Inhibiting Dickkopf-1 (Dkk1) Removes Suppression of Bone Formation and Prevents the Development of Osteolytic Bone Disease in Multiple Myeloma

Abstract

Multiple myeloma (MM) is associated with the development of osteolytic bone disease, mediated by increased osteoclastic bone resorption and impaired osteoblastic bone formation. Dickkopf-1 (Dkk1), a soluble inhibitor of wingless/int (Wnt) signaling and osteoblastogenesis, is elevated in patients with MM and correlates with osteolytic bone disease. In this study, we investigated the effect of inhibiting Dkk1 on the development of osteolytic lesions in the 5T2MM murine model of myeloma. We showed that Dkk1 is expressed by murine 5T2MM myeloma cells. Injection of 5T2MM cells into C57BL/KaLwRij mice resulted in the development of osteolytic bone lesions (p < 0.05), mediated by increased osteoclast numbers (p < 0.001) and a decrease in osteoblast numbers (p < 0.001) and mineralizing surface (p < 0.05). Mice bearing 5T2MM cells were treated with an anti-Dkk1 antibody (BHQ880, 10 mg/kg, IV, twice weekly for 4 wk) from time of paraprotein detection. Anti-Dkk1 treatment prevented 5T2MM-induced suppression of osteoblast numbers (p < 0.001) and surface (p < 0.001). Treatment increased mineralizing surface by 28% and bone formation rate by 25%; however, there was no change in mineral apposition rate. Inhibiting Dkk1 had no effect on osteoclast numbers. mCT analysis showed that anti-Dkk1 treatment significantly protected against 5T2MM-induced trabecular bone loss (p < 0.05) and reduced the development of osteolytic bone lesions (p < 0.05). Treatment had no significant effect on tumor burden. These data suggest that inhibiting Dkk1 prevents the suppression of bone formation and in doing so is effective in preventing the development of osteolytic bone disease in myeloma, offering an effective therapeutic approach to treating this clinically important aspect of myeloma.

Autocrine stimulation of osteoblast activity by Wnt5a in response to TNF-α in human mesenchymal stem cells

“…Since TNF-a seemed to increase the levels of other canonical Wnt proteins, we investigated the activation of the canonical Wnt signaling pathway with anti-Dkk1 antibodies. Stimulatory effects of anti-Dkk1 antibodies have recently been reported in mouse primary osteoblasts [17], and are consistent with the beneficial effects of anti-Dkk1 antibodies on bone formation in vivo [10,17,35,36]. In our experiments, blocking Dkk1 slightly increased TNAP expression in osteoblasts differentiating from human MSCs.…”

Bone Anabolic Agents for the Treatment of Multiple Myeloma

“…In vivo studies using both murine and humanized models of MM-bone disease confirmed the bone-anabolic properties of DKK1 antagonists, with increased bone formation, increased OB number and improvement of osteolytic lesions [31,33,34]. Importantly, two studies showed a significant reduction in tumor burden, mainly as an indirect effect via modification of the tumor microenvironment by DKK1 inhibition [31,33].…”

“…Neutralizing antibodies against DKK1 promote OB differentiation [30] and limit MM cell proliferation when co-cultured with BMSC [33]. In several in-vivo models of MM bone disease, DKK1 inhibition prevents tumor-induced bone destruction, increases trabecular bone formation in both bones bearing MM cells and uninvolved bones, and reduces tumor burden [31,33,34].…”

Mechanisms of multiple myeloma bone disease

“…25 Similarly, enhancing marrow stromal cell differentiation into osteoblasts decreases tumor growth and bone destruction, as well as increases bone formation. 26,27 Unfortunately, myeloma is still incurable for most patients and MMBD remains a major contributor to the morbidity and mortality of myeloma patients.…”