MM-induced osteolysis: partners in crime

In this issue of Blood, Qiang and colleagues explore in detail the role of Wnt inhibition in the progression of multiple myeloma–induced OBLs.

Shaughnessy and colleagues were the first to describe a potential role for the canonical Wnt inhibitor, dickkopf-1 (DKK1), 5 years ago when they reported abnormally high levels of the secreted glycoprotein in the blood of individuals newly diagnosed with multiple myeloma (MM).¹  Of note was a correlation between the levels of DKK1 and the extent of osteolytic bone lesion (OBL) formation, a hallmark characteristic of the disease. In about 80% of MM patients, OBLs occur throughout the skeleton, causing intractable bone pain and pathological fractures. The MM cells flourish and divide within the cytokine-enriched cavities of the OBLs, perpetuating a destructive cycle that is the major cause of morbidity. Historically, the treatment of OBLs has focused on inhibition of osteoclastogenesis, but even when osteoclast activity is controlled, the lesions never repair, suggesting that MM cells also disrupt osteoblastogenesis. There is evidence that DKK1 affects OBL pathogenesis through inhibition of Wnt-mediated differentiation of osteoprogenitors in the bone marrow, and one would predict that this could lead to attenuation of the repair of bone tissue.^1,2  Indeed, Yaccoby, Shaughnessy, and colleagues have demonstrated that administration of DKK1-sequestering antibodies can prevent inhibition of osteogenesis in a model of MM and can reduce the formation of OBLs.^3,4 

In the current study, Qiang and colleagues have expanded our knowledge of the mechanism of DKK1 action by demonstrating that, in addition to inhibition of osteoblastogenesis, DKK1 causes a drop in osteoprotegerin (OPG) expression and an increase in receptor activator of nuclear factor κB ligand (RANKL) output by preexisting osteoblasts. This observation is significant because OPG is the scavenger receptor for the osteoclastogenic protein, RANKL; high ratios of locally secreted RANKL-to-OPG levels result in up-regulated osteoclast activity and bone destruction. Therefore, MM-derived DKK1, in addition to its ability to inhibit osteoblast differentiation, is osteoclastogenic through disruption of RANKL/OPG homeostasis.

In a series of in vitro assays, the investigators demonstrate that addition of recombinant Wnt3a to various cultured osteoblast cell lines resulted in up-regulation of OPG output and reduction of RANKL expression. Addition of recombinant DKK1 attenuated the effect by reducing OPG output. This observation was confirmed by DKK1 overexpression and RNAi-mediated silencing in the osteoblast lines. Significantly, DKK1 present in MM cell–conditioned media had similar effects in increasing the ratio of RANKL-to-OPG expression in osteoblasts, but when immunosequestered from the media, there was recovery of OPG expression and a concomitant reduction in the ratio of RANKL-to-OPG output. In support of these findings, Gunn et al²  reported a similar up-regulation of OPG when Wnt signaling in primary human osteoprogenitor cells was up-regulated by treatment with a glycogen-synthetase-3β-inhibitor. If the cell lines used in the study faithfully recapitulate osteoblast physiology, these observations predict a future strategy for the treatment of MM OBLs through coadministration of DKK1-blocking antibodies and OPG.