Introduction: Patients with multiple myeloma (MM) commonly present with devastating bone disease mediated by increased bone resorption and suppressed bone formation. We have previously shown that blocking activity of the Wnt antagonist Dkk-1 promotes osteoblastogenesis and inhibits development of bone lesions in experimental models of MM. In the 5T murine models of MM, tumour cells home to the bone marrow. Injection of 5T2MM cells into C57BLKalwRij mice results in bone disease whereas injection of 5T33MM cells does not. Microarrays revealed that the Wnt antagonist, Sostdc1, is significantly upregulated in 5T2MM-bearing animals (+4.6-fold, P<0.005), compared to 5T33MM-bearing mice. We hypothesise that elevated levels of secreted Sostdc1 in the bone microenvironment reduce osteoblastogenesis and bone formation, and that this contributes to the bone disease associated with MM.
Methods: Six-Week-old mice were injected subcutaneously, above the calvaria, with rhSOSTDC1 or vehicle and skulls were examined using μCT and histomorphometry. In a second study, 9-week-old C57BLKalwRij mice received intravenous rhSOSTDC1 or vehicle and tibiae were examined, using μCT and both static and dynamic histomorphometry.
Results: In the initial study, μCT analysis of calvariae revealed a reduction in bone volume, which was accompanied by a significant reduction in osteoblast (OB) number (P<0.05) and perimeter (P<0.05). In the second study, reduced tibial bone volume was accompanied by significantly reduced OB number (P<0.01) and OB perimeter (P<0.01) in treated animals. In addition, rhSOSTDC1-treated animals exhibited reduced bone formation and significantly reduced mineral aposition rate (P<0.05). Interestingly, no effect on osteoclast number was observed in either study.
Conclusion: These data suggest that Sostdc1 is a significant inhibitor of OB activity in vivo. Together with separate studies, which demonstrate that rhSOSTDC1 inhibits Wnt- and BMP-induced OB differentiation in vitro, they suggest that blocking myeloma-derived/-induced SOSTDC1 may be of therapeutic value in patients with myeloma bone disease.
18 May 2013 - 22 May 2013