in the abrogation of the “vicious cycle” of cancer-induced bone destruction.
Authorship
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Dr Andreas Evdokiou, Discipline of Orthopaedics and Trauma, Level 4, Bice Building, Royal Adelaide Hospital, North Terrace, Adelaide 5000, South Australia, Australia; e-mail: [email protected].